aztreonam 1 GM Injection

WARNINGS

Both animal and human data suggest that AZACTAM (aztreonam injection) is rarely cross-reactive with other beta-lactam antibiotics and weakly immunogenic.

Treatment with aztreonam can result in hypersensitivity reactions in patients with or without prior exposure.

(See CONTRAINDICATIONS .) Careful inquiry should be made to determine whether the patient has any history of hypersensitivity reactions to any allergens.

While cross-reactivity of aztreonam with other beta-lactam antibiotics is rare, this drug should be administered with caution to any patient with a history of hypersensitivity to beta-lactams (eg, penicillins, cephalosporins, and/or carbapenems).

Treatment with aztreonam can result in hypersensitivity reactions in patients with or without prior exposure to aztreonam.

If an allergic reaction to aztreonam occurs, discontinue the drug and institute supportive treatment as appropriate (eg, maintenance of ventilation, pressor amines, antihistamines, corticosteroids).

Serious hypersensitivity reactions may require epinephrine and other emergency measures.

(See ADVERSE REACTIONS .) Clostridium difficile –associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including AZACTAM, and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C.

difficile .

C.

difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin-producing strains of C.

difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibiotic use.

Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C.

difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C.

difficile , and surgical evaluation should be instituted as clinically indicated.

Rare cases of toxic epidermal necrolysis have been reported in association with aztreonam in patients undergoing bone marrow transplant with multiple risk factors including sepsis, radiation therapy, and other concomitantly administered drugs associated with toxic epidermal necrolysis.

PRECAUTIONS General Prescribing AZACTAM in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

In patients with impaired hepatic or renal function, appropriate monitoring is recommended during therapy.

If an aminoglycoside is used concurrently with aztreonam, especially if high dosages of the former are used or if therapy is prolonged, renal function should be monitored because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics.

The use of antibiotics may promote the overgrowth of nonsusceptible organisms, including Gram-positive organisms ( Staphylococcus aureus and Streptococcus faecalis ) and fungi.

Should superinfection occur during therapy, appropriate measures should be taken.

Information for Patients Patients should be counseled that antibacterial drugs including AZACTAM should only be used to treat bacterial infections.

They do not treat viral infections (eg, the common cold).

When AZACTAM is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.

Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by AZACTAM or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued.

Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken the last dose of the antibiotic.

If this occurs, patients should contact their physician as soon as possible.

Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with aztreonam have not been conducted using an intravenous route of administration.

A 104-week rat inhalation toxicology study to assess the carcinogenic potential of aztreonam demonstrated no drug-related increase in the incidence of tumors.

Rats were exposed to aerosolized aztreonam for up to 4 hours per day.

Peak plasma levels of aztreonam averaging approximately 6.8 mcg/mL were measured in rats at the highest dose level.

Genetic toxicology studies performed with aztreonam in vitro (Ames test, mouse lymphoma forward mutation assay, gene conversion assay, chromosome aberration assay in human lymphocytes) and in vivo (mouse bone marrow cytogenetic assay) did not reveal evidence of mutagenic or clastogenic potential.

A two-generation reproduction study in rats at daily doses of 150, 600, or 2400 mg/kg given prior to and during gestation and lactation, revealed no evidence of impaired fertility.

Based on body surface area, the high dose is 2.9-fold greater than the maximum recommended human dose (MRHD) for adults of 8 g per day.

There was a slightly reduced survival rate during the lactation period in the offspring of rats that received the high dose, but not in offspring of rats that received lower doses of aztreonam.

Pregnancy Pregnancy Category B In pregnant women, aztreonam crosses the placenta and enters the fetal circulation.

Developmental toxicity studies in pregnant rats and rabbits with daily doses of aztreonam up to 1800 and 1200 mg/kg, respectively, revealed no evidence of embryotoxicity or fetotoxicity or teratogenicity.

These doses, based on body surface area, are 2.2- and 2.9-fold greater than the MRHD for adults of 8 g per day.

A peri/postnatal study in rats revealed no drug-induced changes in any maternal, fetal, or neonatal parameters.

The highest dose used in this study, 1800 mg/kg/day, is 2.2 times the MRHD based on body surface area.

There are no adequate and well-controlled studies of aztreonam on human pregnancy outcomes.

Because animal reproduction studies are not always predictive of human response, aztreonam should be used during pregnancy only if clearly needed.

Nursing Mothers Aztreonam is excreted in human milk in concentrations that are less than 1% of concentrations determined in simultaneously obtained maternal serum; consideration should be given to temporary discontinuation of nursing and use of formula feedings.

Pediatric Use The safety and effectiveness of intravenous AZACTAM have been established in the age groups 9 months to 16 years.

Use of AZACTAM in these age groups is supported by evidence from adequate and well-controlled studies of AZACTAM in adults with additional efficacy, safety, and pharmacokinetic data from noncomparative clinical studies in pediatric patients.

Sufficient data are not available for pediatric patients under 9 months of age or for the following treatment indications/pathogens: septicemia and skin and skin-structure infections (where the skin infection is believed or known to be due to H.

influenzae type b).

In pediatric patients with cystic fibrosis, higher doses of AZACTAM may be warranted.

(See CLINICAL PHARMACOLOGY , DOSAGE AND ADMINISTRATION , and CLINICAL STUDIES .) Geriatric Use Clinical studies of AZACTAM did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.9-12 In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

In elderly patients, the mean serum half-life of aztreonam increased and the renal clearance decreased, consistent with the age-related decrease in creatinine clearance.1-4 Since aztreonam is known to be substantially excreted by the kidney, the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, renal function should be monitored and dosage adjustments made accordingly (see DOSAGE AND ADMINISTRATION : Renal Impairment in Adult Patients and Dosage in the Elderly ).

AZACTAM contains no sodium.

OVERDOSAGE

If necessary, aztreonam may be cleared from the serum by hemodialysis and/or peritoneal dialysis.

DOSAGE AND ADMINISTRATION Dosage in Adult Patients AZACTAM, an intravenous solution in GALAXY plastic containers (PL 2040), is intended for intravenous use only.

Dosage should be determined by susceptibility of the causative organisms, severity and site of infection, and the condition of the patient.

Table 2: Azactam Dosage Guidelines for Adults* Type of Infection Dose Frequency (hours) Urinary tract infections 500 mg or 1 g 8 or 12 Moderately severe systemic infections 1 g or 2 g 8 or 12 Severe systemic or life-threatening infections 2 g 6 or 8 * Maximum recommended dose is 8 g per day.

Because of the serious nature of infections due to Pseudomonas aeruginosa , dosage of 2 g every six or eight hours is recommended, at least upon initiation of therapy, in systemic infections caused by this organism.

The intravenous route is recommended for patients requiring single doses greater than 1 g or those with bacterial septicemia, localized parenchymal abscess (eg, intra-abdominal abscess), peritonitis, or other severe systemic or life-threatening infections.

The duration of therapy depends on the severity of infection.

Generally, AZACTAM should be continued for at least 48 hours after the patient becomes asymptomatic or evidence of bacterial eradication has been obtained.

Persistent infections may require treatment for several weeks.

Doses smaller than those indicated should not be used.

Renal Impairment in Adult Patients Prolonged serum levels of aztreonam may occur in patients with transient or persistent renal insufficiency.

Therefore, the dosage of AZACTAM should be halved in patients with estimated creatinine clearances between 10 and 30 mL/min/1.73 m2 after an initial loading dose of 1 or 2 g.

When only the serum creatinine concentration is available, the following formula (based on sex, weight, and age of the patient) may be used to approximate the creatinine clearance (Clcr).

The serum creatinine should represent a steady state of renal function.

Males: Clcr = weight (kg) × (140−age) 72 × serum creatinine (mg/dL) Females: 0.85 × above value In patients with severe renal failure (creatinine clearance less than 10 mL/min/1.73 m 2 ), such as those supported by hemodialysis, the usual dose of 500 mg, 1 g, or 2 g should be given initially.

The maintenance dose should be one-fourth of the usual initial dose given at the usual fixed interval of 6, 8, or 12 hours.

For serious or life-threatening infections, in addition to the maintenance doses, one-eighth of the initial dose should be given after each hemodialysis session.

Dosage in the Elderly Renal status is a major determinant of dosage in the elderly; these patients in particular may have diminished renal function.

Serum creatinine may not be an accurate determinant of renal status.

Therefore, as with all antibiotics eliminated by the kidneys, estimates of creatinine clearance should be obtained and appropriate dosage modifications made if necessary.

Dosage in Pediatric Patients AZACTAM should be administered intravenously to pediatric patients with normal renal function.

There are insufficient data regarding intramuscular administration to pediatric patients or dosing in pediatric patients with renal impairment.

(See PRECAUTIONS : Pediatric Use.

) Table 3: Azactam Dosage Guidelines for Pediatric Patients* Type of Infection Dose Frequency (hours) Mild to moderate infections 30 mg/kg 8 Moderate to severe infections 30 mg/kg 6 or 8 * Maximum recommended dose is 120 mg/kg/day.

CLINICAL STUDIES A total of 612 pediatric patients aged 1 month to 12 years were enrolled in uncontrolled clinical trials of aztreonam in the treatment of serious Gram-negative infections, including urinary tract, lower respiratory tract, skin and skin-structure, and intra-abdominal infections.

Directions for Use of AZACTAM (aztreonam injection) in GALAXY Plastic Container (PL 2040).

AZACTAM is to be administered as an intermittent intravenous infusion only.

Storage Store in a freezer capable of maintaining a temperature of −20°C (−4°F).

Thawing of Plastic Containers Thaw frozen container at room temperature, 25°C (77°F) or in a refrigerator, 2°C to 8°C (36°F-46°F).

After thawing is complete, invert the container to assure a well-mixed solution.

( DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION.) Check for minute leaks by squeezing container firmly.

If leaks are detected, discard solution as sterility may be impaired.

The container should be visually inspected.

Thawed solutions should not be used unless clear; solutions will be colorless to yellow.

Components of the solution may precipitate in the frozen state and will dissolve upon reaching room temperature with little or no agitation.

If after visual inspection the solution remains discolored, cloudy, or if an insoluble precipitate is noted or if any seals or outlet ports are not intact, the container should be discarded.

DO NOT ADD SUPPLEMENTARY MEDICATION.

T he thawed solution in GALAXY plastic container (PL 2040) remains chemically stable for either 14 days under refrigeration (2°C-8°C/36°F-46°F) or for 48 hours at room temperature (25°C/77°F).

DO NOT REFREEZE THAWED ANTIBIOTICS.

Preparation for Intravenous Administration Use aseptic technique.

1.

Suspend container(s) from eyelet support.

2.

Remove protector from outlet port at bottom of container.

3.

Attach administration set.

Refer to complete directions accompanying set.

Additives or other medication should not be added to AZACTAM or infused simultaneously through the same intravenous line.

If the same intravenous line is used for sequential infusion of several different drugs, it should be flushed before and after infusion of AZACTAM with an infusion solution compatible with AZACTAM (aztreonam injection) in GALAXY plastic container (PL 2040)* and any other drug(s) administered via this common line.

It is recommended that the intravenous administration apparatus be replaced at least once every 48 hours.

CAUTION: Do not use plastic containers in series connections.

Such use could result in an embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

Intravenous Administration Infusion of AZACTAM should be completed within a 20- to 60-minute period.

The plastic container is a single-dose unit; discard any unused portion remaining in the container.

*The following infusion solutions are compatible with AZACTAM (aztreonam injection) in GALAXY plastic container (PL 2040): Sodium Chloride Injection, USP, 0.9% Ringer’s Injection, USP Lactated Ringer’s Injection, USP Dextrose Injection, USP, 5% or 10% Dextrose and Sodium Chloride Injection, USP, 5%:0.9%, 5%:0.45%, or 5%:0.2% Sodium Lactate Injection, USP (M/6 Sodium Lactate) Ionosol ® B and 5% Dextrose Isolyte ® E Isolyte ® E with 5% Dextrose Isolyte ® M with 5% Dextrose Normosol ® -R Normosol ® -R and 5% Dextrose Normosol ® -M and 5% Dextrose Mannitol Injection, USP, 5% or 10% Lactated Ringer’s and 5% Dextrose Injection Plasma-Lyte M and 5% Dextrose

DESCRIPTION

AZACTAM ® (aztreonam injection) contains the active ingredient aztreonam, a monobactam.

It was originally isolated from Chromobacterium violaceum .

It is a synthetic bactericidal antibiotic.

The monobactams, having a unique monocyclic beta-lactam nucleus, are structurally different from other beta-lactam antibiotics (eg, penicillins, cephalosporins, cephamycins).

The sulfonic acid substituent in the 1-position of the ring activates the beta-lactam moiety; an aminothiazolyl oxime side chain in the 3-position and a methyl group in the 4-position confer the specific antibacterial spectrum and beta-lactamase stability.

Aztreonam is designated chemically as (Z)-2-[[[(2-amino-4-thiazolyl)[[(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]carbamoyl]methylene]amino]oxy]-2-methylpropionic acid.

Structural formula: C 13 H 17 N 5 O 8 S 2 MW 435.44 AZACTAM in the GALAXY plastic container (PL 2040) is a frozen, iso-osmotic, sterile, sodium-free, nonpyrogenic intravenous solution.

Each 50 mL of solution contains 1 g, or 2 g aztreonam with approximately 1.7 g, or 700 mg Dextrose Hydrous, USP added to adjust osmolality, and approximately 780 mg, or 1.6 g of arginine added for pH adjustment, respectively.

Thawed solutions have a pH in the range of 4.5 to 7.5.

The solution is for intravenous administration following thawing at room temperature or under refrigeration.

This GALAXY container is fabricated from a specially designed multilayer plastic (PL 2040).

Solutions are in contact with the polyethylene layer of this container and can leach out certain chemical components of the plastic in very small amounts within the expiration period.

The suitability of the plastic has been confirmed in tests in animals according to the USP biological tests for plastic containers as well as by tissue culture toxicity studies.

Azactam Galaxy Chemical Structure

HOW SUPPLIED

AZACTAM ® (aztreonam injection) in GALAXY plastic container (PL 2040) is supplied as a frozen, 50 mL single-dose intravenous solution as follows: 1 g aztreonam/50 mL container: Packages of 24 NDC 0003-2230-11 2 g aztreonam/50 mL container: Packages of 24 NDC 0003-2240-11 Store at or below –20°C (–4°F) [see Directions for Use of AZACTAM (aztreonam injection) in GALAXY Plastic Container (PL 2040) ].

INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of AZACTAM (aztreonam injection) and other antibacterial drugs, AZACTAM should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.

In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

AZACTAM is indicated for the treatment of the following infections caused by susceptible Gram-negative microorganisms: Urinary Tract Infections (complicated and uncomplicated), including pyelonephritis and cystitis (initial and recurrent) caused by Escherichia coli , Klebsiella pneumoniae , Proteus mirabilis , Pseudomonas aeruginosa , Enterobacter cloacae , Klebsiella oxytoca *, Citrobacter species*, and Serratia marcescens *.

Lower Respiratory Tract Infections , including pneumonia and bronchitis caused by Escherichia coli , Klebsiella pneumoniae , Pseudomonas aeruginosa , Haemophilus influenzae , Proteus mirabilis , Enterobacter species, and Serratia marcescens *.

Septicemia caused by Escherichia coli , Klebsiella pneumoniae , Pseudomonas aeruginosa , Proteus mirabilis *, Serratia marcescens *, and Enterobacter species.

Skin and Skin-Structure Infections , including those associated with postoperative wounds, ulcers, and burns, caused by Escherichia coli , Proteus mirabilis , Serratia marcescens , Enterobacter species, Pseudomonas aeruginosa , Klebsiella pneumoniae , and Citrobacter species*.

Intra-abdominal Infections , including peritonitis caused by Escherichia coli , Klebsiella species including K.

pneumoniae , Enterobacter species including E.

cloacae *, Pseudomonas aeruginosa , Citrobacter species* including C.

freundii *, and Serratia species* including S.

marcescens *.

Gynecologic Infections , including endometritis and pelvic cellulitis caused by Escherichia coli , Klebsiella pneumoniae *, Enterobacter species* including E.

cloacae *, and Proteus mirabilis *.

AZACTAM is indicated for adjunctive therapy to surgery in the management of infections caused by susceptible organisms, including abscesses, infections complicating hollow viscus perforations, cutaneous infections, and infections of serous surfaces.

AZACTAM is effective against most of the commonly encountered Gram-negative aerobic pathogens seen in general surgery.

———————————— * Efficacy for this organism in this organ system was studied in fewer than 10 infections.

Concurrent Therapy Concurrent initial therapy with other antimicrobial agents and AZACTAM is recommended before the causative organism(s) is known in seriously ill patients who are also at risk of having an infection due to Gram-positive aerobic pathogens.

If anaerobic organisms are also suspected as etiologic agents, therapy should be initiated using an anti-anaerobic agent concurrently with AZACTAM (see DOSAGE AND ADMINISTRATION ).

Certain antibiotics (eg, cefoxitin, imipenem) may induce high levels of beta-lactamase in vitro in some Gram-negative aerobes such as Enterobacter and Pseudomonas species, resulting in antagonism to many beta-lactam antibiotics including aztreonam.

These in vitro findings suggest that such beta-lactamase inducing antibiotics not be used concurrently with aztreonam.

Following identification and susceptibility testing of the causative organism(s), appropriate antibiotic therapy should be continued.

PREGNANCY

Pregnancy Pregnancy Category B In pregnant women, aztreonam crosses the placenta and enters the fetal circulation.

Developmental toxicity studies in pregnant rats and rabbits with daily doses of aztreonam up to 1800 and 1200 mg/kg, respectively, revealed no evidence of embryotoxicity or fetotoxicity or teratogenicity.

These doses, based on body surface area, are 2.2- and 2.9-fold greater than the MRHD for adults of 8 g per day.

A peri/postnatal study in rats revealed no drug-induced changes in any maternal, fetal, or neonatal parameters.

The highest dose used in this study, 1800 mg/kg/day, is 2.2 times the MRHD based on body surface area.

There are no adequate and well-controlled studies of aztreonam on human pregnancy outcomes.

Because animal reproduction studies are not always predictive of human response, aztreonam should be used during pregnancy only if clearly needed.

Nursing Mothers Aztreonam is excreted in human milk in concentrations that are less than 1% of concentrations determined in simultaneously obtained maternal serum; consideration should be given to temporary discontinuation of nursing and use of formula feedings.

Pediatric Use The safety and effectiveness of intravenous AZACTAM have been established in the age groups 9 months to 16 years.

Use of AZACTAM in these age groups is supported by evidence from adequate and well-controlled studies of AZACTAM in adults with additional efficacy, safety, and pharmacokinetic data from noncomparative clinical studies in pediatric patients.

Sufficient data are not available for pediatric patients under 9 months of age or for the following treatment indications/pathogens: septicemia and skin and skin-structure infections (where the skin infection is believed or known to be due to H.

influenzae type b).

In pediatric patients with cystic fibrosis, higher doses of AZACTAM may be warranted.

(See CLINICAL PHARMACOLOGY , DOSAGE AND ADMINISTRATION , and CLINICAL STUDIES .) Geriatric Use Clinical studies of AZACTAM did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.9-12 In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

In elderly patients, the mean serum half-life of aztreonam increased and the renal clearance decreased, consistent with the age-related decrease in creatinine clearance.1-4 Since aztreonam is known to be substantially excreted by the kidney, the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, renal function should be monitored and dosage adjustments made accordingly (see DOSAGE AND ADMINISTRATION : Renal Impairment in Adult Patients and Dosage in the Elderly ).

AZACTAM contains no sodium.

Clozapine 25 MG Oral Tablet

DRUG INTERACTIONS

7 Reduce CLOZARIL dose to one-third when coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, enoxacin).

( , ) Concomitant use of Strong CYP1A2 Inhibitors: 2.6 7.1 Concomitant use of is not recommended.

( , ) Strong CYP3A4 Inducers 2.6 7.1 Consider reducing CLOZARIL dose when CYP1A2 (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued.

( , ) Discontinuation of CYP1A2 or CYP3A4 Inducers: 2.6 7.1 7.1 Potential for Other Drugs to Affect CLOZARIL Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6.

Use caution when administering CLOZARIL concomitantly with drugs that are inducers or inhibitors of these enzymes.

CYP1A2 Inhibitors Concomitant use of CLOZARIL and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions.

Reduce the CLOZARIL dose to one-third of the original dose when CLOZARIL is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin).

The CLOZARIL dose should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is discontinued .

[see Dosage and Administration (2.6), Clinical Pharmacology (12.3)] Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine.

Monitor patients closely when CLOZARIL is coadministered with these inhibitors.

Consider reducing the CLOZARIL dosage if necessary .

[see Dosage and Administration (2.6)] CYP2D6 and CYP3A4 Inhibitors Concomitant treatment with CLOZARIL and CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline) can increase clozapine levels and lead to adverse reactions .

Use caution and monitor patients closely when using such inhibitors.

Consider reducing the CLOZARIL dose .

[see Clinical Pharmacology (12.3)] [see Dosage and Administration (2.6)] CYP1A2 and CYP3A4 Inducers Concomitant treatment with drugs that induce CYP1A2 or CYP3A4 can decrease the plasma concentration of clozapine, resulting in decreased effectiveness of CLOZARIL.

Tobacco smoke is a moderate inducer of CYP1A2.

Strong CYP3A4 inducers include carbamazepine, phenytoin, St.

John’s wort, and rifampin.

It may be necessary to increase the CLOZARIL dose if used concomitantly with inducers of these enzymes.

However, concomitant use of CLOZARIL and strong CYP3A4 inducers is not recommended .

[see Dosage and Administration (2.6)] Consider reducing the CLOZARIL dosage when discontinuing coadministered enzyme inducers; because discontinuation of inducers can result in increased clozapine plasma levels and an increased risk of adverse reactions .

[see Dosage and Administration (2.6)] Drugs that Cause QT Interval Prolongation Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine.

Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, and pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) .

[see Warnings and Precautions (5.8)] 7.2 Potential for CLOZARIL to Affect Other Drugs Concomitant use of CLOZARIL with other drugs metabolized by CYP2D6 can increase levels of these CYPD26 substrates.

Use caution when coadministering CLOZARIL with other drugs that are metabolized by CYP2D6.

It may be necessary to use lower doses of such drugs than usually prescribed.

Such drugs include specific antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide).

OVERDOSAGE

10 10.1 Overdosage Experience The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation.

There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure.

Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg.

There have also been reports of patients recovering from overdoses well in excess of 4 g.

10.2 Management of Overdosage For the most up-to-date information on the management of CLOZARIL overdosage, contact a certified Regional Poison Control Center (1-800-222-1222).

Telephone numbers of certified Regional Poison Control Centers are listed in the , a registered trademark of Thomson PDR.

Establish and maintain an airway; ensure adequate oxygenation and ventilation.

Monitor cardiac status and vital signs.

Use general symptomatic and supportive measures.

There are no specific antidotes for CLOZARIL.

**Physicians’ Desk Reference ® In managing overdosage, consider the possibility of multiple-drug involvement.

DESCRIPTION

11 CLOZARIL (clozapine), an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine.

The structural formula is: ® CLOZARIL is available in pale yellow tablets of 25 mg and 100 mg for oral administration.

Active Ingredient: clozapine Inactive Ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch (corn), and talc.

Clozapine structural formula

CLINICAL STUDIES

14 14.1 Treatment Resistant Schizophrenia The efficacy of CLOZARIL in treatment-resistant schizophrenia was established in a multicenter, randomized, double-blind, active-controlled (chlorpromazine) study in patients with a DSM-III diagnosis of schizophrenia who had inadequate responses to at least 3 different antipsychotics (from at least 2 different chemical classes) during the preceding 5 years.

The antipsychotic trials must have been judged adequate; the antipsychotic dosages must have been equivalent to or greater than 1000 mg per day of chlorpromazine for a period of at least 6 weeks, each without significant reduction of symptoms.

There must have been no period of good functioning within the preceding 5 years.

Patients must have had a baseline score of at least 45 on the investigator-rated Brief Psychiatric Rating Scale (BPRS).

On the 18-item BPRS, 1 indicates the absence of symptoms, and 7 indicates severe symptoms; the maximum potential total BPRS score is 126.

At baseline, the mean BPRS score was 61.

In addition, patients must have had a score of at least 4 on at least 2 of the following 4 individual BPRS items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content.

Patients must have had a Clinical Global Impressions–Severity Scale score of at least 4 (moderately ill).

In the prospective, lead-in phase of the trial, all patients (N=305) initially received single-blind treatment with haloperidol (the mean dose was 61 mg per day) for 6 weeks.

More than 80% of patients completed the 6-week trial.

Patients with an inadequate response to haloperidol (n=268) were randomized to double-blind treatment with CLOZARIL (N=126) or chlorpromazine (N=142).

The maximum daily CLOZARIL dose was 900 mg; the mean daily dose was >600 mg.

The maximum daily chlorpromazine dose was 1800 mg; the mean daily dose was >1200 mg.

The primary endpoint was treatment response, predefined as a decrease in BPRS score of at least 20% and either (1) a CGI-S score of <3 (mildly ill), or (2) a BPRS score of <35, at the end of 6 weeks of treatment.

Approximately 88% of patients from the CLOZARIL and chlorpromazine groups completed the 6-week trial.

At the end of 6 weeks, 30% of the CLOZARIL group responded to treatment, and 4% of the chlorpromazine group responded to treatment.

The difference was statistically significant (p <0.001).

The mean change in total BPRS score was -16 and -5 in the CLOZARIL and chlorpromazine group, respectively; the mean change in the 4 key BPRS item scores was -5 and -2 in the CLOZARIL and chlorpromazine group, respectively; and the mean change in CGI-S score was -1.2 and -0.4, in the CLOZARIL and chlorpromazine group, respectively.

These changes in the CLOZARIL group were statistically significantly greater than in the chlorpromazine group (p<0.001 in each analysis).

14.2 Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder The effectiveness of CLOZARIL in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT™, a trademark of Novartis Pharmaceuticals Corporation).

This was a prospective, randomized, open-label, active-controlled, multicenter, international, parallel-group comparison of CLOZARIL versus olanzapine (*Zyprexa®, a registered trademark of Eli Lilly and Company) in 956 patients with schizophrenia or schizoaffective disorder (DSM-IV) who were judged to be at risk for recurrent suicidal behavior.

Only about one-fourth of these patients (27%) were considered resistant to standard antipsychotic drug treatment.

To enter the trial, patients must have met 1 of the following criteria: They had attempted suicide within the 3 years prior to their baseline evaluation.

They had been hospitalized to prevent a suicide attempt within the 3 years prior to their baseline evaluation.

They demonstrated moderate-to-severe suicidal ideation with a depressive component within 1 week prior to their baseline evaluation.

They demonstrated moderate-to-severe suicidal ideation accompanied by command hallucinations to do self-harm within 1 week prior to their baseline evaluation.

Dosing regimens for each treatment group were determined by individual investigators and were individualized by patient.

Dosing was flexible, with a dose range of 200–900 mg/day for CLOZARIL and 5–20 mg/day for olanzapine.

For the 956 patients who received CLOZARIL or olanzapine in this study, there was extensive use of concomitant psychotropics: 84% with antipsychotics, 65% with anxiolytics, 53% with antidepressants, and 28% with mood stabilizers.

There was significantly greater use of concomitant psychotropic medications among the patients in the olanzapine group.

The primary efficacy measure was time to (1) a significant suicide attempt, including a completed suicide; (2) hospitalization due to imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized; or (3) worsening of suicidality severity as demonstrated by “much worsening” or “very much worsening” from baseline in the Clinical Global Impression of Severity of Suicidality as assessed by the Blinded Psychiatrist (CGI-SS-BP) scale.

A determination of whether or not a reported event met criterion 1 or 2 above was made by the Suicide Monitoring Board (SMB), a group of experts blinded to patient data.

A total of 980 patients were randomized to the study and 956 received study medication.

Sixty-two percent of the patients were diagnosed with schizophrenia, and the remainder (38%) were diagnosed with schizoaffective disorder.

Only about one-fourth of the total patient population (27%) was identified as “treatment-resistant” at baseline.

There were more males than females in the study (61% of all patients were male).

The mean age of patients entering the study was 37 years of age (range 18–69).

Most patients were Caucasian (71%), 15% were black, 1% were Asian, and 13% were classified as being of “other” races.

Patients treated with CLOZARIL had a statistically significant longer delay in the time to recurrent suicidal behavior in comparison with olanzapine.

This result should be interpreted only as evidence of the effectiveness of CLOZARIL in delaying time to recurrent suicidal behavior and not a demonstration of the superior efficacy of CLOZARIL over olanzapine.

The probability of experiencing (1) a significant suicide attempt, including a completed suicide, or (2) hospitalization because of imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized, was lower for CLOZARIL patients than for olanzapine patients at Week 104: CLOZARIL 24% versus olanzapine 32%; 95% CI of the difference: 2%, 14% (Figure 2).

Figure 2.

Cumulative Probability of a Significant Suicide Attempt or Hospitalization to Prevent Suicide in Patients with Schizophrenia or Schizoaffective Disorder at High Risk of Suicidality Figure 2: Kaplan Meier Estimates of Cumulative Probability of a Significant Suicide Attempt or Hospitalization to Prevent Suicide.

HOW SUPPLIED

16 /STORAGE AND HANDLING NDC:64725-1260-1 in a CONTAINER of 30 TABLETS 16.1 How Supplied CLOZARIL® (clozapine) is available as 25 mg and 100 mg round, pale-yellow, uncoated tablets with a facilitated score on one side.

CLOZARIL® (clozapine) Tablets 25 mg Engraved with “CLOZARIL” once on the periphery of one side.

Engraved with a facilitated score and “25” once on the other side.

Bottle of 100 NDC 0078-0126-05 Bottle of 500 NDC 0078-0126-08 Unit dose packages of 100: 2 x 5 strips, 10 blisters per strip NDC 0078-0126-06 100 mg Engraved with “CLOZARIL” once on the periphery of one side.

Engraved with a facilitated score and “100” once on the other side.

Bottle of 100 NDC 0078-0127-05 Bottle of 500 NDC 0078-0127-08 Unit dose packages of 100: 2 x 5 strips, 10 blisters per strip NDC 0078-0127-06 16.2 Storage and Handling Storage temperature should not exceed 30°C (86°F).

Keep out of reach of children.

RECENT MAJOR CHANGES

Dosage and Administration ( , , ) 07/2013 2.1 2.6 2.7 Contraindications ( ) 07/2013 4 Warnings and Precautions ( , ) 07/2013 5.2 5.3

GERIATRIC USE

8.5 Geriatric Use There have not been sufficient numbers of geriatric patients in clinical studies utilizing CLOZARIL to determine whether those over 65 years of age differ from younger subjects in their response to CLOZARIL.

Orthostatic hypotension and tachycardia can occur with CLOZARIL treatment .

Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects.

[see Boxed Warning and Warnings and Precautions (5.3)] Elderly patients may be particularly susceptible to the anticholinergic effects of CLOZARIL, such as urinary retention and constipation .

[see Warnings and Precautions (5.13)] Carefully select CLOZARIL doses in elderly patients, taking into consideration their greater frequency of decreased hepatic, renal, or cardiac function, as well as other concomitant disease and other drug therapy.

Clinical experience suggests that the prevalence of tardive dyskinesia appears to be highest among the elderly; especially elderly women .

[see Warnings and Precautions (5.15)]

DOSAGE FORMS AND STRENGTHS

3 CLOZARIL (clozapine) is available as 25 mg and 100 mg round, pale-yellow, uncoated tablets with a facilitated score on one side.

25 mg and 100 mg tablets with a facilitated score on one side ( ) 3

MECHANISM OF ACTION

12.1 Mechanism of Action The mechanism of action of clozapine is unknown.

However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D ) and the serotonin type 2A (5-HT ) receptors.

CLOZARIL also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors.

2 2A

INDICATIONS AND USAGE

1 CLOZARIL is an atypical antipsychotic indicated for: Treatment-resistant schizophrenia.

Efficacy was established in an active-controlled study.

( , ) 1.1 14.1 Reducing suicidal behavior in patients with schizophrenia or schizoaffective disorder.

Efficacy was established in an active-controlled study.

( , ) 1.2 14.2 1.1 Treatment Resistant Schizophrenia CLOZARIL is indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment.

Because of the significant risk of agranulocytosis and seizure associated with its use, CLOZARIL should be used only in patients who have failed to respond adequately to standard antipsychotic treatment .

[see Warnings and Precautions (5.1, 5.4)] The effectiveness of CLOZARIL in treatment-resistant schizophrenia was demonstrated in a 6-week, randomized, double-blind, active-controlled study comparing CLOZARIL and chlorpromazine in patients who had failed other antipsychotics .

[see Clinical Studies (14.1)] 1.2 Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder CLOZARIL is indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state.

Suicidal behavior refers to actions by a patient that put him/herself at risk for death.

The effectiveness of CLOZARIL in reducing the risk of recurrent suicidal behavior was demonstrated over a 2-year treatment period in the InterSePT trial .

TM [see Clinical Studies (14.2)]

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

PREGNANCY

8.1 Pregnancy Pregnancy Category B Risk Summary There are no adequate or well-controlled studies of clozapine in pregnant women.

Reproduction studies have been performed in rats and rabbits at doses up to 0.4 and 0.9 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m body surface area basis.

The studies revealed no evidence of impaired fertility or harm to the fetus due to clozapine.

Because animal reproduction studies are not always predictive of human response, CLOZARIL should be used during pregnancy only if clearly needed.

2 Clinical Considerations Consider the risk of exacerbation of psychosis when discontinuing or changing treatment with antipsychotic medications during pregnancy and postpartum.

Consider early screening for gestational diabetes for patients treated with antipsychotic medications .

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.

Monitor neonates for symptoms of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding difficulties.

The severity of complications can vary from self-limited symptoms to some neonates requiring intensive care unit support and prolonged hospitalization.

[see Warnings and Precautions (5.9)] Animal Data In embryofetal developmental studies, clozapine had no effects on maternal parameters, litter sizes, or fetal parameters when administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 0.4 and 0.9 times, respectively, the MRHD of 900 mg/day on a mg/m body surface area basis.

2 In peri/postnatal developmental studies, pregnant female rats were administered clozapine over the last third of pregnancy and until day 21 postpartum.

Observations were made on fetuses at birth and during the postnatal period; the offspring were allowed to reach sexual maturity and mated.

Clozapine caused a decrease in maternal body weight but had no effects on litter size or body weights of either F1or F2 generations at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m body surface area basis.

2

NUSRING MOTHERS

8.3 Nursing Mothers CLOZARIL is present in human milk.

Because of the potential for serious adverse reactions in nursing infants from CLOZARIL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

BOXED WARNING

WARNING: AGRANULOCYTOSIS; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Agranulocytosis CLOZARIL treatment has caused agranulocytosis, defined as an absolute neutrophil count (ANC) less than 500/mm .

Agranulocytosis can lead to serious infection and death.

Prior to initiating treatment with CLOZARIL, obtain a baseline white blood cell (WBC) count and ANC.

The ANC must be greater than or equal to 2000/mm and the WBC must be greater than or equal to 3500/mm for a patient to begin treatment with CLOZARIL.

During treatment, patients must have regular monitoring of ANC and WBC.

Discontinue CLOZARIL and do not rechallenge if the ANC is less than 1000/mm or the WBC is less than 2000/mm .

Advise patients to immediately report symptoms consistent with agranulocytosis or infection (e.g., fever, weakness, lethargy, or sore throat) .

3 3 3 3 3 [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)] Because of the risk of agranulocytosis, CLOZARIL is available only through a restricted program called the CLOZARIL National Registry.

Under the CLOZARIL National Registry, prescribers, patients, and pharmacies must enroll in the program .

[see Warnings and Precautions (5.2)] Orthostatic Hypotension, Bradycardia, Syncope Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred with CLOZARIL treatment.

The risk is highest during the initial titration period, particularly with rapid dose escalation.

These reactions can occur with the first dose, with doses as low as 12.5 mg per day.

Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages.

Use CLOZARIL cautiously in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications) .

[see Dosage and Administration (2.2, and 2.5) and Warnings and Precautions (5.3)] Seizures Seizures have occurred with CLOZARIL treatment.

The risk is dose-related.

Initiate treatment at 12.5 mg, titrate gradually, and use divided dosing.

Use caution when administering CLOZARIL to patients with a history of seizures or other predisposing risk factors for seizure (CNS pathology, medications that lower the seizure threshold, alcohol abuse).

Caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others .

[see Dosage and Administration (2.2), Warnings and Precautions (5.4)] Myocarditis and Cardiomyopathy Fatal myocarditis and cardiomyopathy have occurred with CLOZARIL treatment.

Discontinue CLOZARIL and obtain a cardiac evaluation upon suspicion of these reactions.

Generally, patients with CLOZARIL-related myocarditis or cardiomyopathy should not be rechallenged with CLOZARIL.

Consider the possibility of myocarditis or cardiomyopathy if chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or ECG changes occur .

[see Warnings and Precautions (5.5)] Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

CLOZARIL is not approved for use in patients with dementia-related psychosis .

[see Warnings and Precautions (5.6)] WARNING: AGRANULOCYTOSIS; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning.

Agranulocytosis: Can lead to serious infection and death.

Monitor white blood cell count and absolute neutrophil count prior to and during treatment.

Monitor for symptoms of agranulocytosis and infection.

( , ) 2.1 5.1 Because of risk of agranulocytosis, CLOZARIL is available only through a restricted program called the CLOZARIL National Registry.

Prescribers, patients, and pharmacies must enroll in the program.

( ) 5.2 Orthostatic Hypotension, Bradycardia, and Syncope: Risk is dose-related.

Starting dose is 12.5 mg.

Titrate gradually and use divided dosages.

( , , ) 2.2 2.5 5.3 Seizure: Risk is dose-related.

Titrate gradually and use divided doses.

Use with caution in patients with history of seizure or risk factors for seizure.

( , ) 2.2 5.4 Myocarditis and Cardiomyopathy: Can be fatal.

Discontinue and obtain cardiac evaluation if findings suggest these cardiac reactions.

( ) 5.5 Increased Mortality in Elderly Patients with Dementia-Related Psychosis: CLOZARIL is not approved for this condition.

( ) 5.6

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Assess for organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis).

Discontinue if these occur.

( ) Eosinophilia: 5.7 Can be fatal.

Consider additional risk factors for prolonged QT interval (disorders and drugs).

( ) QT Interval Prolongation: 5.8 Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/ cerebrovascular risk.

These metabolic changes include: Metabolic Changes: Monitor for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.

Monitor glucose regularly in patients with diabetes or at risk for diabetes.

( ) Hyperglycemia and Diabetes Mellitus: 5.9 Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics.

( ) Dyslipidemia: 5.9 Significant weight gain has occurred.

Monitor weight gain.

( ) Weight Gain: 5.9 Immediately discontinue and monitor closely.

Assess for co-morbid conditions.

( ) Neuroleptic Malignant Syndrome (NMS): 5.10 Evaluate for infection, agranulocytosis, NMS.

( ) Fever: 5.11 Consider PE if respiratory distress, chest pain, or deep vein thrombosis occur.

( ) Pulmonary Embolism (PE): 5.12 Use cautiously in presence of specific conditions (e.g., narrow angle glaucoma, use of anticholinergic drugs).

( ) Anticholinergic Toxicity: 5.13 Advise caution when operating machinery, including automobiles.

( ) Interference with Cognitive and Motor Performance: 5.14 5.1 Agranulocytosis Background Agranulocytosis, defined as an ANC of less than 500/mm , has been estimated to occur in association with clozapine use at a cumulative incidence at 1 year of approximately 1.3%, based on the occurrence of 15 US cases out of 1743 patients exposed to CLOZARIL during its clinical testing prior to domestic marketing.

All of these cases occurred at a time when the need for close monitoring of WBC counts was already recognized.

A hematologic risk analysis was conducted based upon the available information in the CLOZARIL National Registry for US patients.

Based upon a cut-off date of April 30, 1995, the incidence rates of agranulocytosis based upon a weekly monitoring schedule rose steeply during the first 2 months of therapy, peaking in the third month.

Among clozapine patients who continued the drug beyond the third month, the weekly incidence of agranulocytosis fell a substantial degree.

After 6 months, the weekly incidence of agranulocytosis declines still further; however, it never reaches zero.

It should be noted that any type of reduction in the frequency of monitoring WBC counts may result in an increased incidence of agranulocytosis.

3 Risk Factors Experience from clinical development, as well as from examples in the medical literature, suggests that patients who have developed agranulocytosis during clozapine therapy are at increased risk of subsequent episodes of agranulocytosis.

Analysis of WBC count data from the CLOZARIL National Registry also suggests that patients who have an initial episode of moderate leukopenia (3000/mm >WBC count ≥2000/mm ) are at an increased risk of subsequent episodes of agranulocytosis.

Except for bone-marrow suppression during initial clozapine therapy, there are no other established risk factors based on worldwide experience for the development of agranulocytosis in association with clozapine use.

However, a disproportionate number of the US cases of agranulocytosis occurred in patients of Jewish background compared to the overall proportion of such patients exposed during domestic development of clozapine.

Most of the US cases of agranulocytosis occurred within 4–10 weeks of exposure, but neither dose nor duration is a reliable predictor of this problem.

Agranulocytosis associated with other antipsychotic drugs has been reported to occur with a greater frequency in women, the elderly, and in patients who are cachectic or have serious underlying medical illness; such patients may also be at particular risk with clozapine, although this has not been definitively demonstrated.

3 3 WBC Count and ANC Clinical Monitoring Schedule CLOZARIL is available only through a distribution system that ensures monitoring of WBC count and ANC according to the schedule described below prior to delivery of the next supply of medication.

As described in Table 2, patients who are being treated with CLOZARIL must have a baseline WBC count and ANC before initiation of treatment, and a WBC count and ANC every week for the first 6 months.

Thereafter, if acceptable WBC counts and ANCs (WBC count ≥3500/mm and ANC ≥2000/mm ) have been maintained during the first 6 months of continuous therapy, WBC counts and ANCs can be monitored every 2 weeks for the next 6 months.

Thereafter, if acceptable WBC counts and ANCs (WBC count ≥3500/mm and ANC ≥2000/mm ) have been maintained during the second 6 months of continuous therapy, WBC count and ANC can be monitored every 4 weeks.

3 3 3 3 When treatment with CLOZARIL is discontinued (regardless of the reason), WBC count and ANC must be monitored weekly for at least 4 weeks from the day of discontinuation or until WBC count ≥3500/mm and ANC ≥2000/mm .

3 3 Table 2 provides a summary of the frequency of monitoring that should occur based on various stages of therapy (e.g., initiation of therapy) or results from WBC count and ANC monitoring tests (e.g., moderate leukopenia).

The text that follows should be consulted for additional details regarding the treatment of patients under the various conditions (e.g., severe leukopenia).

Advise patients to immediately report the appearance of signs/symptoms consistent with agranulocytosis or infection (e.g., fever, weakness, lethargy, or sore throat) at any time during CLOZARIL therapy.

Such patients should have a WBC count and an ANC performed promptly.

Table 2.

Frequency of Monitoring Based on Stage of Therapy or Results from WBC Count and ANC Monitoring Tests WBC=White blood cell ANC=Absolute neutrophil count Situation Hematological Values for Monitoring Frequency of WBC Count and ANC Monitoring Initiation of therapy WBC count≥3500/mm and ANC≥2000/mm Note: Do not initiate in patients with a history of clozapine-induced agranulocytosis or severe granulocytopenia.

3 3 Weekly for 6 months 6 to 12 months of therapy WBC ≥3500/mm and ANC ≥2000/mm 3 3 Every 2 weeks for 6 months 12 months of therapy WBC ≥3500/mm and ANC ≥2000/mm 3 3 Every 4 weeks ad infinitum Immature forms present N/A Repeat WBC and ANC Discontinuation of therapy N/A Weekly for at least 4 weeks from day of discontinuation or until WBC ≥3500/mm and ANC ≥2000/mm 3 3 Substantial drop in WBC or ANC Single drop or cumulative drop within 3 weeks of: WBC ≥3000/mm or ANC ≥1500/mm 3 3 Repeat WBC and ANC If repeat values are: WBC 3000/mm to 3500 and ANC >2000/mm , then monitor twice weekly 3 3 Mild leukopenia and/or Mild granulocytopenia If WBC 3000 mm to <3500/mm and/or ANC 1500/mm to 3500/mm and ANC >2000/mm then return to previous monitoring frequency 3 3 Moderate leukopenia and/or Moderate granulocytopenia WBC 2000/mm to <3000/mm and/or ANC 1000/mm to 3000/mm and ANC >1500/mm 3 3 Twice weekly until WBC >3500/mm and ANC >2000/mm 3 3 May rechallenge when WBC >3500/mm and ANC >2000/mm 3 3 If rechallenged, monitor weekly for 1 year before returning to the usual monitoring schedule of every 2 weeks for 6 months and then every 4 weeks ad infinitum Severe leukopenia and/or Severe granulocytopenia WBC count <2000/mm and/or ANC 3000/mm and ANC >1500/mm 3 3 Twice weekly until WBC >3500/mm and ANC >2000/mm 3 3 Weekly after WBC >3500/mm 3 Agranulocytosis ANC 3000/mm and ANC >1500/mm 3 3 Twice weekly until WBC >3500/mm and ANC >2000/mm 3 3 Weekly after WBC >3500/mm 3 Decrements in WBC Count and/or ANC Consult Table 2 above to determine how to monitor patients who experience decrements in WBC count and/or ANC at any point during treatment.

Additionally, patients should be carefully monitored for flu-like symptoms or other symptoms suggestive of infection.

Nonrechallengeable Patients If the total WBC count falls below 2000/mm or the ANC falls below 1000/mm , bone-marrow aspiration should be considered to ascertain granulopoietic status and patients should not be rechallenged with clozapine.

Protective isolation with close observation may be indicated if granulopoiesis is determined to be deficient.

Should evidence of infection develop, the patient should have appropriate cultures performed and an appropriate antibiotic regimen instituted.

3 3 Patients discontinued from clozapine therapy due to significant granulopoietic suppression have been found to develop agranulocytosis upon rechallenge, often with a shorter latency on re-exposure.

To reduce the chances of rechallenge occurring in patients who have experienced significant bone-marrow suppression during clozapine therapy, a single, national master file (i.e., Nonrechallengeable Database) is confidentially maintained.

Treatment of Rechallengeable Patients Patients may be rechallenged with clozapine if their WBC count does not fall below 2000/mm and the ANC does not fall below 1000/mm .

However, analysis of the data from the CLOZARIL National Registry suggests that patients who have an initial episode of moderate leukopenia (3000/mm >WBC count ≥2000/mm ) have up to a 12-fold increased risk of having a subsequent episode of agranulocytosis when rechallenged as compared to the full cohort of patients treated with clozapine.

Although CLOZARIL therapy may be resumed if no symptoms of infection develop and when the WBC count rises above 3500/mm and the ANC rises above 2000/mm , prescribers are strongly advised to consider whether the benefit of continuing CLOZARIL treatment outweighs the increased risk of agranulocytosis.

3 3 3 3 3 3 Analyses of the CLOZARIL National Registry have shown an increased risk of having a subsequent episode of granulopoietic suppression up to a year after recovery from the initial episode.

Therefore, as noted in Table 2, patients must undergo weekly WBC count and ANC monitoring for 1 year following recovery from an episode of moderate leukopenia and/or moderate granulocytopenia regardless of when the episode develops.

If acceptable WBC counts and ANC (WBC count ≥3500/mm and ANC ≥2000/mm ) have been maintained during the year of weekly monitoring, WBC counts can be monitored every 2 weeks for the next 6 months.

If acceptable WBC counts and ANC (WBC count ≥3500/mm and ANC ≥2000/mm ) continue to be maintained during the 6 months of every 2-week monitoring, WBC counts can be monitored every 4 weeks thereafter, ad infinitum.

3 3 3 3 Interruptions in Therapy Figure 1 provides instructions regarding re-initiating therapy and subsequently the frequency of WBC count and ANC monitoring after a period of interruption.

Figure 1.

Resuming Monitoring Frequency after Interruption of Therapy Figure 1: Resuming Monitoring Frequency after Interruption in Therapy 5.2 CLOZARIL National Registry Because of the Risk of Agranulocytosis Because of the risk of agranulocytosis, CLOZARIL is available only through a restricted program called the CLOZARIL National Registry.

Under the CLOZARIL National Registry, prescribers, patients, pharmacies, and distributors must enroll in the program.

Required components of the CLOZARIL National Registry are: Healthcare professionals who prescribe CLOZARIL must enroll in the program and comply with the Registry requirements.

Pharmacies that dispense CLOZARIL must enroll in the program and comply with the Registry requirements.

Routine monitoring and submission of laboratory results (WBC and ANC) is required during treatment with CLOZARIL .

[see Warnings and Precautions (5.1)] Patients who receive CLOZARIL must be enrolled in a registry.

Further information is available at or 1-888-669-6682.

http://www.clozarilregistry.com 5.3 Orthostatic Hypotension, Bradycardia, and Syncope Hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment.

The risk is highest during the initial titration period, particularly with rapid dose-escalation.

These reactions can occur with the first dose, at doses as low as 12.5 mg.

These reactions can be fatal.

The syndrome is consistent with neurally mediated reflex bradycardia (NMRB).

Treatment must begin at a maximum dose of 12.5 mg once daily or twice daily.

The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks.

Subsequently, the dose can be increased weekly or twice weekly, in increments of up to 100 mg.

The maximum dose is 900 mg per day.

Use cautious titration and a divided dosage schedule to minimize the risk of serious cardiovascular reactions .

Consider reducing the dose if hypotension occurs.

When restarting patients who have had even a brief interval off CLOZARIL (i.e., 2 days or more since the last dose), re-initiate treatment at 12.5 mg once daily or twice daily .

[see Dosage and Administration (2.2)] [see Dosage and Administration (2.5)] Use CLOZARIL cautiously in patients with cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (e.g., concomitant use of antihypertensives, dehydration and hypovolemia).

5.4 Seizures Seizure has been estimated to occur in association with clozapine use at a cumulative incidence at 1 year of approximately 5%, based on the occurrence of 1 or more seizures in 61 of 1743 patients exposed to clozapine during its clinical testing prior to domestic marketing (i.e., a crude rate of 3.5%).

The risk of seizure is dose-related.

Initiate treatment with a low dose (12.5 mg), titrate slowly, and use divided dosing.

Use caution when administering CLOZARIL to patients with a history of seizures or other predisposing risk factors for seizure (e.g., head trauma or other CNS pathology, use of medications that lower the seizure threshold, or alcohol abuse).

Because of the substantial risk of seizure associated with CLOZARIL use, caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., driving an automobile, operating complex machinery, swimming, climbing).

5.5 Myocarditis and Cardiomyopathy Myocarditis and cardiomyopathy have occurred with the use of CLOZARIL.

These reactions can be fatal.

Discontinue CLOZARIL and obtain a cardiac evaluation upon suspicion of myocarditis or cardiomyopathy.

Generally, patients with a history of clozapine-associated myocarditis or cardiomyopathy should not be rechallenged with CLOZARIL.

However, if the benefit of CLOZARIL treatment is judged to outweigh the potential risks of recurrent myocarditis or cardiomyopathy, the clinician may consider rechallenge with CLOZARIL in consultation with a cardiologist, after a complete cardiac evaluation, and under close monitoring.

Consider the possibility of myocarditis or cardiomyopathy in patients receiving CLOZARIL who present with chest pain, dyspnea, persistent tachycardia at rest, palpitations, fever, flu-like symptoms, hypotension, other signs or symptoms of heart failure, or electrocardiographic findings (low voltages, ST-T abnormalities, arrhythmias, right axis deviation, and poor R wave progression).

Myocarditis most frequently presents within the first 2 months of clozapine treatment.

Symptoms of cardiomyopathy generally occur later than clozapine-associated myocarditis and usually after 8 weeks of treatment.

However, myocarditis and cardiomyopathy can occur at any period during treatment with CLOZARIL.

It is common for nonspecific flu-like symptoms such as malaise, myalgia, pleuritic chest pain, and low-grade fevers to precede more overt signs of heart failure.

Typical laboratory findings include elevated troponin I or T, elevated creatinine kinase-MB, peripheral eosinophilia, and elevated C-reactive protein (CRP).

Chest roentgenogram may demonstrate cardiac silhouette enlargement, and cardiac imaging (echocardiogram, radionucleotide studies, or cardiac catheterization) may reveal evidence of left ventricular dysfunction.

5.6 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients.

Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.

Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality in this population.

The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

CLOZARIL is not approved for the treatment of patients with dementia-related psychosis .

[see Boxed Warning] 5.7 Eosinophilia Eosinophilia, defined as a blood eosinophil count of greater than 700/mm , has occurred with CLOZARIL treatment.

In clinical trials, approximately 1% of patients developed eosinophilia.

Clozapine-related eosinophilia usually occurs during the first month of treatment.

In some patients, it has been associated with myocarditis, pancreatitis, hepatitis, colitis, and nephritis.

Such organ involvement could be consistent with a drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, also known as drug induced hypersensitivity syndrome (DIHS).

If eosinophilia develops during CLOZARIL treatment, evaluate promptly for signs and symptoms of systemic reactions, such as rash or other allergic symptoms, myocarditis, or other organ-specific disease associated with eosinophilia.

If CLOZARIL-related systemic disease is suspected, discontinue CLOZARIL immediately.

3 If a cause of eosinophilia unrelated to CLOZARIL is identified (e.g., asthma, allergies, collagen vascular disease, parasitic infections, and specific neoplasms), treat the underlying cause and continue CLOZARIL.

Clozapine-related eosinophilia has also occurred in the absence of organ involvement and can resolve without intervention.

There are reports of successful rechallenge after discontinuation of clozapine, without recurrence of eosinophilia.

In the absence of organ involvement, continue CLOZARIL under careful monitoring.

If the total eosinophil count continues to increase over several weeks in the absence of systemic disease, the decision to interrupt CLOZARIL therapy and rechallenge after the eosinophil count decreases should be based on the overall clinical assessment, in consultation with an internist or hematologist.

5.8 QT Interval Prolongation QT prolongation, Torsades de Pointes and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have occurred with CLOZARIL treatment.

When prescribing CLOZARIL, consider the presence of additional risk factors for QT prolongation and serious cardiovascular reactions.

Conditions that increase these risks include the following: history of QT prolongation, long QT syndrome, family history of long QT syndrome or sudden cardiac death, significant cardiac arrhythmia, recent myocardial infarction, uncompensated heart failure, treatment with other medications that cause QT prolongation, treatment with medications that inhibit the metabolism of clozapine, and electrolyte abnormalities.

Prior to initiating treatment with CLOZARIL, perform a careful physical examination, medical history, and concomitant medication history.

Consider obtaining a baseline ECG and serum chemistry panel.

Correct electrolyte abnormalities.

Discontinue CLOZARIL if the QTc interval exceeds 500 msec.

If patients experience symptoms consistent with Torsades de Pointes, or other arrhythmias, (e.g., syncope, presyncope, dizziness, or palpitations), obtain a cardiac evaluation and discontinue CLOZARIL.

Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of CLOZARIL.

Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmic medications (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus).

Clozapine is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4.

Concomitant treatment with inhibitors of these enzymes can increase the concentration of CLOZARIL .

[see Drug Interactions (7.1) and Clinical Pharmacology (12.3)] Hypokalemia and hypomagnesemia increase the risk of QT prolongation.

Hypokalemia can result from diuretic therapy, diarrhea, and other causes.

Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia.

Obtain baseline measurements of serum potassium and magnesium levels, and periodically monitor electrolytes.

Correct electrolyte abnormalities before initiating treatment with CLOZARIL.

5.9 Metabolic Changes Atypical antipsychotic drugs, including CLOZARIL have been associated with metabolic changes that can increase cardiovascular and cerebrovascular risk.

These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain.

While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including CLOZARIL.

Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population.

Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood.

However, epidemiological studies suggest an increased risk of treatment-emergent, hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on CLOZARIL should be monitored regularly for worsening of glucose control.

Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment.

Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.

Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing.

In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

In a pooled data analysis of 8 studies in adult subjects with schizophrenia, the mean changes in fasting glucose concentration in the CLOZARIL and chlorpromazine groups were +11 mg/dL and +4 mg/dL respectively.

A higher proportion of the CLOZARIL group demonstrated categorical increases from baseline in fasting glucose concentrations, compared to the chlorpromazine group (Table 3).

The CLOZARIL doses were 100–900 mg per day (mean modal dose: 512 mg per day).

The maximum chlorpromazine dose was 1800 mg per day (mean modal dose: 1029 mg per day).

The median duration of exposure was 42 days for CLOZARIL and chlorpromazine.

Table 3.

Categorical Changes in Fasting Glucose Level in Studies in Adult Subjects with Schizophrenia Laboratory Parameter Category Change (at least once) from baseline Treatment Arm N n (%) Fasting Glucose Normal (<100 mg/dL) to High (≥126 mg/dL) CLOZARIL 198 53 (27) Chlorpromazine 135 14 (10) Borderline (100 to 125 mg/dL) to High (≥126 mg/dL) CLOZARIL 57 24 (42) Chlorpromazine 43 12 (28) Dyslipidemia Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including CLOZARIL.

Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using CLOZARIL, is recommended.

In a pooled data analysis of 10 studies in adult subjects with schizophrenia, CLOZARIL treatment was associated with increases in serum total cholesterol.

No data were collected on LDL and HDL cholesterol.

The mean increase in total cholesterol was 13 mg/dL in the CLOZARIL group and 15 mg/dL in the chlorpromazine group.

In a pooled data analysis of 2 studies in adult subjects with schizophrenia, CLOZARIL treatment was associated with increases in fasting serum triglyceride.

The mean increase in fasting triglyceride was 71 mg/dL (54%) in the CLOZARIL group and 39 mg/dL (35%) in the chlorpromazine group (Table 4).

In addition, CLOZARIL treatment was associated with categorical increases in serum total cholesterol and triglyceride, as illustrated in Table 5.The proportion of patients with categorical increases in total cholesterol or fasting triglyceride increased with the duration of exposure.

The median duration of CLOZARIL and chlorpromazine exposure was 45 days and 38 days, respectively.

The CLOZARIL dose range was 100 mg to 900 mg daily; the maximum chlorpromazine dose was 1800 mg daily.

Table 4.

Mean Changes in Total Cholesterol and Triglyceride Concentration in Studies in Adult Subjects with Schizophrenia Treatment Arm Baseline total cholesterol concentration (mg/dL) Change from baseline mg/dL (%) CLOZARIL (N=334) 184 +13 (7) Chlorpromazine (185) 182 +15 (8) Baseline triglyceride concentration (mg/dL) Change from baseline mg/dL (%) CLOZARIL (N=6) 130 +71 (54) Chlorpromazine (N=7) 110 +39 (35) Table 5.

Categorical Changes in Lipid Concentrations in Studies in Adult Subjects with Schizophrenia Laboratory Parameter Category Change (at least once) from baseline Treatment Arm N n (%) Total Cholesterol (random or fasting) Increase by ≥40 mg/dL CLOZARIL 334 111 (33) Chlorpromazine 185 46 (25) Normal (<200 mg/dL) to High (≥240 mg/dL) CLOZARIL 222 18 (8) Chlorpromazine 132 3 (2) Borderline (200-239 mg/dL) to High (≥240 mg/dL) CLOZARIL 79 30 (38) Chlorpromazine 34 14 (41) Triglycerides (fasting) Increase by ≥50 mg/dL CLOZARIL 6 3 (50) Chlorpromazine 7 3 (43) Normal (<150 mg/dL) to High (≥200 mg/dL) CLOZARIL 4 0 (0) Chlorpromazine 6 2 (33) Borderline (≥150 mg/dL and <200 mg/dL) to High (≥200 mg/dL) CLOZARIL 1 1 (100) Chlorpromazine 1 0 (0) Weight Gain Weight gain has occurred with the use of antipsychotics, including CLOZARIL.

Monitor weight during treatment with CLOZARIL.

Table 6 summarizes the data on weight gain by the duration of exposure pooled from 11 studies with CLOZARIL and active comparators.

The median duration of exposure was 609, 728, and 42 days, in the CLOZARIL, olanzapine, and chlorpromazine group, respectively.

Table 6.

Mean Change in Body Weight (kg) by duration of exposure from studies in adult subjects with schizophrenia Metabolic parameter Exposure duration CLOZARIL (N=669) Olanzapine (N=442) Chlorpromazine (N=155) n Mean n Mean n Mean Weight change from baseline 2 weeks (Day 11–17) 6 +0.9 3 +0.7 2 -0.5 4 weeks (Day 21–35) 23 +0.7 8 +0.8 17 +0.6 8 weeks (Day 49–63) 12 +1.9 13 +1.8 16 +0.9 12 weeks (Day 70–98) 17 +2.8 5 +3.1 0 0 24 weeks (154–182) 42 – 0.6 12 +5.7 0 0 48 weeks (Day 322–350) 3 +3.7 3 +13.7 0 0 Table 7 summarizes pooled data from 11 studies in adult subjects with schizophrenia demonstrating weight gain ≥7% of body weight relative to baseline.

The median duration of exposure was 609, 728, and 42 days, in the CLOZARIL, olanzapine, and chlorpromazine group, respectively.

Table 7.

Proportion of Adult Subjects in Schizophrenia Studies with Weight Gain ≥7% Relative to Baseline Body Weight Weight change CLOZARIL Olanzapine Chlorpromazine N 669 442 155 ≥7% (inclusive) 236 (35%) 203 (46%) 13 (8%) 5.10 Neuroleptic Malignant Syndrome Antipsychotic drugs including CLOZARIL can cause a potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS).

Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).

Associated findings can include elevated creatine phosphokinase (CPK), myoglobinuria, rhabdomyolysis, and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated.

It is important to consider the presence of other serious medical conditions (e.g., agranulocytosis, infection, heat stroke, primary CNS pathology, central anticholinergic toxicity, extrapyramidal symptoms, and drug fever).

The management of NMS should include (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, (2) intensive symptomatic treatment and medical monitoring, and (3) treatment of comorbid medical conditions.

There is no general agreement about specific pharmacological treatments for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.

NMS can recur.

Monitor closely if restarting treatment with antipsychotics.

NMS has occurred with CLOZARIL monotherapy and with concomitant CNS-active medications, including lithium.

5.11 Fever During clozapine therapy, patients have experienced transient, clozapine-related fever.

The peak incidence is within the first 3 weeks of treatment.

While this fever is generally benign and self-limited, it may necessitate discontinuing treatment.

The fever can be associated with an increase or decrease in WBC count.

Carefully evaluate patients with fever to rule out agranulocytosis or infection.

Consider the possibility of NMS .

[see Warnings and Precautions (5.10)] 5.12 Pulmonary Embolism Pulmonary embolism and deep vein thrombosis have occurred in patients treated with CLOZARIL.

Consider the possibility of pulmonary embolism in patients who present with deep-vein thrombosis, acute dyspnea, chest pain, or with other respiratory signs and symptoms.

Whether pulmonary embolus and deep vein thrombosis can be attributed to clozapine or some characteristic(s) of patients is not clear.

5.13 Anticholinergic Toxicity CLOZARIL has potent anticholinergic effects.

Treatment with CLOZARIL can result in CNS and peripheral anticholinergic toxicity.

Use with caution in the presence of narrow-angle glaucoma, concomitant anticholinergic medications, prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions.

Treatment with CLOZARIL can result in gastrointestinal adverse reactions, including constipation, intestinal obstruction, fecal impaction, and paralytic ileus.

Such reactions can be fatal.

Constipation should be initially treated by ensuring adequate hydration and use of ancillary therapy such as bulk laxatives.

Consultation with a gastroenterologist is advisable in more serious cases.

5.14 Interference with Cognitive and Motor Performance CLOZARIL can cause sedation and impairment of cognitive and motor performance.

Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that CLOZARIL does not affect them adversely.

These reactions may be dose-related.

Consider reducing the dose if they occur.

5.15 Tardive Dyskinesia Tardive dyskinesia (TD) has occurred in patients treated with antipsychotic drugs, including CLOZARIL.

The syndrome consists of potentially irreversible, involuntary, dyskinetic movements.

The risk of TD and the likelihood that it will become irreversible are believed to increase with greater durations of treatment and higher total cumulative doses.

However, the syndrome can develop after relatively brief treatment periods at low doses.

Prescribe CLOZARIL in a manner that is most likely to minimize the risk of developing TD.

Use the lowest effective dose and the shortest duration necessary to control symptoms.

Periodically assess the need for continued treatment.

Consider discontinuing treatment if TD occurs.

However, some patients may require treatment with CLOZARIL despite the presence of the syndrome.

There is no known treatment for TD.

However, the syndrome may remit partially or completely if treatment is discontinued.

Antipsychotic treatment, itself, may suppress (or partially suppress) the signs and symptoms, and it has the potential to mask the underlying process.

The effect of symptom suppression on the long-term course of TD is unknown.

5.16 Cerebrovascular Adverse Reactions In controlled trials, elderly patients with dementia-related psychosis treated with some atypical antipsychotics had an increased risk (compared to placebo) of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities.

The mechanism for this increased risk is not known.

An increased risk cannot be excluded for CLOZARIL or other antipsychotics or other patient populations.

CLOZARIL should be used with caution in patients with risk factors for cerebrovascular adverse reactions.

5.17 Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation of CLOZARIL If abrupt discontinuation of CLOZARIL is necessary (because of agranulocytosis or another medical condition, for example), monitor carefully for the recurrence of psychotic symptoms and adverse reactions related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and diarrhea.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Discuss the following issues with patients and caregivers: Prior to initiating treatment, educate patients and caregivers about the significant risk of developing agranulocytosis.

Advise them to immediately report the appearance of signs or symptoms consistent with agranulocytosis or infection (e.g., fever; mucus membrane ulcers; skin, pharyngeal, vaginal, urinary, or pulmonary infection; or extreme weakness or lethargy) at any time during CLOZARIL therapy .

Agranulocytosis: [see Boxed Warning and Warnings and Precautions (5.1)] Inform patients and caregivers that CLOZARIL will be made available only through a special program (CLOZARIL National Registry) designed to ensure the required blood monitoring, in order to reduce the risk of developing agranulocytosis.

Inform patients and caregivers the WBC count and ANC will be monitored as follows: Weekly blood tests are required for the first 6 months.

If acceptable WBC counts and ANCs (WBC count ≥3500/mm and ANC ≥2000/mm ) have been maintained during the first 6 months of continuous therapy, then WBC counts and ANCs can be monitored every 2 weeks for the next 6 months.

3 3 Thereafter, if acceptable WBC counts and ANCs have been maintained during the second 6 months of continuous therapy, WBC counts and ANCs can be monitored every 4 weeks.

Inform patients and caregivers about the risk of orthostatic hypotension and syncope, especially during the period of initial dose titration.

Instruct them to strictly follow the clinician’s instructions for dosage and administration.

Advise patients to consult their clinician immediately if they feel faint, lose consciousness or have signs or symptoms suggestive of bradycardia or arrhythmia .

Orthostatic Hypotension, Bradycardia, and Syncope: [see Dosage and Administration (2.2) and Warnings and Precautions (5.3)] Inform patients and caregivers about the significant risk of seizure during CLOZARIL treatment.

Caution them about driving and any other potentially hazardous activity while taking CLOZARIL .

Seizures: [see Warnings and Precautions (5.4)] Advise patients to consult their clinician immediately if they feel faint, lose consciousness or have signs or symptoms suggestive of arrhythmia.

Instruct patients to not take CLOZARIL with other drugs that cause QT interval prolongation.

Instruct patients to inform their clinicians that they are taking CLOZARIL before any new drug .

QT Interval Prolongation: [see Warnings and Precautions (5.8.) and Drug Interactions (7.1)] Educate patients and caregivers about the risk of metabolic changes and the need for specific monitoring.

The risks include hyperglycemia and diabetes mellitus, dyslipidemia, weight gain, and cardiovascular reactions.

Educate patients and caregivers about the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus (e.g., polydipsia, polyuria, polyphagia, and weakness).

Monitor all patients for these symptoms.

Patients who are diagnosed with diabetes or have risk factors for diabetes (obesity, family history of diabetes) should have their fasting blood glucose monitored before beginning treatment and periodically during treatment.

Patients who develop symptoms of hyperglycemia should have assessments of fasting glucose.

Clinical monitoring of weight is recommended .

Metabolic Changes (hyperglycemia and diabetes mellitus, dyslipidemia, weight gain): [see Warnings and Precautions (5.9)] Because CLOZARIL may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that CLOZARIL therapy does not affect them adversely .

Interference with Cognitive and Motor Performance: [see Warnings and Precautions (5.14)] Inform patients and caregivers that if the patient misses taking CLOZARIL for more than 2 days, they should not restart their medication at the same dosage but should contact their physician for dosing instructions adversely .

Missed Doses and Re-initiating Treatment: [see Dosage and Administration (2.5) and Warnings and Precautions (5.3)] Patients and caregivers should notify the clinician if the patient becomes pregnant or intends to become pregnant during therapy .

Pregnancy: [see Use in Specific Populations (8.1)] Advice patients and caregivers that the patient should not breast feed an infant if they are taking CLOZARIL [see Use in Specific Populations (8.3)].

Nursing: Advise patients to inform their health care provider if they are taking, or plan to take, any prescription or over-the-counter drugs; there is a potential for significant drug-drug interactions .

Concomitant Medication: [see Dosage and Administrations (2.6) and Drug Interactions (7.1)] *Zyprexa® (olanzapine) is a registered trademark of Eli Lilly and Company.

**Trademark of Thomson Healthcare, Inc.

CLOZARIL® is a registered trademark of Novartis Pharmaceuticals Corporation.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2013-114 November 2013

DOSAGE AND ADMINISTRATION

2 Starting Dose: 12.5 mg once daily or twice daily.

( ) 2.2 Use cautious titration and divided dosage schedule.

( , ) 2.2 5.3 Titration: increase the total daily dosage in increments of 25 mg to 50 mg per day, if well-tolerated.

( ) 2.2 Target dose: 300 mg to 450 mg per day, in divided doses, by the end of 2 weeks.

( ) 2.2 Subsequent increases: increase in increments of 100 mg or less, once or twice weekly.

( ) 2.2 Maximum daily dose: 900 mg ( ) 2.2 2.1 Required Laboratory Testing Prior to Initiation and During Therapy Prior to initiating treatment with CLOZARIL, obtain a complete blood count (CBC) with differential.

The absolute neutrophil count (ANC) must be greater than or equal to 2000/mm and the WBC must be greater than or equal to 3500 mm in order to initiate treatment.

To continue treatment, the ANC and WBC must be monitored regularly .

3 3 [see Warnings and Precautions (5.1)] 2.2 Dosing Information The starting dose is 12.5 mg once daily or twice daily.

The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to achieve a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks.

Subsequently, the dose can be increased once weekly or twice weekly, in increments of up to 100 mg.

The maximum dose is 900 mg per day.

To minimize the risk of orthostatic hypotension, bradycardia, and syncope, it is necessary to use this low starting dose, gradual titration schedule, and divided dosages .

[see Warnings and Precautions (5.3)] CLOZARIL can be taken with or without food .

[see Pharmacokinetics (12.3)] 2.3 Maintenance Treatment Generally, it is recommended that patients responding to CLOZARIL continue maintenance treatment on their effective dose beyond the acute episode.

2.4 Discontinuation of Treatment In the event of planned termination of CLOZARIL therapy, reduce the dose gradually over a period of 1 to 2 weeks.

If abrupt discontinuation is necessary (because of agranulocytosis or another medical condition, for example), monitor carefully for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting, and diarrhea.

2.5 Re-Initiation of Treatment When restarting CLOZARIL in patients who have discontinued CLOZARIL (i.e., 2 days or more since the last dose), re-initiate with 12.5-mg once daily or twice daily.

This is necessary to minimize the risk of hypotension, bradycardia, and syncope .

If that dose is well tolerated, the dose may be increased to the previously therapeutic dose more quickly than recommended for initial treatment.

[see Warnings and Precautions (5.3)] 2.6 Dosage Adjustments with Concomitant use of CYP1A2, CYP2D6, CYP3A4 Inhibitors or CYP1A2, CYP3A4 Inducers Dose adjustments may be necessary in patients with concomitant use of: strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin); moderate or weak CYP1A2 inhibitors (e.g., oral contraceptives, or caffeine); CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline); CYP3A4 inducers (e.g., phenytoin, carbamazepine, St.

John’s wort, and rifampin); or CYP1A2 inducers (e.g., tobacco smoking) (Table 1) .

[see Drug Interactions (7)] Table 1.

Dose Adjustment in Patients Taking Concomitant Medications Comedications Scenarios Initiating CLOZARIL while taking a comedication Adding a comedication while taking CLOZARIL Discontinuing a comedication while continuing CLOZARIL Strong CYP1A2 Inhibitors Use one-third of the CLOZARIL dose.

Increase CLOZARIL dose based on clinical response.

Moderate or Weak CYP1A2 Inhibitors Monitor for adverse reactions.

Consider reducing the CLOZARIL dose if necessary.

Monitor for lack of effectiveness.

Consider increasing CLOZARIL dose if necessary.

CYP2D6 or CYP3A4 Inhibitors Strong CYP3A4 Inducers Concomitant use is not recommended.

However, if the inducer is necessary, it may be necessary to increase the CLOZARIL dose.

Monitor for decreased effectiveness.

Reduce CLOZARIL dose based on clinical response.

Moderate or weak CYP1A2 or CYP3A4 Inducers Monitor for decreased effectiveness.

Consider increasing the CLOZARIL dose if necessary.

Monitor for adverse reactions.

Consider reducing the CLOZARIL dose if necessary.

2.7 Renal or Hepatic Impairment or CYP2D6 Poor Metabolizers It may be necessary to reduce the CLOZARIL dose in patients with significant renal or hepatic impairment, or in CYP2D6 poor metabolizers .

[see Use in Specific Populations (8.6, 8.7)]

DRUG INTERACTIONS

7 Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, phenobarbital, primidone, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance.

Therefore increased monitoring of valproate and concomitant drug concentrations and dosage adjustment are indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn ( 7.1 ) Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations is recommended ( 7.1 ) Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g.

diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement ( 7.2 ) Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine may be necessary if used concomitantly with valproic acid capsules ( 7.2 ) Topiramate: Hyperammonemia and encephalopathy ( 5.11 , 7.3 ) 7.1 Effects of Co-Administered Drugs on Valproate Clearance Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase the clearance of valproate.

For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate.

Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs.

In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation.

Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn.

The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics.

The list is not exhaustive nor could it be, since new interactions are continuously being reported.

Drugs for which a potentially important interaction has been observed Aspirin A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of metabolism of valproate.

Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone.

The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin.

Caution should be observed if valproate and aspirin are to be co-administered.

Carbapenem Antibiotics A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control.

The mechanism of this interaction is not well understood.

Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy.

Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.14) ] .

Felbamate A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone.

Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase).

A decrease in valproate dosage may be necessary when felbamate therapy is initiated.

Rifampin A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate.

Valproate dosage adjustment may be necessary when it is co-administered with rifampin.

Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Antacids A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac – 160 mEq doses) did not reveal any effect on the extent of absorption of valproate.

Chlorpromazine A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate.

Haloperidol A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels.

Cimetidine and Ranitidine Cimetidine and ranitidine do not affect the clearance of valproate.

7.2 Effects of Valproate on Other Drugs Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronyltransferases.

The following list provides information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications.

The list is not exhaustive, since new interactions are continuously being reported.

Drugs for which a potentially important valproate interaction has been observed Amitriptyline/Nortriptyline Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline.

Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received.

Concurrent use of valproate and amitriptyline has rarely been associated with toxicity.

Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline.

Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate.

Carbamazepine/carbamazepine-10,11-Epoxide Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients.

Clonazepam The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures.

Diazepam Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.

Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n = 6).

Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate.

The elimination half-life of diazepam remained unchanged upon addition of valproate.

Ethosuximide Valproate inhibits the metabolism of ethosuximide.

Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone.

Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs.

Lamotrigine In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase).

The dose of lamotrigine should be reduced when co-administered with valproate.

Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration.

See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration.

Phenobarbital Valproate was found to inhibit the metabolism of phenobarbital.

Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose).

The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate.

There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations.

All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity.

Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.

Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate.

Phenytoin Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism.

Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin.

Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate.

Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%.

In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin.

The dosage of phenytoin should be adjusted as required by the clinical situation.

Tolbutamide From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate.

The clinical relevance of this displacement is unknown.

Warfarin In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%.

The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants.

Zidovudine In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected.

Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Acetaminophen Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients.

Clozapine In psychotic patients (n = 11), no interaction was observed when valproate was co-administered with clozapine.

Lithium Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.

Lorazepam Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.

Oral Contraceptive Steroids Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction.

7.3 Topiramate Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.10 , 5.11) ] .

Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone.

It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.10 , 5.12) ] .

OVERDOSAGE

10 Overdosage with valproate may result in somnolence, heart block, and deep coma.

Fatalities have been reported; however, patients have recovered from valproate levels as high as 2120 mcg/mL.

In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug.

The benefit of gastric lavage or emesis will vary with the time since ingestion.

General supportive measures should be applied with particular attention to the maintenance of adequate urinary output.

Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.

Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy.

DESCRIPTION

11 Valproic acid is a carboxylic acid designated as 2-propylpentanoic acid.

It is also known as dipropylacetic acid.

Valproic acid has the following structure: Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a characteristic odor.

It is slightly soluble in water (1.3 mg/mL) and very soluble in organic solvents.

Valproic Acid Capsules, USP are antiepileptics for oral administration.

Each soft gelatin capsule contains 250 mg valproic acid.

Inactive Ingredients Peanut oil, gelatin, glycerin and titanium dioxide Chemical Structure

CLINICAL STUDIES

14 The studies described in the following section were conducted using divalproex sodium tablets.

14.1 Epilepsy The efficacy of divalproex sodium tablets in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials.

In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the “therapeutic range” were randomized to receive, in addition to their original antiepilepsy drug (AED), either divalproex sodium tablets or placebo.

Randomized patients were to be followed for a total of 16 weeks.

The following Table presents the findings.

Table 5.

Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks Add-on Treatment Number of Patients Baseline Incidence Experimental Incidence Divalproex Sodium Tablets 75 16.0 8.9 Reduction from baseline statistically significantly greater for divalproex sodium tablets than placebo at p ≤ 0.05 level.

Placebo 69 14.5 11.5 Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study.

A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening.

Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo.

This Figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for divalproex sodium tablets than for placebo.

For example, 45% of patients treated with divalproex sodium tablets had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo.

Figure 1 The second study assessed the capacity of divalproex sodium tablets to reduce the incidence of CPS when administered as the sole AED.

The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm.

Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to divalproex sodium tablets.

Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks.

Less than 50% of the patients randomized, however, completed the study.

In patients converted to divalproex sodium tablets monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively.

The following Table presents the findings for all patients randomized who had at least one post-randomization assessment.

Table 6.

Monotherapy Study Median Incidence of CPS per 8 Weeks Treatment Number of Patients Baseline Incidence Randomized Phase Incidence High dose 131 13.2 10.7 Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level.

Divalproex Sodium Tablets Low dose 134 14.2 13.8 Divalproex Sodium Tablets Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study.

A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening.

Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment.

This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose divalproex sodium tablets than for low dose divalproex sodium tablets.

For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose divalproex sodium tablets monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose divalproex sodium tablets.

Figure 2 Figure 1 Figure 2

HOW SUPPLIED

16 /STORAGE AND HANDLING Repackaged by Aphena Pharma Solutions – TN.

See Repackaging Information for available configurations.

Valproic Acid Capsules, USP 250 mg are off-white colored soft gelatin capsules, imprinted with “U-S 250”, containing Valproic Acid, USP, and packaged in bottles of 100 capsules (NDC 0832-1008-11).

Store at 20-25°C (68-77°F).

Excursions permitted to 15-30°C (59-86°F).

[See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container with a child-resistant closure.

RECENT MAJOR CHANGES

Boxed Warning, Hepatotoxicity 05/2013 Boxed Warning, Fetal Risk 05/2013 Indications and Usage, Important Limitations ( 1.2 ) 05/2013 Contraindications, Known or Suspected Mitochondrial Disorders ( 4 ) 05/2013 Warnings and Precautions, Hepatotoxicity ( 5.1 ) 05/2013 Warnings and Precautions, Birth Defects ( 5.2 ) 05/2013 Warnings and Precautions, Decreased IQ ( 5.3 ) 05/2013 Warnings and Precautions, Use in Women of Childbearing Potential ( 5.4 ) 05/2013 Warnings and Precautions, Brain Atrophy ( 5.7 ) 05/2013

GERIATRIC USE

8.5 Geriatric Use No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness.

In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age.

A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor.

Discontinuation of valproate was occasionally associated with the latter two events.

It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients.

A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.15) ] .

The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.2) ] .

DOSAGE FORMS AND STRENGTHS

3 Valproic acid capsules are supplied as 250 mg off-white colored soft gelatin capsules, imprinted with “U-S 250”, packaged in bottles containing 100.

Capsules: 250 mg valproic acid

MECHANISM OF ACTION

12.1 Mechanism of Action Valproic acid dissociates to the valproate ion in the gastrointestinal tract.

The mechanisms by which valproate exerts its antiepileptic effects have not been established.

It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).

INDICATIONS AND USAGE

1 Valproic Acid Capsules, USP are an anti-epileptic drug indicated for: Monotherapy and adjunctive therapy of complex partial seizures; sole and adjunctive therapy of simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures ( 1 ) 1.1 Epilepsy Valproic Acid Capsules, USP are indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures.

Valproic Acid Capsules, USP are indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types which include absence seizures.

Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs.

Complex absence is the term used when other signs are also present.

See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.

1.2 Important Limitations Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition [see Warnings and Precautions (5.2 , 5.3 , 5.4) , Use in Specific Populations (8.1) , and Patient Counseling Information (17.3) ].

PEDIATRIC USE

8.4 Pediatric Use Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning ] .

When valproic acid capsules are used in this patient group, it should be used with extreme caution and as a sole agent.

The benefits of therapy should be weighed against the risks.

Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproic acid concentrations.

Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults.

Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.

The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations.

Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding.

Pediatric Clinical Trials Divalproex sodium tablets were studied in seven pediatric clinical trials.

Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of divalproex sodium tablets ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on divalproex sodium tablets ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on divalproex sodium tablets ER).

Efficacy was not established for either the treatment of migraine or the treatment of mania.

The most common drug-related adverse reactions (reported >5% and twice the rate of placebo) reported in the controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash.

The remaining five trials were long term safety studies.

Two six-month pediatric studies were conducted to evaluate the long-term safety of divalproex sodium tablets ER for the indication of mania (292 patients aged 10 to 17 years).

Two twelve-month pediatric studies were conducted to evaluate the long-term safety of divalproex sodium tablets ER for the indication of migraine (353 patients aged 12 to 17 years).

One twelve-month study was conducted to evaluate the safety of divalproex sodium sprinkle capsules in the indication of partial seizures (169 patients aged 3 to 10 years).

In these seven trials, the safety and tolerability of divalproex sodium tablets in pediatric patients were shown to be comparable to those in adults [see Adverse Reactions (6) ] .

Juvenile Animal Toxicology In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.

The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m 2 basis.

PREGNANCY

8.1 Pregnancy Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2 , 5.3) ] .

Pregnancy Registry To collect information on the effects of in utero exposure to valproic acid, physicians should encourage pregnant patients taking valproic acid capsules to enroll in the NAAED Pregnancy Registry.

This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves.

Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/.

Fetal Risk Summary All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure.

Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations).

The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy.

The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies [see Warnings and Precautions (5.3) ] .

Exposure in utero to valproate products has been associated with cerebral atrophy [see Warnings and Precautions (5.7) and Adverse Reactions (6.4) ] .

Several published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero [see Warnings and Precautions (5.3) ] .

In animal studies, offspring with prenatal exposure to valproate had structural malformations similar to those seen in humans and demonstrated neurobehavioral deficits.

Clinical Considerations Neural tube defects are the congenital malformation most strongly associated with maternal valproate use.

The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births).

Valproate can cause decreased IQ scores in children whose mothers were treated with valproate during pregnancy.

Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events, which may occur very early in pregnancy: Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition.

This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine).

Valproic acid capsules should not be used to treat women with epilepsy who are pregnant or who plan to become pregnant unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable.

In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks.

When treating a pregnant woman or a woman of childbearing potential, carefully consider both the potential risks and benefits of treatment and provide appropriate counseling.

To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life.

Even minor seizures may pose some hazard to the developing embryo or fetus.

However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient.

Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate.

Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population.

It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation.

Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate.

Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.9) ] .

A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage.

If valproate is used in pregnancy, the clotting parameters should be monitored carefully.

Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and Precautions (5.1) ] .

Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy.

Data Human There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities.

Based on published data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%.

The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to 2%.

In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal valproate exposure were reported among offspring of 149 enrolled women who used valproate during pregnancy.

Three of the 16 cases were neural tube defects; the remaining cases included craniofacial defects, cardiovascular malformations and malformations of varying severity involving other body systems.

The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I.

6.3% – 16.9%) in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500-2000 mg/day).

The major malformation rate among the internal comparison group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy was 2.9% (95% CI 2.0% to 4.1%).

These data show a four-fold increased risk for any major malformation (Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk following exposure in utero to any other antiepileptic drug monotherapy.

Published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero .

The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I.

94-101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I.

105-110]), carbamazepine (105 [95% C.I.

102-108]) and phenytoin (108 [95% C.I.

104-112]).

It is not known when during pregnancy cognitive effects in valproate-exposed children occur.

Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed.

Although all of the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on cognitive development.

There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy.

Animal In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body surface area basis).

Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects.

In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels.

Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate.

NUSRING MOTHERS

8.3 Nursing Mothers Valproate is excreted in human milk.

Caution should be exercised when valproate is administered to a nursing woman.

BOXED WARNING

WARNING: LIFE THREATENING ADVERSE REACTIONS WARNINGS: LIFE THREATENING ADVERSE REACTIONS See full prescribing information for complete boxed warning Hepatotoxicity, including fatalities, usually during first 6 months of treatment.

Children under the age of two years and patients with mitochondrial disorders are at higher risk.

Monitor patients closely, and perform serum liver testing prior to therapy and at frequent intervals thereafter ( 5.1 ) Fetal Risk, particularly neural tube defects, other major malformations, and decreased IQ ( 5.2 , 5.3 , 5.4 ) Pancreatitis, including fatal hemorrhagic cases ( 5.5 ) Hepatotoxicity General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate.

These incidents usually have occurred during the first six months of treatment.

Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting.

In patients with epilepsy, a loss of seizure control may also occur.

Patients should be monitored closely for appearance of these symptoms.

Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1) ] .

Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease.

When valproic acid products are used in this patient group, they should be used with extreme caution and as a sole agent.

The benefits of therapy should be weighed against the risks.

The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.

Alpers Huttenlocher Syndrome).

Valproic acid is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4) ] .

In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, valproic acid should only be used after other anticonvulsants have failed.

This older group of patients should be closely monitored during treatment with valproic acid for the development of acute liver injury with regular clinical assessments and serum liver testing.

POLG mutation screening should be performed in accordance with current clinical practice [see Warnings and Precautions (5.1) ] .

Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida).

In addition, valproate can cause decreased IQ scores following in utero exposure.

Valproate should only be used to treat pregnant women with epilepsy if other medications have failed to control their symptoms or are otherwise unacceptable.

Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition.

This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine).

Women should use effective contraception while using valproate [see Warnings and Precautions (5.2 , 5.3 , 5.4) ] .

A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information (17) ] .

Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate.

Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death.

Cases have been reported shortly after initial use as well as after several years of use.

Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation.

If pancreatitis is diagnosed, valproate should ordinarily be discontinued.

Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions (5.5) ] .

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Hepatotoxicity; evaluate high risk populations and monitor serum liver tests ( 5.1 ) Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG) ( 4 , 5.1 ) Suspected POLG-related disorder in children under two years of age ( 4 , 5.1 ) Birth defects and decreased IQ following in utero exposure; only use to treat pregnant women with epilepsy if other medications are unacceptable; should not be administered to a woman of childbearing potential unless essential ( 5.2 , 5.3 , 5.4 ) Pancreatitis; valproic acid capsules should ordinarily be discontinued ( 5.5 ) Brain Atrophy; evaluate for continued use in the presence of suspected or apparent signs of reversible or irreversible cerebral and cerebellar atrophy ( 5.6 ) Suicidal behavior or ideation; Antiepileptic drugs, including valproic acid capsules, increase the risk of suicidal thoughts or behavior ( 5.8 ) Thrombocytopenia; monitor platelet counts and coagulation tests ( 5.9 ) Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status ( 5.10 , 5.11 ) Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia.

This adverse reaction can also occur in patients using concomitant topiramate ( 5.12 ) Multi-organ hypersensitivity reaction; discontinue valproic acid capsules ( 5.13 ) Somnolence in the elderly can occur.

Valproic acid capsules dosage should be increased slowly and with regular monitoring for fluid and nutritional intake ( 5.15 ) 5.1 Hepatotoxicity General Information on Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate.

These incidents usually have occurred during the first six months of treatment.

Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting.

In patients with epilepsy, a loss of seizure control may also occur.

Patients should be monitored closely for appearance of these symptoms.

Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months.

However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination.

Caution should be observed when administering valproate products to patients with a prior history of hepatic disease.

Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk.

See below, “Patients with Known or Suspected Mitochondrial Disease.” Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.

When valproic acid capsules products are used in this patient group, they should be used with extreme caution and as a sole agent.

The benefits of therapy should be weighed against the risks.

In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably.

Patients with Known or Suspected Mitochondrial Disease Valproic acid capsules are contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4) ] .

Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-Huttenlocher Syndrome) at a higher rate than those without these syndromes.

Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents.

POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura.

POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders.

The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders.

In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, valproic acid capsules should only be used after other anticonvulsants have failed.

This older group of patients should be closely monitored during treatment with valproic acid capsules for the development of acute liver injury with regular clinical assessments and serum liver test monitoring.

The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent.

In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug [see Boxed Warning and Contraindications (4) ] .

5.2 Birth Defects Valproate can cause fetal harm when administered to a pregnant woman.

Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations and malformations involving various body systems).

The rate of congenital malformations among babies born to mothers using valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies.

Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population.

5.3 Decreased IQ Following in utero Exposure Valproate can cause decreased IQ scores following in utero exposure.

Published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic drugs.

The largest of these studies 1 is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I.

94-101]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I.

105-110]), carbamazepine (105 [95% C.I.

102-108]), and phenytoin (108 [95% C.I.

104-112]).

It is not known when during pregnancy cognitive effects in valproate-exposed children occur.

Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed.

Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero can cause decreased IQ in children.

In animal studies, offspring with prenatal exposure to valproate had malformations similar to those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific Populations (8.1) ] .

Women with epilepsy who are pregnant or who plan to become pregnant should not be treated with valproate unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable.

In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks.

5.4 Use in Women of Childbearing Potential Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural tube defects), which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition.

This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine).

Women should use effective contraception while using valproate.

Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients [see Boxed Warning and Use in Specific Populations (8.1) ] .

To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life.

Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population.

It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation.

Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate.

5.5 Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate.

Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death.

Some cases have occurred shortly after initial use as well as after several years of use.

The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate.

In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416 patients, representing 1044 patient-years experience.

Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation.

If pancreatitis is diagnosed, valproate should ordinarily be discontinued.

Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed Warning ] .

5.6 Urea Cycle Disorders (UCD) Valproic acid is contraindicated in patients with known urea cycle disorders.

Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency.

Prior to the initiation of valproate therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD.

Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.11) ] .

5.7 Brain Atrophy There have been postmarketing reports of reversible and irreversible cerebral and cerebellar atrophy temporally associated with the use valproate products; in some cases, patients recovered with permanent sequelae [see Adverse Reactions (6.4) ] .

The motor and cognitive functions of patients on valproate should be routinely monitored and drug should be evaluated for continued use in the presence of suspected or apparent signs of brain atrophy.

Reports of cerebral atrophy have also been reported in children who were exposed in utero to valproate products [see Use in Specific Populations (8.1) ] .

5.8 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including valproic acid capsules, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.

In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.

There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed.

Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.

The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.

The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.

Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

Table 2.

Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing valproic acid capsules or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.

Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.

Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Behaviors of concern should be reported immediately to healthcare providers.

5.9 Thrombocytopenia The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may be dose-related.

In a clinical trial of divalproex sodium as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 × 10 9 /L.

Approximately half of these patients had treatment discontinued, with return of platelet counts to normal.

In the remaining patients, platelet counts normalized with continued treatment.

In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males).

The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects.

Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals.

It is recommended that patients receiving valproic acid capsules be monitored for platelet count and coagulation parameters prior to planned surgery.

Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.

5.10 Hyperammonemia Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests.

In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.

Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and Precautions (5.12) ] .

If ammonia is increased, valproate therapy should be discontinued.

Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6 , 5.11) ] .

Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels.

If the elevation persists, discontinuation of valproate therapy should be considered.

5.11 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone.

Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting.

Hypothermia can also be a manifestation of hyperammonemia [see Warnings and Precautions (5.12) ] .

In most cases, symptoms and signs abated with discontinuation of either drug.

This adverse reaction is not due to a pharmacokinetic interaction.

It is not known if topiramate monotherapy is associated with hyperammonemia.

Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy.

Although not studied, an interaction of topiramate and valproate may exacerbate existing defects or unmask deficiencies in susceptible persons.

In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.6 , 5.10) ] .

5.12 Hypothermia Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia.

This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3) ] .

Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems.

Clinical management and assessment should include examination of blood ammonia levels.

5.13 Multi-Organ Hypersensitivity Reactions Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days).

Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported.

Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement.

Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia.

Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur.

If this reaction is suspected, valproate should be discontinued and an alternative treatment started.

Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.

5.14 Interaction with Carbapenem Antibiotics Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control.

Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy.

Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates [see Drug Interactions (7.1) ] .

5.15 Somnolence in the Elderly In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day.

A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration.

Discontinuations for somnolence were also significantly higher than with placebo.

In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss.

There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN.

In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions.

Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see Dosage and Administration (2.2) ] .

5.16 Monitoring: Drug Plasma Concentration Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see Drug Interactions (7) ] .

5.17 Effect on Ketone and Thyroid Function Tests Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test.

There have been reports of altered thyroid function tests associated with valproate.

The clinical significance of these is unknown.

5.18 Effect on HIV and CMV Viruses Replication There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions.

The clinical consequence, if any, is not known.

Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy.

Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-Approved Medication Guide 17.1 Hepatotoxicity Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.1) ] .

17.2 Pancreatitis Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.5) ] .

17.3 Birth Defects and Decreased IQ Inform pregnant women and women of childbearing potential that use of valproate during pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.

Advise women to use effective contraception while using valproate.

When appropriate, counsel these patients about alternative therapeutic options.

This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death.

Advise patients to read the Medication Guide, which appears as the last section of the labeling [see Warnings and Precautions (5.2 , 5.3 , 5.4) and Use in Specific Populations (8.1) ] .

Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact their doctor immediately if they think they are pregnant.

Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant.

This registry is collecting information about the safety of antiepileptic drugs during pregnancy.

To enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations (8.1) ] .

17.4 Suicidal Thinking and Behavior Counsel patients, their caregivers, and families that AEDs, including valproic acid capsules, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Instruct patients, caregivers, and families to report behaviors of concern immediately to the healthcare providers [see Warnings and Precautions (5.8) ].

17.5 Hyperammonemia Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.10 , 5.11) ] .

17.6 CNS Depression Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug.

17.7 Multi-Organ Hypersensitivity Reactions Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see Warnings and Precautions (5.13) ] .

DOSAGE AND ADMINISTRATION

2 Valproic acid capsules are intended for oral administration.

( 2.1 ) Simple and Complex Absence Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/week until seizure control or limiting side effects ( 2.1 ) Safety of doses above 60 mg/kg/day is not established ( 2.1 , 2.2 ) 2.1 Epilepsy Valproic acid capsules are intended for oral administration.

Valproic acid capsules should be swallowed whole without chewing to avoid local irritation of the mouth and throat.

Patients should be informed to take valproic acid capsules every day as prescribed.

If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose.

If a dose is skipped, the patient should not double the next dose.

Valproic acid capsules are indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures.

As the valproic acid capsules dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2) ] .

Complex Partial Seizures For adults and children 10 years of age or older.

Monotherapy (Initial Therapy) Valproic acid capsules have not been systematically studied as initial therapy.

Patients should initiate therapy at 10 to 15 mg/kg/day.

The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response.

Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day.

If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL).

No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males.

The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

Conversion to Monotherapy Patients should initiate therapy at 10 to 15 mg/kg/day.

The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response.

Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day.

If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL).

No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks.

This reduction may be started at initiation of valproic acid capsules therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction.

The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.

Adjunctive Therapy Valproic acid capsules may be added to the patient’s regimen at a dosage of 10 to 15 mg/kg/day.

The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response.

Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day.

If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL).

No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

If the total daily dose exceeds 250 mg, it should be given in divided doses.

In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to divalproex sodium tablets, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14) ] .

However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7) ] .

Simple and Complex Absence Seizures The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases.

The maximum recommended dosage is 60 mg/kg/day.

If the total daily dose exceeds 250 mg, it should be given in divided doses.

A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect.

However, therapeutic valproate serum concentration for most patients with absence seizures is considered to range from 50 to 100 mcg/mL.

Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3) ].

As the valproic acid capsules dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2) ] .

Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.

The following Table is a guide for the initial daily dose of valproic acid capsules (15 mg/kg/day): Table 1.

Initial Daily Dose Weight Total Daily Dose (mg) Number of Capsules (Kg) (Lb) Dose 1 Dose 2 Dose 3 10 – 24.9 22 – 54.9 250 0 0 1 25 – 39.9 55 – 87.9 500 1 0 1 40 – 59.9 88 – 131.9 750 1 1 1 60 – 74.9 132 – 164.9 1,000 1 1 2 75 – 89.9 165 – 197.9 1,250 2 1 2 2.2 General Dosing Advice Dosing in Elderly Patients Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients.

Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions.

Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence.

The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.15) , Use in Specific Populations (8.5) and Clinical Pharmacology (12.3) ] .

Dose-Related Adverse Reactions The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related.

The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.9) ] .

The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

G.I.

Irritation Patients who experience G.I.

irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.

Generic Name: MEROPENEM
Brand Name: MEROPENEM
  • Substance Name(s):
  • MEROPENEM

DRUG INTERACTIONS

7 Co-administration of meropenem with probenecid inhibits renal excretion of meropenem and is therefore not recommended.

( 7.1 ) The concomitant use of meropenem and valproic acid or divalproex sodium is generally not recommended.

Antibacterial drugs other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium.

( 5.4 , 7.2 ) 7.1 Probenecid Probenecid competes with meropenem for active tubular secretion, resulting in increased plasma concentrations of meropenem.

Co-administration of probenecid with meropenem is not recommended.

7.2 Valproic Acid Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations.

The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures.

Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid.

If administration of meropenem is necessary, then supplemental anti-convulsant therapy should be considered [ see Warnings and Precautions (5.4) ] .

OVERDOSAGE

10 In mice and rats, large intravenous doses of meropenem (2200 mg/kg to 4000 mg/kg) have been associated with ataxia, dyspnea, convulsions, and mortalities.

Intentional overdosing of meropenem is unlikely, although accidental overdosing might occur if large doses are given to patients with reduced renal function.

The largest dose of meropenem administered in clinical trials has been 2 grams given intravenously every 8 hours.

At this dosage, no adverse pharmacological effects or increased safety risks have been observed.

Limited postmarketing experience indicates that if adverse events occur following overdosage, they are consistent with the adverse event profile described in the Adverse Reactions section and are generally mild in severity and resolve on withdrawal or dose reduction.

Consider symptomatic treatments.

In individuals with normal renal function, rapid renal elimination takes place.

Meropenem and its metabolite are readily dialyzable and effectively removed by hemodialysis; however, no information is available on the use of hemodialysis to treat overdosage.

DESCRIPTION

11 Meropenem for injection is a sterile, pyrogen-free, synthetic, carbapenem antibacterial for intravenous administration.

It is (4R,5S,6S)-3- [[(3S,5S)-5-(Dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxilic acid trihydrate.

Its empirical formula is C 17 H 25 N 3 O 5 S∙3H 2 O with a molecular weight of 437.52.

Its structural formula is: Meropenem for injection is a white to pale yellow crystalline powder.

The solution varies from colorless to yellow depending on the concentration.

The pH of freshly constituted solutions is between 7.3 and 8.3.

Meropenem is soluble in 5% monobasic potassium phosphate solution, sparingly soluble in water, very slightly soluble in hydrated ethanol, and practically insoluble in acetone or ether.

When re-constituted as instructed, each 1 gram meropenem for injection vial will deliver 1 gram of meropenem and 90.2 mg of sodium as sodium carbonate (3.92 mEq).

Each 500 mg meropenem for injection vial will deliver 500 mg meropenem and 45.1 mg of sodium as sodium carbonate (1.96 mEq) [ see Dosage and Administration (2.4) ] .

Chemical Structure

CLINICAL STUDIES

14 14.1 Complicated Skin and Skin Structure Infections Adult patients with complicated skin and skin structure infections including complicated cellulitis, complex abscesses, perirectal abscesses, and skin infections requiring intravenous antimicrobials, hospitalization, and surgical intervention were enrolled in a randomized, multi-center, international, double-blind trial.

The study evaluated meropenem at doses of 500 mg administered intravenously every 8 hours and imipenem-cilastatin at doses of 500 mg administered intravenously every 8 hours.

The study compared the clinical response between treatment groups in the clinically evaluable population at the follow-up visit (test-of-cure).

The trial was conducted in the United States, South Africa, Canada, and Brazil.

At enrollment, approximately 37% of the patients had underlying diabetes, 12% had underlying peripheral vascular disease and 67% had a surgical intervention.

The study included 510 patients randomized to meropenem and 527 patients randomized to imipenem-cilastatin.

Two hundred and sixty one (261) patients randomized to meropenem and 287 patients randomized to imipenem-cilastatin were clinically evaluable.

The success rates in the clinically evaluable patients at the follow-up visit were 86% (225/261) in the meropenem arm and 83% (238/287) in imipenem-cilastatin arm.

The success rates for the clinically evaluable population are provided in Table 7 .

Table 7: Success Rates at Test-of-Cure Visit for Clinically Evaluable Population with Complicated Skin and Skin Structure Infections Population Meropenem n n = number of patients with satisfactory response.

/N N = number of patients in the clinically evaluable population or respective subgroup within treatment groups.

(%) Imipenem-cilastatin n /N (%) Total 225/261 (86) 238/287 (83) Diabetes mellitus 83/97 (86) 76/105 (72) No diabetes mellitus 142/164 (87) 162/182 (89) Less than 65 years of age 190/218 (87) 205/241 (85) 65 years of age or older 35/43 (81) 33/46 (72) Men 130/148 (88) 137/172 (80) Women 95/113 (84) 101/115 (88) The clinical efficacy rates by pathogen are provided in Table 8.

The values represent the number of patients clinically cured/number of clinically evaluable patients at the post-treatment follow-up visit, with the percent cure in parentheses (Fully Evaluable analysis set).

Table 8: Clinical Efficacy Rate by Pathogen for Clinically Evaluable Population MICROORGANISMS Patients may have more than one pretreatment pathogen.

Meropenem n n = number of patients with satisfactory response.

/N N = number of patients in the clinically evaluable population or subgroup within treatment groups.

(%) % = Percent of satisfactory clinical response at follow-up evaluation.

Imipenem-cilastatin n /N (%) Gram-positive aerobes Staphylococcus aureus, methicillin susceptible 82/88 (93) 84/100 (84) Streptococcus pyogenes (Group A) 26/29 (90) 28/32 (88) Streptococcus agalactiae (Group B) 12/17 (71) 16/19 (84) Enterococcus faecalis 9/12 (75) 14/20 (70) Viridans group streptococci 11/12 (92) 5/6 (83) Gram-negative aerobes Escherichia coli 12/15 (80) 15/21 (71) Pseudomonas aeruginosa 11/15 (73) 13/15 (87) Proteus mirabilis 11/13 (85) 6/7 (86) Anaerobes Bacteroides fragilis 10/11 (91) 9/10 (90) Peptostreptococcus species 10/13 (77) 14/16 (88) The proportion of patients who discontinued study treatment due to an adverse event was similar for both treatment groups (meropenem, 2.5% and imipenem-cilastatin, 2.7%).

14.2 Complicated Intra-Abdominal Infections One controlled clinical study of complicated intra-abdominal infection was performed in the United States where meropenem was compared with clindamycin/tobramycin.

Three controlled clinical studies of complicated intra-abdominal infections were performed in Europe; meropenem was compared with imipenem (two trials) and cefotaxime/metronidazole (one trial).

Using strict evaluability criteria and microbiologic eradication and clinical cures at follow-up which occurred 7 or more days after completion of therapy, the presumptive microbiologic eradication/clinical cure rates and statistical findings are provided in Table 9: Table 9: Presumptive Microbiologic Eradication and Clinical Cure Rates at Test-of-Cure Visit in the Evaluable Population with Complicated Intra-Abdominal Infection Treatment Arm No.

evaluable/No.

enrolled (%) Microbiologic Eradication Rate Clinical Cure Rate Outcome meropenem 146/516 (28%) 98/146 (67%) 101/146 (69%) imipenem 65/220 (30%) 40/65 (62%) 42/65 (65%) meropenem equivalent to control cefotaxime/metronidazole 26/85 (30%) 22/26 (85%) 22/26 (85%) meropenem not equivalent to control clindamycin/tobramycin 50/212 (24%) 38/50 (76%) 38/50 (76%) meropenem equivalent to control The finding that meropenem was not statistically equivalent to cefotaxime/metronidazole may have been due to uneven assignment of more seriously ill patients to the meropenem arm.

Currently there is no additional information available to further interpret this observation.

14.3 Bacterial Meningitis Four hundred forty-six patients (397 pediatric patients 3 months to less than 17 years of age) were enrolled in 4 separate clinical trials and randomized to treatment with meropenem (n=225) at a dose of 40 mg/kg every 8 hours or a comparator drug, i.e., cefotaxime (n=187) or ceftriaxone (n=34), at the approved dosing regimens.

A comparable number of patients were found to be clinically evaluable (ranging from 61-68%) and with a similar distribution of pathogens isolated on initial CSF culture.

Patients were defined as clinically not cured if any one of the following three criteria were met: At the 5 to 7 week post-completion of therapy visit, the patient had any one of the following: moderate to severe motor, behavior or development deficits, hearing loss of greater than 60 decibels in one or both ears, or blindness.

During therapy the patient’s clinical status necessitated the addition of other antibacterial drugs.

Either during or post-therapy, the patient developed a large subdural effusion needing surgical drainage, or a cerebral abscess, or a bacteriologic relapse.

Using the definition, the following efficacy rates were obtained, per organism (noted in Table 10 ).

The values represent the number of patients clinically cured/number of clinically evaluable patients, with the percent cure in parentheses.

Table 10: Efficacy rates by Pathogen in the Clinically Evaluable Population with Bacterial Meningitis MICROORGANISMS Meropenem COMPARATOR S.

pneumoniae 17/24 (71) 19/30 (63) H.

influenzae (+) (+) β-lactamase-producing 8/10 (80) 6/6 (100) H.

influenzae (-/NT) (-/NT) non-β-lactamase-producing or not tested 44/59 (75) 44/60 (73) N.

meningitidis 30/35 (86) 35/39 (90) Total (including others) 102/131 (78) 108/140 (77) Sequelae were the most common reason patients were assessed as clinically not cured.

Five patients were found to be bacteriologically not cured, 3 in the comparator group (1 relapse and 2 patients with cerebral abscesses) and 2 in the meropenem group (1 relapse and 1 with continued growth of Pseudomonas aeruginosa ).

With respect to hearing loss, 263 of the 271 evaluable patients had at least one hearing test performed post-therapy.

The following Table 11 shows the degree of hearing loss between the meropenem-treated patients and the comparator-treated patients.

Table 11: Hearing Loss at Post-Therapy in the Evaluable Population Treated with Meropenem Degree of Hearing Loss (in one or both ears) Meropenem n = 128 Comparator n = 135 No loss 61% 56% 20-40 decibels 20% 24% Greater than 40-60 decibels 8% 7% Greater than 60 decibels 9% 10%

HOW SUPPLIED

16 /STORAGE AND HANDLING Meropenem for injection is supplied in 20 mL and 30 mL injection vials containing sufficient meropenem to deliver 500 mg or 1 gram for intravenous administration, respectively.

The dry powder should be stored at controlled room temperature 20º to 25ºC (68º to 77ºF) [see USP].

500 mg Injection Vial (NDC 0781-3000-94) and packaged in cartons of 10 vials (NDC 0781-3000-95) and cartons of 25 vials (NDC 0781-3000-96).

1 gram Injection Vial (NDC 0781-3098-94) and packaged in cartons of 10 vials (NDC 0781-3098-95) and cartons of 25 vials (NDC 0781-3098-96).

GERIATRIC USE

8.5 Geriatric Use Of the total number of subjects in clinical studies of meropenem, approximately 1100 (30%) were 65 years of age and older, while 400 (11%) were 75 years and older.

Additionally, in a study of 511 patients with complicated skin and skin structure infections, 93 (18%) were 65 years of age and older, while 38 (7%) were 75 years and older.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects; spontaneous reports and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Meropenem is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

A pharmacokinetic study with meropenem in elderly patients has shown a reduction in the plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance [ see Clinical Pharmacology (12.3) ] .

DOSAGE FORMS AND STRENGTHS

3 Single dose clear glass vials of meropenem for injection containing 500 mg or 1 gram (as the trihydrate blended with anhydrous sodium carbonate for re-constitution) of sterile meropenem powder.

500 mg Meropenem for Injection Vial ( 3 ) 1 gram Meropenem for Injection Vial ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Meropenem is an antibacterial drug [ see Microbiology (12.4) ] .

INDICATIONS AND USAGE

1 Meropenem for injection is a penem antibacterial indicated for the treatment of: Complicated skin and skin structure infections (adult patients and pediatric patients 3 months of age and older only).

( 1.1 ) Complicated intra-abdominal infections (adult and pediatric patients).

( 1.2 ) Bacterial meningitis (pediatric patients 3 months of age and older only).

( 1.3 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of meropenem for injection and other antibacterial drugs, meropenem for injection should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

1.1 Complicated Skin and Skin Structure Infections (Adult Patients and Pediatric Patients 3 Months of age and older only) Meropenem for injection is indicated for the treatment of complicated skin and skin structure infections (cSSSI) due to Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus pyogenes, Streptococcus agalactiae , viridans group streptococci, Enterococcus faecalis (vancomycin-susceptible isolates only), Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Bacteroides fragilis, and Peptostreptococcus species .

1.2 Complicated Intra-abdominal Infections (Adult and Pediatric Patients) Meropenem for injection is indicated for the treatment of complicated appendicitis and peritonitis caused by viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B.

thetaiotaomicron, and Peptostreptococcus species .

1.3 Bacterial Meningitis (Pediatric Patients 3 Months of age and older only) Meropenem for injection is indicated for the treatment of bacterial meningitis caused by Haemophilus influenzae , and Neisseria meningitidis and penicillin-susceptible isolates of Streptococcus pneumoniae.

Meropenem for injection has been found to be effective in eliminating concurrent bacteremia in association with bacterial meningitis.

1.4 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of meropenem for injection and other antibacterial drugs, meropenem for injection should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.

In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of meropenem have been established for pediatric patients 3 months of age and older with complicated skin and skin structure infections and bacterial meningitis, and for pediatric patients of all ages with complicated intra-abdominal infections.

Skin and Skin Structure Infections Use of meropenem in pediatric patients 3 months of age and older with complicated skin and skin structure infections is supported by evidence from an adequate and well-controlled study in adults and additional data from pediatric pharmacokinetics studies [ see Indications and Usage (1.3) , Dosage and Administration (2.3) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.1) ] .

Intra-abdominal Infections Use of meropenem in pediatric patients 3 months of age and older with intra-abdominal infections is supported by evidence from adequate and well-controlled studies in adults with additional data from pediatric pharmacokinetics studies and controlled clinical trials in pediatric patients.

Use of meropenem in pediatric patients less than 3 months of age with intra-abdominal infections is supported by evidence from adequate and well-controlled studies in adults with additional data from a pediatric pharmacokinetic and safety study [ see Indications and Usage (1.2) , Dosage and Administration (2.3) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14.2) ] .

Bacterial Meningitis Use of meropenem in pediatric patients 3 months of age and older with bacterial meningitis is supported by evidence from adequate and well-controlled studies in the pediatric population [ see Indications and Usage (1.3) , Dosage and Administration (2.3) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.3) ] .

PREGNANCY

8.1 Pregnancy Risk Summary There are insufficient human data to establish whether there is a drug-associated risk of major birth defects or miscarriages with meropenem in pregnant women.

No fetal toxicity or malformations were observed in pregnant rats and Cynomolgus monkeys administered intravenous meropenem during organogenesis at doses up to 2.4 and 2.3 times the maximum recommended human dose (MRHD) based on body surface area comparison, respectively.

In rats administered intravenous meropenem in late pregnancy and during the lactation period, there were no adverse effects on offspring at doses equivalent to approximately 3.2 times the MRHD based on body surface area comparison (see Data ).

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data Meropenem administered to pregnant rats during organogenesis (Gestation Day 6 to Gestation Day 17) in intravenous doses of 240, 500, and 750 mg/kg/day was associated with mild maternal weight loss at all doses, but did not produce malformations or fetal toxicity.

The no-observed-adverse-effect-level (NOAEL) for fetal toxicity in this study was considered to be the high dose of 750 mg/kg/day (equivalent to approximately 2.4 times the MRHD of 1 gram every 8 hours based on body surface area comparison).

Meropenem administered intravenously to pregnant Cynomolgus monkeys during organogenesis from Day 20 to 50 after mating at doses of 120, 240, and 360 mg/kg/day did not produce maternal or fetal toxicity at the NOAEL dose of 360 mg/kg/day (approximately 2.3 times the MRHD based on body surface area comparison).

In a peri-postnatal study in rats described in the published literature 2 , intravenous meropenem was administered to dams from Gestation Day 17 until Lactation Day 21 at doses of 240, 500, and 1000 mg/kg/day.

There were no adverse effects in the dams and no adverse effects in the first generation offspring (including developmental, behavioral, and functional assessments and reproductive parameters) except that female offspring exhibited lowered body weights which continued during gestation and nursing of the second generation offspring.

Second generation offspring showed no meropenem-related effects.

The NOAEL value was considered to be 1000 mg/kg/day (approximately 3.2 times the MRHD based on body surface area comparisons).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving β-lactams.

( 5.1 ) Severe cutaneous adverse reactions have been reported in patients receiving meropenem.

( 5.2 ) Seizures and other adverse CNS experiences have been reported during treatment.

( 5.3 ) Co-administration of meropenem with valproic acid or divalproex sodium reduces the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures.

( 5.4 , 7.2 ) Clostridium difficile -associated diarrhea (ranging from mild diarrhea to fatal colitis) has been reported.

Evaluate if diarrhea occurs.

( 5.5 ) In patients with renal dysfunction, thrombocytopenia has been observed.

( 5.8 ) 5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with β-lactams.

These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens.

There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another β-lactam.

Before initiating therapy with meropenem, it is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens.

If an allergic reaction to meropenem occurs, discontinue the drug immediately.

5.2 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM) and acute generalized exanthematous pustulosis (AGEP) have been reported in patients receiving meropenem [ see Adverse Reactions (6.2) ] .

If signs and symptoms suggestive of these reactions appear, meropenem should be withdrawn immediately and an alternative treatment should be considered.

5.3 Seizure Potential Seizures and other adverse CNS experiences have been reported during treatment with meropenem.

These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) or with bacterial meningitis and/or compromised renal function [ see Adverse Reactions (6.1) , Drug Interactions (7.2) ] .

During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with the overall seizure rate being 0.7% (based on 20 patients with this adverse event).

All meropenem-treated patients with seizures had pre-existing contributing factors.

Among these are included prior history of seizures or CNS abnormality and concomitant medications with seizure potential.

Dosage adjustment is recommended in patients with advanced age and/or adult patients with creatinine clearance of 50 mL/min or less [ see Dosage and Administration (2.2) ] .

Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity.

Continue anti-convulsant therapy in patients with known seizure disorders.

If focal tremors, myoclonus, or seizures occur, evaluate neurologically, placed on anti-convulsant therapy if not already instituted, and re-examine the dosage of meropenem to determine whether it should be decreased or discontinued.

5.4 Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid The concomitant use of meropenem and valproic acid or divalproex sodium is generally not recommended.

Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations.

The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures.

Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction.

Consider administration of antibacterial drugs other than carbapenems to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium.

If administration of meropenem is necessary, consider supplemental anti-convulsant therapy [ see Drug Interactions (7.2) ] .

5.5 Clostridium difficile-associated Diarrhea Clostridium difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including meropenem, and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C.

difficile .

C.

difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing isolates of C.

difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibacterial drug use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C.

difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C.

difficile , and surgical evaluation should be instituted as clinically indicated.

5.6 Development of Drug-Resistant Bacteria Prescribing meropenem in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

5.7 Overgrowth of Nonsusceptible Organisms As with other broad-spectrum antibacterial drugs, prolonged use of meropenem may result in overgrowth of nonsusceptible organisms.

Repeated evaluation of the patient is essential.

If superinfection does occur during therapy, appropriate measures should be taken.

5.8 Thrombocytopenia In patients with renal impairment, thrombocytopenia has been observed but no clinical bleeding reported [ see Dosage and Administration (2.2) , Adverse Reactions (6.1) , Use In Specific Populations (8.5) , (8.6) , Clinical Pharmacology (12.3) ] .

5.9 Potential for Neuromotor Impairment Alert patients receiving meropenem on an outpatient basis regarding adverse events such as seizures, delirium, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment.

Until it is reasonably well established that meropenem is well tolerated, advise patients not to operate machinery or motorized vehicles [ see Adverse Reactions (6.1) ] .

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Counsel patients that antibacterial drugs including meropenem for injection should only be used to treat bacterial infections.

They do not treat viral infections (e.g., the common cold).

When meropenem for injection is prescribed to treat a bacterial infection, tell patients that although it is common to feel better early in the course of therapy, take the medication exactly as directed.

Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by meropenem for injection or other antibacterial drugs in the future.

Counsel patients that diarrhea is a common problem caused by antibacterial drugs which usually ends when the antibacterial drug is discontinued.

Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug.

If this occurs, patients should contact their physician as soon as possible [ see Warnings and Precautions (5.5) ] .

Counsel patients to inform their physician if they are taking valproic acid or divalproex sodium.

Valproic acid concentrations in the blood may drop below the therapeutic range upon co-administration with meropenem for injection.

If treatment with meropenem for injection is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed [ see Warnings and Precautions (5.4) ] .

Patients receiving meropenem for injection on an outpatient basis must be alerted of adverse events such as seizures, delirium, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment.

Until it is reasonably well established that meropenem for injection is well tolerated, patients should not operate machinery or motorized vehicles [ see Warnings and Precautions (5.9) ] .

DOSAGE AND ADMINISTRATION

2 500 mg every 8 hours by intravenous infusion over 15 to 30 minutes for complicated skin and skin structure infections (cSSSI) for adult patients.

When treating infections caused by Pseudomonas aeruginosa , a dose of 1 gram every 8 hours is recommended.

( 2.1 ) 1 gram every 8 hours by intravenous infusion over 15 minutes to 30 minutes for intra-abdominal infections for adult patients.

( 2.1 ) 1 gram every 8 hours by intravenous bolus injection (5 mL to 20 mL) over 3 minutes to 5 minutes for adult patients.

( 2.1 ) Dosage should be reduced in adult patients with renal impairment.

( 2.2 ) Recommended Meropenem for Injection Dosage Schedule for Adult Patients with Renal Impairment Creatinine Clearance (mL/min) Dose (dependent on type of infection) Dosing Interval Greater than 50 Recommended dose (500 mg cSSSI and 1 gram Intra-abdominal) Every 8 hours 26-50 Recommended dose Every 12 hours 10-25 One-half recommended dose Every 12 hours Less than 10 One-half recommended dose Every 24 hours Pediatric patients 3 months of age and older Recommended Meropenem for Injection Dosage Schedule for Pediatric Patients 3 Months of Age and Older with Normal Renal Function (2.3) Type of Infection Dose (mg/kg) Up to a Maximum Dose Dosing Interval Complicated skin and skin structure* 10 500 mg Every 8 hours Intra-abdominal 20 1 gram Every 8 hours Meningitis 40 2 gram Every 8 hours – Intravenous infusion is to be given over approximately 15 minutes to 30 minutes.

– Intravenous bolus injection (5 mL to 20 mL) is to be given over approximately 3 minutes to 5 minutes.

– There is no experience in pediatric patients with renal impairment.

*20 mg/kg (or 1 gram for pediatric patients weighing over 50 kg) every 8 hours is recommended when treating complicated skin and skin structure infections caused by P.

aeruginosa.

(2.3) Pediatric patients less than 3 months of age Recommended Meropenem for Injection Dosage Schedule for Pediatric Patients Less than 3 Months of Age with Complicated Intra-Abdominal Infections and Normal Renal Function (2.3) Age Group Dose (mg/kg) Dose Interval Infants less than 32 weeks GA and PNA less than 2 weeks 20 Every 12 hours Infants less than 32 weeks GA and PNA 2 weeks and older 20 Every 8 hours Infants 32 weeks and older GA and PNA less than 2 weeks 20 Every 8 hours Infants 32 weeks and older GA and PNA 2 weeks and older 30 Every 8 hours – Intravenous infusion is to be given over 30 minutes.

– There is no experience in pediatric patients with renal impairment.

GA: gestational age and PNA: postnatal age 2.1 Adult Patients The recommended dose of meropenem for injection is 500 mg given every 8 hours for skin and skin structure infections and 1 gram given every 8 hours for intra-abdominal infections.

When treating complicated skin and skin structure infections caused by P.aeruginosa , a dose of 1 gram every 8 hours is recommended.

Meropenem for injection should be administered by intravenous infusion over approximately 15 minutes to 30 minutes.

Doses of 1 gram may also be administered as an intravenous bolus injection (5 mL to 20 mL) over approximately 3 minutes to 5 minutes.

2.2 Use in Adult Patients with Renal Impairment Dosage should be reduced in patients with creatinine clearance of 50 mL/min or less.

(See dosing Table 1 below.) When only serum creatinine is available, the following formula (Cockcroft and Gault equation) 1 may be used to estimate creatinine clearance.

Males: Creatinine Clearance (mL/min) = Weight (kg) × (140 – age) 72 × serum creatinine (mg/dL) Females: 0.85 × above value Table 1: Recommended Meropenem for Injection Dosage Schedule for Adult Patients with Renal Impairment Creatinine Clearance (mL/min) Dose (dependent on type of infection) Dosing Interval Greater than 50 Recommended dose (500 mg cSSSI and 1 gram Intra-abdominal) Every 8 hours 26-50 Recommended dose Every 12 hours 10-25 One-half recommended dose Every 12 hours Less than 10 One-half recommended dose Every 24 hours There is inadequate information regarding the use of meropenem for injection in patients on hemodialysis or peritoneal dialysis.

2.3 Use in Pediatric Patients Pediatric Patients 3 Months of Age and Older For pediatric patients 3 months of age and older, the Meropenem for Injection dose is 10 mg/kg, 20 mg/kg or 40 mg/kg every 8 hours (maximum dose is 2 grams every 8 hours), depending on the type of infection (cSSSI, cIAI, intra-abdominal infection or meningitis).

See dosing Table 2 below.

For pediatric patients weighing over 50 kg administer meropenem for injection at a dose of 500 mg every 8 hours for cSSSI, 1 gram every 8 hours for cIAI and 2 grams every 8 hours for meningitis.

Administer meropenem for injection as an intravenous infusion over approximately 15 minutes to 30 minutes or as an intravenous bolus injection (5 mL to 20 mL) over approximately 3 minutes to 5 minutes.

There is limited safety data available to support the administration of a 40 mg/kg (up to a maximum of 2 grams) bolus dose.

Table 2: Recommended Meropenem for Injection Dosage Schedule for Pediatric Patients 3 Months of Age and Older with Normal Renal Function Type of Infection Dose (mg/kg) Up to a Maximum Dose Dosing Interval Complicated skin and skin structure Infections 10 500 mg Every 8 hours Complicated Intra-abdominal Infections 20 1 gram Every 8 hours Meningitis 40 2 grams Every 8 hours There is no experience in pediatric patients with renal impairment.

When treating cSSSI caused by P.

aeruginosa , a dose of 20 mg/kg (or 1 gram for pediatric patients weighing over 50 kg) every 8 hours is recommended.

Pediatric Patients Less Than 3 Months of Age For pediatric patients (with normal renal function) less than 3 months of age, with complicated intra-abdominal infections, the meropenem for injection dose is based on gestational age (GA) and postnatal age (PNA).

See dosing Table 3 below.

Meropenem for injection should be given as intravenous infusion over 30 minutes.

Table 3: Recommended Meropenem for Injection Dosage Schedule for Pediatric Patients Less than 3 Months of Age with Complicated Intra-abdominal Infections and Normal Renal Function Age Group Dose (mg/kg) Dose Interval Infants less than 32 weeks GA and PNA less than 2 weeks 20 Every 12 hours Infants less than 32 weeks GA and PNA 2 weeks and older 20 Every 8 hours Infants 32 weeks and older GA and PNA less than 2 weeks 20 Every 8 hours Infants 32 weeks and older GA and PNA 2 weeks and older 30 Every 8 hours There is no experience in pediatric patients with renal impairment.

2.4 Preparation and Administration of Meropenem for Injection Important Administration Instructions: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

For Intravenous Bolus Administration Re-constitute injection vials (500 mg and 1 gram) with sterile Water for Injection (see Table 4 below).

Shake to dissolve and let stand until clear.

Table 4: Volume of Sterile Water for Injection for Reconstitution of Injection Vials Vial Size Amount of Diluent Added (mL) Approximate Withdrawable Volume (mL) Approximate Average Concentration (mg/mL) 500 mg 10 10 50 1 gram 20 20 50 For Infusion Injection vials (500 mg and 1 gram) may be directly re-constituted with a compatible infusion fluid.

Alternatively, an injection vial may be re-constituted, then the resulting solution added to an intravenous container and further diluted with an appropriate infusion fluid [ see Dosage and Administration (2.5) and (2.6) ] .

Do not use flexible container in series connections.

2.5 Compatibility Compatibility of meropenem for injection with other drugs has not been established.

Meropenem for injection should not be mixed with or physically added to solutions containing other drugs.

2.6 Stability and Storage Freshly prepared solutions of meropenem for injection should be used.

However, re-constituted solutions of meropenem for injection maintain satisfactory potency under the conditions described below.

Solutions of intravenous meropenem for injection should not be frozen.

Intravenous Bolus Administration Meropenem for injection vials re-constituted with sterile Water for Injection for bolus administration (up to 50 mg/mL of meropenem for injection) may be stored for up to 3 hours at up to 25°C (77°F) or for 13 hours at up to 5°C (41°F).

Intravenous Infusion Administration Solutions prepared for infusion (meropenem for injection concentrations ranging from 1 mg/mL to 20 mg/mL) re-constituted with Sodium Chloride Injection 0.9% may be stored for 1 hour at up to 25°C (77°F) or 15 hours at up to 5°C (41°F).

Solutions prepared for infusion (meropenem for injection concentrations ranging from 1 mg/mL to 20 mg/mL) re-constituted with Dextrose Injection 5% should be used immediately.

Generic Name: MEROPENEM
Brand Name: MEROPENEM
  • Substance Name(s):
  • MEROPENEM

DRUG INTERACTIONS

7 Co-administration of meropenem with probenecid inhibits renal excretion of meropenem and is therefore not recommended.

( 7.1 ) The concomitant use of meropenem and valproic acid or divalproex sodium is generally not recommended.

Antibacterial drugs other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium.

( 5.4 , 7.2 ) 7.1 Probenecid Probenecid competes with meropenem for active tubular secretion, resulting in increased plasma concentrations of meropenem.

Co-administration of probenecid with meropenem is not recommended.

7.2 Valproic Acid Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations.

The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures.

Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid.

If administration of meropenem is necessary, then supplemental anti-convulsant therapy should be considered [ see Warnings and Precautions (5.4) ] .

OVERDOSAGE

10 In mice and rats, large intravenous doses of meropenem (2200 mg/kg to 4000 mg/kg) have been associated with ataxia, dyspnea, convulsions, and mortalities.

Intentional overdosing of meropenem is unlikely, although accidental overdosing might occur if large doses are given to patients with reduced renal function.

The largest dose of meropenem administered in clinical trials has been 2 grams given intravenously every 8 hours.

At this dosage, no adverse pharmacological effects or increased safety risks have been observed.

Limited postmarketing experience indicates that if adverse events occur following overdosage, they are consistent with the adverse event profile described in the Adverse Reactions section and are generally mild in severity and resolve on withdrawal or dose reduction.

Consider symptomatic treatments.

In individuals with normal renal function, rapid renal elimination takes place.

Meropenem and its metabolite are readily dialyzable and effectively removed by hemodialysis; however, no information is available on the use of hemodialysis to treat overdosage.

DESCRIPTION

11 Meropenem for injection is a sterile, pyrogen-free, synthetic, carbapenem antibacterial for intravenous administration.

It is (4R,5S,6S)-3- [[(3S,5S)-5-(Dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxilic acid trihydrate.

Its empirical formula is C 17 H 25 N 3 O 5 S∙3H 2 O with a molecular weight of 437.52.

Its structural formula is: Meropenem for injection is a white to pale yellow crystalline powder.

The solution varies from colorless to yellow depending on the concentration.

The pH of freshly constituted solutions is between 7.3 and 8.3.

Meropenem is soluble in 5% monobasic potassium phosphate solution, sparingly soluble in water, very slightly soluble in hydrated ethanol, and practically insoluble in acetone or ether.

When re-constituted as instructed, each 1 gram meropenem for injection vial will deliver 1 gram of meropenem and 90.2 mg of sodium as sodium carbonate (3.92 mEq).

Each 500 mg meropenem for injection vial will deliver 500 mg meropenem and 45.1 mg of sodium as sodium carbonate (1.96 mEq) [ see Dosage and Administration (2.4) ] .

Chemical Structure

CLINICAL STUDIES

14 14.1 Complicated Skin and Skin Structure Infections Adult patients with complicated skin and skin structure infections including complicated cellulitis, complex abscesses, perirectal abscesses, and skin infections requiring intravenous antimicrobials, hospitalization, and surgical intervention were enrolled in a randomized, multi-center, international, double-blind trial.

The study evaluated meropenem at doses of 500 mg administered intravenously every 8 hours and imipenem-cilastatin at doses of 500 mg administered intravenously every 8 hours.

The study compared the clinical response between treatment groups in the clinically evaluable population at the follow-up visit (test-of-cure).

The trial was conducted in the United States, South Africa, Canada, and Brazil.

At enrollment, approximately 37% of the patients had underlying diabetes, 12% had underlying peripheral vascular disease and 67% had a surgical intervention.

The study included 510 patients randomized to meropenem and 527 patients randomized to imipenem-cilastatin.

Two hundred and sixty one (261) patients randomized to meropenem and 287 patients randomized to imipenem-cilastatin were clinically evaluable.

The success rates in the clinically evaluable patients at the follow-up visit were 86% (225/261) in the meropenem arm and 83% (238/287) in imipenem-cilastatin arm.

The success rates for the clinically evaluable population are provided in Table 7 .

Table 7: Success Rates at Test-of-Cure Visit for Clinically Evaluable Population with Complicated Skin and Skin Structure Infections Population Meropenem n n = number of patients with satisfactory response.

/N N = number of patients in the clinically evaluable population or respective subgroup within treatment groups.

(%) Imipenem-cilastatin n /N (%) Total 225/261 (86) 238/287 (83) Diabetes mellitus 83/97 (86) 76/105 (72) No diabetes mellitus 142/164 (87) 162/182 (89) Less than 65 years of age 190/218 (87) 205/241 (85) 65 years of age or older 35/43 (81) 33/46 (72) Men 130/148 (88) 137/172 (80) Women 95/113 (84) 101/115 (88) The clinical efficacy rates by pathogen are provided in Table 8.

The values represent the number of patients clinically cured/number of clinically evaluable patients at the post-treatment follow-up visit, with the percent cure in parentheses (Fully Evaluable analysis set).

Table 8: Clinical Efficacy Rate by Pathogen for Clinically Evaluable Population MICROORGANISMS Patients may have more than one pretreatment pathogen.

Meropenem n n = number of patients with satisfactory response.

/N N = number of patients in the clinically evaluable population or subgroup within treatment groups.

(%) % = Percent of satisfactory clinical response at follow-up evaluation.

Imipenem-cilastatin n /N (%) Gram-positive aerobes Staphylococcus aureus, methicillin susceptible 82/88 (93) 84/100 (84) Streptococcus pyogenes (Group A) 26/29 (90) 28/32 (88) Streptococcus agalactiae (Group B) 12/17 (71) 16/19 (84) Enterococcus faecalis 9/12 (75) 14/20 (70) Viridans group streptococci 11/12 (92) 5/6 (83) Gram-negative aerobes Escherichia coli 12/15 (80) 15/21 (71) Pseudomonas aeruginosa 11/15 (73) 13/15 (87) Proteus mirabilis 11/13 (85) 6/7 (86) Anaerobes Bacteroides fragilis 10/11 (91) 9/10 (90) Peptostreptococcus species 10/13 (77) 14/16 (88) The proportion of patients who discontinued study treatment due to an adverse event was similar for both treatment groups (meropenem, 2.5% and imipenem-cilastatin, 2.7%).

14.2 Complicated Intra-Abdominal Infections One controlled clinical study of complicated intra-abdominal infection was performed in the United States where meropenem was compared with clindamycin/tobramycin.

Three controlled clinical studies of complicated intra-abdominal infections were performed in Europe; meropenem was compared with imipenem (two trials) and cefotaxime/metronidazole (one trial).

Using strict evaluability criteria and microbiologic eradication and clinical cures at follow-up which occurred 7 or more days after completion of therapy, the presumptive microbiologic eradication/clinical cure rates and statistical findings are provided in Table 9: Table 9: Presumptive Microbiologic Eradication and Clinical Cure Rates at Test-of-Cure Visit in the Evaluable Population with Complicated Intra-Abdominal Infection Treatment Arm No.

evaluable/No.

enrolled (%) Microbiologic Eradication Rate Clinical Cure Rate Outcome meropenem 146/516 (28%) 98/146 (67%) 101/146 (69%) imipenem 65/220 (30%) 40/65 (62%) 42/65 (65%) meropenem equivalent to control cefotaxime/metronidazole 26/85 (30%) 22/26 (85%) 22/26 (85%) meropenem not equivalent to control clindamycin/tobramycin 50/212 (24%) 38/50 (76%) 38/50 (76%) meropenem equivalent to control The finding that meropenem was not statistically equivalent to cefotaxime/metronidazole may have been due to uneven assignment of more seriously ill patients to the meropenem arm.

Currently there is no additional information available to further interpret this observation.

14.3 Bacterial Meningitis Four hundred forty-six patients (397 pediatric patients 3 months to less than 17 years of age) were enrolled in 4 separate clinical trials and randomized to treatment with meropenem (n=225) at a dose of 40 mg/kg every 8 hours or a comparator drug, i.e., cefotaxime (n=187) or ceftriaxone (n=34), at the approved dosing regimens.

A comparable number of patients were found to be clinically evaluable (ranging from 61-68%) and with a similar distribution of pathogens isolated on initial CSF culture.

Patients were defined as clinically not cured if any one of the following three criteria were met: At the 5 to 7 week post-completion of therapy visit, the patient had any one of the following: moderate to severe motor, behavior or development deficits, hearing loss of greater than 60 decibels in one or both ears, or blindness.

During therapy the patient’s clinical status necessitated the addition of other antibacterial drugs.

Either during or post-therapy, the patient developed a large subdural effusion needing surgical drainage, or a cerebral abscess, or a bacteriologic relapse.

Using the definition, the following efficacy rates were obtained, per organism (noted in Table 10 ).

The values represent the number of patients clinically cured/number of clinically evaluable patients, with the percent cure in parentheses.

Table 10: Efficacy rates by Pathogen in the Clinically Evaluable Population with Bacterial Meningitis MICROORGANISMS Meropenem COMPARATOR S.

pneumoniae 17/24 (71) 19/30 (63) H.

influenzae (+) (+) β-lactamase-producing 8/10 (80) 6/6 (100) H.

influenzae (-/NT) (-/NT) non-β-lactamase-producing or not tested 44/59 (75) 44/60 (73) N.

meningitidis 30/35 (86) 35/39 (90) Total (including others) 102/131 (78) 108/140 (77) Sequelae were the most common reason patients were assessed as clinically not cured.

Five patients were found to be bacteriologically not cured, 3 in the comparator group (1 relapse and 2 patients with cerebral abscesses) and 2 in the meropenem group (1 relapse and 1 with continued growth of Pseudomonas aeruginosa ).

With respect to hearing loss, 263 of the 271 evaluable patients had at least one hearing test performed post-therapy.

The following Table 11 shows the degree of hearing loss between the meropenem-treated patients and the comparator-treated patients.

Table 11: Hearing Loss at Post-Therapy in the Evaluable Population Treated with Meropenem Degree of Hearing Loss (in one or both ears) Meropenem n = 128 Comparator n = 135 No loss 61% 56% 20-40 decibels 20% 24% Greater than 40-60 decibels 8% 7% Greater than 60 decibels 9% 10%

HOW SUPPLIED

16 /STORAGE AND HANDLING Meropenem for injection is supplied in 20 mL and 30 mL injection vials containing sufficient meropenem to deliver 500 mg or 1 gram for intravenous administration, respectively.

The dry powder should be stored at controlled room temperature 20º to 25ºC (68º to 77ºF) [see USP].

500 mg Injection Vial (NDC 0781-3000-94) and packaged in cartons of 10 vials (NDC 0781-3000-95) and cartons of 25 vials (NDC 0781-3000-96).

1 gram Injection Vial (NDC 0781-3098-94) and packaged in cartons of 10 vials (NDC 0781-3098-95) and cartons of 25 vials (NDC 0781-3098-96).

GERIATRIC USE

8.5 Geriatric Use Of the total number of subjects in clinical studies of meropenem, approximately 1100 (30%) were 65 years of age and older, while 400 (11%) were 75 years and older.

Additionally, in a study of 511 patients with complicated skin and skin structure infections, 93 (18%) were 65 years of age and older, while 38 (7%) were 75 years and older.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects; spontaneous reports and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Meropenem is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

A pharmacokinetic study with meropenem in elderly patients has shown a reduction in the plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance [ see Clinical Pharmacology (12.3) ] .

DOSAGE FORMS AND STRENGTHS

3 Single dose clear glass vials of meropenem for injection containing 500 mg or 1 gram (as the trihydrate blended with anhydrous sodium carbonate for re-constitution) of sterile meropenem powder.

500 mg Meropenem for Injection Vial ( 3 ) 1 gram Meropenem for Injection Vial ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Meropenem is an antibacterial drug [ see Microbiology (12.4) ] .

INDICATIONS AND USAGE

1 Meropenem for injection is a penem antibacterial indicated for the treatment of: Complicated skin and skin structure infections (adult patients and pediatric patients 3 months of age and older only).

( 1.1 ) Complicated intra-abdominal infections (adult and pediatric patients).

( 1.2 ) Bacterial meningitis (pediatric patients 3 months of age and older only).

( 1.3 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of meropenem for injection and other antibacterial drugs, meropenem for injection should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

1.1 Complicated Skin and Skin Structure Infections (Adult Patients and Pediatric Patients 3 Months of age and older only) Meropenem for injection is indicated for the treatment of complicated skin and skin structure infections (cSSSI) due to Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus pyogenes, Streptococcus agalactiae , viridans group streptococci, Enterococcus faecalis (vancomycin-susceptible isolates only), Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Bacteroides fragilis, and Peptostreptococcus species .

1.2 Complicated Intra-abdominal Infections (Adult and Pediatric Patients) Meropenem for injection is indicated for the treatment of complicated appendicitis and peritonitis caused by viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B.

thetaiotaomicron, and Peptostreptococcus species .

1.3 Bacterial Meningitis (Pediatric Patients 3 Months of age and older only) Meropenem for injection is indicated for the treatment of bacterial meningitis caused by Haemophilus influenzae , and Neisseria meningitidis and penicillin-susceptible isolates of Streptococcus pneumoniae.

Meropenem for injection has been found to be effective in eliminating concurrent bacteremia in association with bacterial meningitis.

1.4 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of meropenem for injection and other antibacterial drugs, meropenem for injection should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.

In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of meropenem have been established for pediatric patients 3 months of age and older with complicated skin and skin structure infections and bacterial meningitis, and for pediatric patients of all ages with complicated intra-abdominal infections.

Skin and Skin Structure Infections Use of meropenem in pediatric patients 3 months of age and older with complicated skin and skin structure infections is supported by evidence from an adequate and well-controlled study in adults and additional data from pediatric pharmacokinetics studies [ see Indications and Usage (1.3) , Dosage and Administration (2.3) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.1) ] .

Intra-abdominal Infections Use of meropenem in pediatric patients 3 months of age and older with intra-abdominal infections is supported by evidence from adequate and well-controlled studies in adults with additional data from pediatric pharmacokinetics studies and controlled clinical trials in pediatric patients.

Use of meropenem in pediatric patients less than 3 months of age with intra-abdominal infections is supported by evidence from adequate and well-controlled studies in adults with additional data from a pediatric pharmacokinetic and safety study [ see Indications and Usage (1.2) , Dosage and Administration (2.3) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14.2) ] .

Bacterial Meningitis Use of meropenem in pediatric patients 3 months of age and older with bacterial meningitis is supported by evidence from adequate and well-controlled studies in the pediatric population [ see Indications and Usage (1.3) , Dosage and Administration (2.3) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.3) ] .

PREGNANCY

8.1 Pregnancy Risk Summary There are insufficient human data to establish whether there is a drug-associated risk of major birth defects or miscarriages with meropenem in pregnant women.

No fetal toxicity or malformations were observed in pregnant rats and Cynomolgus monkeys administered intravenous meropenem during organogenesis at doses up to 2.4 and 2.3 times the maximum recommended human dose (MRHD) based on body surface area comparison, respectively.

In rats administered intravenous meropenem in late pregnancy and during the lactation period, there were no adverse effects on offspring at doses equivalent to approximately 3.2 times the MRHD based on body surface area comparison (see Data ).

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data Meropenem administered to pregnant rats during organogenesis (Gestation Day 6 to Gestation Day 17) in intravenous doses of 240, 500, and 750 mg/kg/day was associated with mild maternal weight loss at all doses, but did not produce malformations or fetal toxicity.

The no-observed-adverse-effect-level (NOAEL) for fetal toxicity in this study was considered to be the high dose of 750 mg/kg/day (equivalent to approximately 2.4 times the MRHD of 1 gram every 8 hours based on body surface area comparison).

Meropenem administered intravenously to pregnant Cynomolgus monkeys during organogenesis from Day 20 to 50 after mating at doses of 120, 240, and 360 mg/kg/day did not produce maternal or fetal toxicity at the NOAEL dose of 360 mg/kg/day (approximately 2.3 times the MRHD based on body surface area comparison).

In a peri-postnatal study in rats described in the published literature 2 , intravenous meropenem was administered to dams from Gestation Day 17 until Lactation Day 21 at doses of 240, 500, and 1000 mg/kg/day.

There were no adverse effects in the dams and no adverse effects in the first generation offspring (including developmental, behavioral, and functional assessments and reproductive parameters) except that female offspring exhibited lowered body weights which continued during gestation and nursing of the second generation offspring.

Second generation offspring showed no meropenem-related effects.

The NOAEL value was considered to be 1000 mg/kg/day (approximately 3.2 times the MRHD based on body surface area comparisons).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving β-lactams.

( 5.1 ) Severe cutaneous adverse reactions have been reported in patients receiving meropenem.

( 5.2 ) Seizures and other adverse CNS experiences have been reported during treatment.

( 5.3 ) Co-administration of meropenem with valproic acid or divalproex sodium reduces the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures.

( 5.4 , 7.2 ) Clostridium difficile -associated diarrhea (ranging from mild diarrhea to fatal colitis) has been reported.

Evaluate if diarrhea occurs.

( 5.5 ) In patients with renal dysfunction, thrombocytopenia has been observed.

( 5.8 ) 5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with β-lactams.

These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens.

There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another β-lactam.

Before initiating therapy with meropenem, it is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens.

If an allergic reaction to meropenem occurs, discontinue the drug immediately.

5.2 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM) and acute generalized exanthematous pustulosis (AGEP) have been reported in patients receiving meropenem [ see Adverse Reactions (6.2) ] .

If signs and symptoms suggestive of these reactions appear, meropenem should be withdrawn immediately and an alternative treatment should be considered.

5.3 Seizure Potential Seizures and other adverse CNS experiences have been reported during treatment with meropenem.

These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) or with bacterial meningitis and/or compromised renal function [ see Adverse Reactions (6.1) , Drug Interactions (7.2) ] .

During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with the overall seizure rate being 0.7% (based on 20 patients with this adverse event).

All meropenem-treated patients with seizures had pre-existing contributing factors.

Among these are included prior history of seizures or CNS abnormality and concomitant medications with seizure potential.

Dosage adjustment is recommended in patients with advanced age and/or adult patients with creatinine clearance of 50 mL/min or less [ see Dosage and Administration (2.2) ] .

Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity.

Continue anti-convulsant therapy in patients with known seizure disorders.

If focal tremors, myoclonus, or seizures occur, evaluate neurologically, placed on anti-convulsant therapy if not already instituted, and re-examine the dosage of meropenem to determine whether it should be decreased or discontinued.

5.4 Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid The concomitant use of meropenem and valproic acid or divalproex sodium is generally not recommended.

Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations.

The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures.

Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction.

Consider administration of antibacterial drugs other than carbapenems to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium.

If administration of meropenem is necessary, consider supplemental anti-convulsant therapy [ see Drug Interactions (7.2) ] .

5.5 Clostridium difficile-associated Diarrhea Clostridium difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including meropenem, and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C.

difficile .

C.

difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing isolates of C.

difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibacterial drug use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C.

difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C.

difficile , and surgical evaluation should be instituted as clinically indicated.

5.6 Development of Drug-Resistant Bacteria Prescribing meropenem in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

5.7 Overgrowth of Nonsusceptible Organisms As with other broad-spectrum antibacterial drugs, prolonged use of meropenem may result in overgrowth of nonsusceptible organisms.

Repeated evaluation of the patient is essential.

If superinfection does occur during therapy, appropriate measures should be taken.

5.8 Thrombocytopenia In patients with renal impairment, thrombocytopenia has been observed but no clinical bleeding reported [ see Dosage and Administration (2.2) , Adverse Reactions (6.1) , Use In Specific Populations (8.5) , (8.6) , Clinical Pharmacology (12.3) ] .

5.9 Potential for Neuromotor Impairment Alert patients receiving meropenem on an outpatient basis regarding adverse events such as seizures, delirium, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment.

Until it is reasonably well established that meropenem is well tolerated, advise patients not to operate machinery or motorized vehicles [ see Adverse Reactions (6.1) ] .

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Counsel patients that antibacterial drugs including meropenem for injection should only be used to treat bacterial infections.

They do not treat viral infections (e.g., the common cold).

When meropenem for injection is prescribed to treat a bacterial infection, tell patients that although it is common to feel better early in the course of therapy, take the medication exactly as directed.

Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by meropenem for injection or other antibacterial drugs in the future.

Counsel patients that diarrhea is a common problem caused by antibacterial drugs which usually ends when the antibacterial drug is discontinued.

Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug.

If this occurs, patients should contact their physician as soon as possible [ see Warnings and Precautions (5.5) ] .

Counsel patients to inform their physician if they are taking valproic acid or divalproex sodium.

Valproic acid concentrations in the blood may drop below the therapeutic range upon co-administration with meropenem for injection.

If treatment with meropenem for injection is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed [ see Warnings and Precautions (5.4) ] .

Patients receiving meropenem for injection on an outpatient basis must be alerted of adverse events such as seizures, delirium, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment.

Until it is reasonably well established that meropenem for injection is well tolerated, patients should not operate machinery or motorized vehicles [ see Warnings and Precautions (5.9) ] .

DOSAGE AND ADMINISTRATION

2 500 mg every 8 hours by intravenous infusion over 15 to 30 minutes for complicated skin and skin structure infections (cSSSI) for adult patients.

When treating infections caused by Pseudomonas aeruginosa , a dose of 1 gram every 8 hours is recommended.

( 2.1 ) 1 gram every 8 hours by intravenous infusion over 15 minutes to 30 minutes for intra-abdominal infections for adult patients.

( 2.1 ) 1 gram every 8 hours by intravenous bolus injection (5 mL to 20 mL) over 3 minutes to 5 minutes for adult patients.

( 2.1 ) Dosage should be reduced in adult patients with renal impairment.

( 2.2 ) Recommended Meropenem for Injection Dosage Schedule for Adult Patients with Renal Impairment Creatinine Clearance (mL/min) Dose (dependent on type of infection) Dosing Interval Greater than 50 Recommended dose (500 mg cSSSI and 1 gram Intra-abdominal) Every 8 hours 26-50 Recommended dose Every 12 hours 10-25 One-half recommended dose Every 12 hours Less than 10 One-half recommended dose Every 24 hours Pediatric patients 3 months of age and older Recommended Meropenem for Injection Dosage Schedule for Pediatric Patients 3 Months of Age and Older with Normal Renal Function (2.3) Type of Infection Dose (mg/kg) Up to a Maximum Dose Dosing Interval Complicated skin and skin structure* 10 500 mg Every 8 hours Intra-abdominal 20 1 gram Every 8 hours Meningitis 40 2 gram Every 8 hours – Intravenous infusion is to be given over approximately 15 minutes to 30 minutes.

– Intravenous bolus injection (5 mL to 20 mL) is to be given over approximately 3 minutes to 5 minutes.

– There is no experience in pediatric patients with renal impairment.

*20 mg/kg (or 1 gram for pediatric patients weighing over 50 kg) every 8 hours is recommended when treating complicated skin and skin structure infections caused by P.

aeruginosa.

(2.3) Pediatric patients less than 3 months of age Recommended Meropenem for Injection Dosage Schedule for Pediatric Patients Less than 3 Months of Age with Complicated Intra-Abdominal Infections and Normal Renal Function (2.3) Age Group Dose (mg/kg) Dose Interval Infants less than 32 weeks GA and PNA less than 2 weeks 20 Every 12 hours Infants less than 32 weeks GA and PNA 2 weeks and older 20 Every 8 hours Infants 32 weeks and older GA and PNA less than 2 weeks 20 Every 8 hours Infants 32 weeks and older GA and PNA 2 weeks and older 30 Every 8 hours – Intravenous infusion is to be given over 30 minutes.

– There is no experience in pediatric patients with renal impairment.

GA: gestational age and PNA: postnatal age 2.1 Adult Patients The recommended dose of meropenem for injection is 500 mg given every 8 hours for skin and skin structure infections and 1 gram given every 8 hours for intra-abdominal infections.

When treating complicated skin and skin structure infections caused by P.aeruginosa , a dose of 1 gram every 8 hours is recommended.

Meropenem for injection should be administered by intravenous infusion over approximately 15 minutes to 30 minutes.

Doses of 1 gram may also be administered as an intravenous bolus injection (5 mL to 20 mL) over approximately 3 minutes to 5 minutes.

2.2 Use in Adult Patients with Renal Impairment Dosage should be reduced in patients with creatinine clearance of 50 mL/min or less.

(See dosing Table 1 below.) When only serum creatinine is available, the following formula (Cockcroft and Gault equation) 1 may be used to estimate creatinine clearance.

Males: Creatinine Clearance (mL/min) = Weight (kg) × (140 – age) 72 × serum creatinine (mg/dL) Females: 0.85 × above value Table 1: Recommended Meropenem for Injection Dosage Schedule for Adult Patients with Renal Impairment Creatinine Clearance (mL/min) Dose (dependent on type of infection) Dosing Interval Greater than 50 Recommended dose (500 mg cSSSI and 1 gram Intra-abdominal) Every 8 hours 26-50 Recommended dose Every 12 hours 10-25 One-half recommended dose Every 12 hours Less than 10 One-half recommended dose Every 24 hours There is inadequate information regarding the use of meropenem for injection in patients on hemodialysis or peritoneal dialysis.

2.3 Use in Pediatric Patients Pediatric Patients 3 Months of Age and Older For pediatric patients 3 months of age and older, the Meropenem for Injection dose is 10 mg/kg, 20 mg/kg or 40 mg/kg every 8 hours (maximum dose is 2 grams every 8 hours), depending on the type of infection (cSSSI, cIAI, intra-abdominal infection or meningitis).

See dosing Table 2 below.

For pediatric patients weighing over 50 kg administer meropenem for injection at a dose of 500 mg every 8 hours for cSSSI, 1 gram every 8 hours for cIAI and 2 grams every 8 hours for meningitis.

Administer meropenem for injection as an intravenous infusion over approximately 15 minutes to 30 minutes or as an intravenous bolus injection (5 mL to 20 mL) over approximately 3 minutes to 5 minutes.

There is limited safety data available to support the administration of a 40 mg/kg (up to a maximum of 2 grams) bolus dose.

Table 2: Recommended Meropenem for Injection Dosage Schedule for Pediatric Patients 3 Months of Age and Older with Normal Renal Function Type of Infection Dose (mg/kg) Up to a Maximum Dose Dosing Interval Complicated skin and skin structure Infections 10 500 mg Every 8 hours Complicated Intra-abdominal Infections 20 1 gram Every 8 hours Meningitis 40 2 grams Every 8 hours There is no experience in pediatric patients with renal impairment.

When treating cSSSI caused by P.

aeruginosa , a dose of 20 mg/kg (or 1 gram for pediatric patients weighing over 50 kg) every 8 hours is recommended.

Pediatric Patients Less Than 3 Months of Age For pediatric patients (with normal renal function) less than 3 months of age, with complicated intra-abdominal infections, the meropenem for injection dose is based on gestational age (GA) and postnatal age (PNA).

See dosing Table 3 below.

Meropenem for injection should be given as intravenous infusion over 30 minutes.

Table 3: Recommended Meropenem for Injection Dosage Schedule for Pediatric Patients Less than 3 Months of Age with Complicated Intra-abdominal Infections and Normal Renal Function Age Group Dose (mg/kg) Dose Interval Infants less than 32 weeks GA and PNA less than 2 weeks 20 Every 12 hours Infants less than 32 weeks GA and PNA 2 weeks and older 20 Every 8 hours Infants 32 weeks and older GA and PNA less than 2 weeks 20 Every 8 hours Infants 32 weeks and older GA and PNA 2 weeks and older 30 Every 8 hours There is no experience in pediatric patients with renal impairment.

2.4 Preparation and Administration of Meropenem for Injection Important Administration Instructions: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

For Intravenous Bolus Administration Re-constitute injection vials (500 mg and 1 gram) with sterile Water for Injection (see Table 4 below).

Shake to dissolve and let stand until clear.

Table 4: Volume of Sterile Water for Injection for Reconstitution of Injection Vials Vial Size Amount of Diluent Added (mL) Approximate Withdrawable Volume (mL) Approximate Average Concentration (mg/mL) 500 mg 10 10 50 1 gram 20 20 50 For Infusion Injection vials (500 mg and 1 gram) may be directly re-constituted with a compatible infusion fluid.

Alternatively, an injection vial may be re-constituted, then the resulting solution added to an intravenous container and further diluted with an appropriate infusion fluid [ see Dosage and Administration (2.5) and (2.6) ] .

Do not use flexible container in series connections.

2.5 Compatibility Compatibility of meropenem for injection with other drugs has not been established.

Meropenem for injection should not be mixed with or physically added to solutions containing other drugs.

2.6 Stability and Storage Freshly prepared solutions of meropenem for injection should be used.

However, re-constituted solutions of meropenem for injection maintain satisfactory potency under the conditions described below.

Solutions of intravenous meropenem for injection should not be frozen.

Intravenous Bolus Administration Meropenem for injection vials re-constituted with sterile Water for Injection for bolus administration (up to 50 mg/mL of meropenem for injection) may be stored for up to 3 hours at up to 25°C (77°F) or for 13 hours at up to 5°C (41°F).

Intravenous Infusion Administration Solutions prepared for infusion (meropenem for injection concentrations ranging from 1 mg/mL to 20 mg/mL) re-constituted with Sodium Chloride Injection 0.9% may be stored for 1 hour at up to 25°C (77°F) or 15 hours at up to 5°C (41°F).

Solutions prepared for infusion (meropenem for injection concentrations ranging from 1 mg/mL to 20 mg/mL) re-constituted with Dextrose Injection 5% should be used immediately.

DRUG INTERACTIONS

7 Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, phenobarbital, primidone, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance.

Therefore increased monitoring of valproate and concomitant drug concentrations and dosage adjustment are indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn ( 7.1 ) Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations is recommended ( 7.1 ) Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g.

diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement ( 7.2 ) Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine may be necessary if used concomitantly with valproic acid capsules ( 7.2 ) Topiramate: Hyperammonemia and encephalopathy ( 5.11 , 7.3 ) 7.1 Effects of Co-Administered Drugs on Valproate Clearance Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase the clearance of valproate.

For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate.

Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs.

In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation.

Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn.

The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics.

The list is not exhaustive nor could it be, since new interactions are continuously being reported.

Drugs for which a potentially important interaction has been observed Aspirin A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of metabolism of valproate.

Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone.

The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin.

Caution should be observed if valproate and aspirin are to be co-administered.

Carbapenem Antibiotics A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control.

The mechanism of this interaction is not well understood.

Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy.

Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.14) ] .

Felbamate A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone.

Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase).

A decrease in valproate dosage may be necessary when felbamate therapy is initiated.

Rifampin A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate.

Valproate dosage adjustment may be necessary when it is co-administered with rifampin.

Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Antacids A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac – 160 mEq doses) did not reveal any effect on the extent of absorption of valproate.

Chlorpromazine A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate.

Haloperidol A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels.

Cimetidine and Ranitidine Cimetidine and ranitidine do not affect the clearance of valproate.

7.2 Effects of Valproate on Other Drugs Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronyltransferases.

The following list provides information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications.

The list is not exhaustive, since new interactions are continuously being reported.

Drugs for which a potentially important valproate interaction has been observed Amitriptyline/Nortriptyline Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline.

Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received.

Concurrent use of valproate and amitriptyline has rarely been associated with toxicity.

Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline.

Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate.

Carbamazepine/carbamazepine-10,11-Epoxide Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients.

Clonazepam The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures.

Diazepam Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.

Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n = 6).

Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate.

The elimination half-life of diazepam remained unchanged upon addition of valproate.

Ethosuximide Valproate inhibits the metabolism of ethosuximide.

Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone.

Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs.

Lamotrigine In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase).

The dose of lamotrigine should be reduced when co-administered with valproate.

Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration.

See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration.

Phenobarbital Valproate was found to inhibit the metabolism of phenobarbital.

Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose).

The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate.

There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations.

All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity.

Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.

Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate.

Phenytoin Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism.

Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin.

Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate.

Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%.

In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin.

The dosage of phenytoin should be adjusted as required by the clinical situation.

Tolbutamide From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate.

The clinical relevance of this displacement is unknown.

Warfarin In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%.

The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants.

Zidovudine In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected.

Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Acetaminophen Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients.

Clozapine In psychotic patients (n = 11), no interaction was observed when valproate was co-administered with clozapine.

Lithium Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.

Lorazepam Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.

Oral Contraceptive Steroids Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction.

7.3 Topiramate Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.10 , 5.11) ] .

Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone.

It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.10 , 5.12) ] .

OVERDOSAGE

10 Overdosage with valproate may result in somnolence, heart block, and deep coma.

Fatalities have been reported; however, patients have recovered from valproate levels as high as 2120 mcg/mL.

In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug.

The benefit of gastric lavage or emesis will vary with the time since ingestion.

General supportive measures should be applied with particular attention to the maintenance of adequate urinary output.

Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.

Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy.

DESCRIPTION

11 Valproic acid is a carboxylic acid designated as 2-propylpentanoic acid.

It is also known as dipropylacetic acid.

Valproic acid has the following structure: Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a characteristic odor.

It is slightly soluble in water (1.3 mg/mL) and very soluble in organic solvents.

Valproic Acid Capsules, USP are antiepileptics for oral administration.

Each soft gelatin capsule contains 250 mg valproic acid.

Inactive Ingredients Peanut oil, gelatin, glycerin and titanium dioxide Chemical Structure

CLINICAL STUDIES

14 The studies described in the following section were conducted using divalproex sodium tablets.

14.1 Epilepsy The efficacy of divalproex sodium tablets in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials.

In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the “therapeutic range” were randomized to receive, in addition to their original antiepilepsy drug (AED), either divalproex sodium tablets or placebo.

Randomized patients were to be followed for a total of 16 weeks.

The following Table presents the findings.

Table 5.

Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks Add-on Treatment Number of Patients Baseline Incidence Experimental Incidence Divalproex Sodium Tablets 75 16.0 8.9 Reduction from baseline statistically significantly greater for divalproex sodium tablets than placebo at p ≤ 0.05 level.

Placebo 69 14.5 11.5 Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study.

A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening.

Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo.

This Figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for divalproex sodium tablets than for placebo.

For example, 45% of patients treated with divalproex sodium tablets had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo.

Figure 1 The second study assessed the capacity of divalproex sodium tablets to reduce the incidence of CPS when administered as the sole AED.

The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm.

Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to divalproex sodium tablets.

Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks.

Less than 50% of the patients randomized, however, completed the study.

In patients converted to divalproex sodium tablets monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively.

The following Table presents the findings for all patients randomized who had at least one post-randomization assessment.

Table 6.

Monotherapy Study Median Incidence of CPS per 8 Weeks Treatment Number of Patients Baseline Incidence Randomized Phase Incidence High dose 131 13.2 10.7 Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level.

Divalproex Sodium Tablets Low dose 134 14.2 13.8 Divalproex Sodium Tablets Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study.

A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening.

Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment.

This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose divalproex sodium tablets than for low dose divalproex sodium tablets.

For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose divalproex sodium tablets monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose divalproex sodium tablets.

Figure 2 Figure 1 Figure 2

HOW SUPPLIED

16 /STORAGE AND HANDLING Repackaged by Aphena Pharma Solutions – TN.

See Repackaging Information for available configurations.

Valproic Acid Capsules, USP 250 mg are off-white colored soft gelatin capsules, imprinted with “U-S 250”, containing Valproic Acid, USP, and packaged in bottles of 100 capsules (NDC 0832-1008-11).

Store at 20-25°C (68-77°F).

Excursions permitted to 15-30°C (59-86°F).

[See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container with a child-resistant closure.

RECENT MAJOR CHANGES

Boxed Warning, Hepatotoxicity 05/2013 Boxed Warning, Fetal Risk 05/2013 Indications and Usage, Important Limitations ( 1.2 ) 05/2013 Contraindications, Known or Suspected Mitochondrial Disorders ( 4 ) 05/2013 Warnings and Precautions, Hepatotoxicity ( 5.1 ) 05/2013 Warnings and Precautions, Birth Defects ( 5.2 ) 05/2013 Warnings and Precautions, Decreased IQ ( 5.3 ) 05/2013 Warnings and Precautions, Use in Women of Childbearing Potential ( 5.4 ) 05/2013 Warnings and Precautions, Brain Atrophy ( 5.7 ) 05/2013

GERIATRIC USE

8.5 Geriatric Use No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness.

In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age.

A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor.

Discontinuation of valproate was occasionally associated with the latter two events.

It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients.

A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.15) ] .

The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.2) ] .

DOSAGE FORMS AND STRENGTHS

3 Valproic acid capsules are supplied as 250 mg off-white colored soft gelatin capsules, imprinted with “U-S 250”, packaged in bottles containing 100.

Capsules: 250 mg valproic acid

MECHANISM OF ACTION

12.1 Mechanism of Action Valproic acid dissociates to the valproate ion in the gastrointestinal tract.

The mechanisms by which valproate exerts its antiepileptic effects have not been established.

It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).

INDICATIONS AND USAGE

1 Valproic Acid Capsules, USP are an anti-epileptic drug indicated for: Monotherapy and adjunctive therapy of complex partial seizures; sole and adjunctive therapy of simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures ( 1 ) 1.1 Epilepsy Valproic Acid Capsules, USP are indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures.

Valproic Acid Capsules, USP are indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types which include absence seizures.

Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs.

Complex absence is the term used when other signs are also present.

See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.

1.2 Important Limitations Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition [see Warnings and Precautions (5.2 , 5.3 , 5.4) , Use in Specific Populations (8.1) , and Patient Counseling Information (17.3) ].

PEDIATRIC USE

8.4 Pediatric Use Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning ] .

When valproic acid capsules are used in this patient group, it should be used with extreme caution and as a sole agent.

The benefits of therapy should be weighed against the risks.

Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproic acid concentrations.

Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults.

Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.

The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations.

Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding.

Pediatric Clinical Trials Divalproex sodium tablets were studied in seven pediatric clinical trials.

Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of divalproex sodium tablets ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on divalproex sodium tablets ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on divalproex sodium tablets ER).

Efficacy was not established for either the treatment of migraine or the treatment of mania.

The most common drug-related adverse reactions (reported >5% and twice the rate of placebo) reported in the controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash.

The remaining five trials were long term safety studies.

Two six-month pediatric studies were conducted to evaluate the long-term safety of divalproex sodium tablets ER for the indication of mania (292 patients aged 10 to 17 years).

Two twelve-month pediatric studies were conducted to evaluate the long-term safety of divalproex sodium tablets ER for the indication of migraine (353 patients aged 12 to 17 years).

One twelve-month study was conducted to evaluate the safety of divalproex sodium sprinkle capsules in the indication of partial seizures (169 patients aged 3 to 10 years).

In these seven trials, the safety and tolerability of divalproex sodium tablets in pediatric patients were shown to be comparable to those in adults [see Adverse Reactions (6) ] .

Juvenile Animal Toxicology In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.

The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m 2 basis.

PREGNANCY

8.1 Pregnancy Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2 , 5.3) ] .

Pregnancy Registry To collect information on the effects of in utero exposure to valproic acid, physicians should encourage pregnant patients taking valproic acid capsules to enroll in the NAAED Pregnancy Registry.

This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves.

Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/.

Fetal Risk Summary All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure.

Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations).

The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy.

The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies [see Warnings and Precautions (5.3) ] .

Exposure in utero to valproate products has been associated with cerebral atrophy [see Warnings and Precautions (5.7) and Adverse Reactions (6.4) ] .

Several published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero [see Warnings and Precautions (5.3) ] .

In animal studies, offspring with prenatal exposure to valproate had structural malformations similar to those seen in humans and demonstrated neurobehavioral deficits.

Clinical Considerations Neural tube defects are the congenital malformation most strongly associated with maternal valproate use.

The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births).

Valproate can cause decreased IQ scores in children whose mothers were treated with valproate during pregnancy.

Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events, which may occur very early in pregnancy: Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition.

This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine).

Valproic acid capsules should not be used to treat women with epilepsy who are pregnant or who plan to become pregnant unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable.

In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks.

When treating a pregnant woman or a woman of childbearing potential, carefully consider both the potential risks and benefits of treatment and provide appropriate counseling.

To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life.

Even minor seizures may pose some hazard to the developing embryo or fetus.

However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient.

Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate.

Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population.

It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation.

Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate.

Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.9) ] .

A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage.

If valproate is used in pregnancy, the clotting parameters should be monitored carefully.

Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and Precautions (5.1) ] .

Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy.

Data Human There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities.

Based on published data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%.

The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to 2%.

In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal valproate exposure were reported among offspring of 149 enrolled women who used valproate during pregnancy.

Three of the 16 cases were neural tube defects; the remaining cases included craniofacial defects, cardiovascular malformations and malformations of varying severity involving other body systems.

The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I.

6.3% – 16.9%) in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500-2000 mg/day).

The major malformation rate among the internal comparison group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy was 2.9% (95% CI 2.0% to 4.1%).

These data show a four-fold increased risk for any major malformation (Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk following exposure in utero to any other antiepileptic drug monotherapy.

Published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero .

The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I.

94-101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I.

105-110]), carbamazepine (105 [95% C.I.

102-108]) and phenytoin (108 [95% C.I.

104-112]).

It is not known when during pregnancy cognitive effects in valproate-exposed children occur.

Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed.

Although all of the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on cognitive development.

There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy.

Animal In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body surface area basis).

Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects.

In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels.

Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate.

NUSRING MOTHERS

8.3 Nursing Mothers Valproate is excreted in human milk.

Caution should be exercised when valproate is administered to a nursing woman.

BOXED WARNING

WARNING: LIFE THREATENING ADVERSE REACTIONS WARNINGS: LIFE THREATENING ADVERSE REACTIONS See full prescribing information for complete boxed warning Hepatotoxicity, including fatalities, usually during first 6 months of treatment.

Children under the age of two years and patients with mitochondrial disorders are at higher risk.

Monitor patients closely, and perform serum liver testing prior to therapy and at frequent intervals thereafter ( 5.1 ) Fetal Risk, particularly neural tube defects, other major malformations, and decreased IQ ( 5.2 , 5.3 , 5.4 ) Pancreatitis, including fatal hemorrhagic cases ( 5.5 ) Hepatotoxicity General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate.

These incidents usually have occurred during the first six months of treatment.

Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting.

In patients with epilepsy, a loss of seizure control may also occur.

Patients should be monitored closely for appearance of these symptoms.

Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1) ] .

Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease.

When valproic acid products are used in this patient group, they should be used with extreme caution and as a sole agent.

The benefits of therapy should be weighed against the risks.

The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.

Alpers Huttenlocher Syndrome).

Valproic acid is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4) ] .

In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, valproic acid should only be used after other anticonvulsants have failed.

This older group of patients should be closely monitored during treatment with valproic acid for the development of acute liver injury with regular clinical assessments and serum liver testing.

POLG mutation screening should be performed in accordance with current clinical practice [see Warnings and Precautions (5.1) ] .

Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida).

In addition, valproate can cause decreased IQ scores following in utero exposure.

Valproate should only be used to treat pregnant women with epilepsy if other medications have failed to control their symptoms or are otherwise unacceptable.

Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition.

This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine).

Women should use effective contraception while using valproate [see Warnings and Precautions (5.2 , 5.3 , 5.4) ] .

A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information (17) ] .

Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate.

Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death.

Cases have been reported shortly after initial use as well as after several years of use.

Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation.

If pancreatitis is diagnosed, valproate should ordinarily be discontinued.

Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions (5.5) ] .

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Hepatotoxicity; evaluate high risk populations and monitor serum liver tests ( 5.1 ) Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG) ( 4 , 5.1 ) Suspected POLG-related disorder in children under two years of age ( 4 , 5.1 ) Birth defects and decreased IQ following in utero exposure; only use to treat pregnant women with epilepsy if other medications are unacceptable; should not be administered to a woman of childbearing potential unless essential ( 5.2 , 5.3 , 5.4 ) Pancreatitis; valproic acid capsules should ordinarily be discontinued ( 5.5 ) Brain Atrophy; evaluate for continued use in the presence of suspected or apparent signs of reversible or irreversible cerebral and cerebellar atrophy ( 5.6 ) Suicidal behavior or ideation; Antiepileptic drugs, including valproic acid capsules, increase the risk of suicidal thoughts or behavior ( 5.8 ) Thrombocytopenia; monitor platelet counts and coagulation tests ( 5.9 ) Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status ( 5.10 , 5.11 ) Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia.

This adverse reaction can also occur in patients using concomitant topiramate ( 5.12 ) Multi-organ hypersensitivity reaction; discontinue valproic acid capsules ( 5.13 ) Somnolence in the elderly can occur.

Valproic acid capsules dosage should be increased slowly and with regular monitoring for fluid and nutritional intake ( 5.15 ) 5.1 Hepatotoxicity General Information on Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate.

These incidents usually have occurred during the first six months of treatment.

Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting.

In patients with epilepsy, a loss of seizure control may also occur.

Patients should be monitored closely for appearance of these symptoms.

Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months.

However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination.

Caution should be observed when administering valproate products to patients with a prior history of hepatic disease.

Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk.

See below, “Patients with Known or Suspected Mitochondrial Disease.” Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.

When valproic acid capsules products are used in this patient group, they should be used with extreme caution and as a sole agent.

The benefits of therapy should be weighed against the risks.

In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably.

Patients with Known or Suspected Mitochondrial Disease Valproic acid capsules are contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4) ] .

Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-Huttenlocher Syndrome) at a higher rate than those without these syndromes.

Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents.

POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura.

POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders.

The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders.

In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, valproic acid capsules should only be used after other anticonvulsants have failed.

This older group of patients should be closely monitored during treatment with valproic acid capsules for the development of acute liver injury with regular clinical assessments and serum liver test monitoring.

The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent.

In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug [see Boxed Warning and Contraindications (4) ] .

5.2 Birth Defects Valproate can cause fetal harm when administered to a pregnant woman.

Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations and malformations involving various body systems).

The rate of congenital malformations among babies born to mothers using valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies.

Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population.

5.3 Decreased IQ Following in utero Exposure Valproate can cause decreased IQ scores following in utero exposure.

Published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic drugs.

The largest of these studies 1 is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I.

94-101]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I.

105-110]), carbamazepine (105 [95% C.I.

102-108]), and phenytoin (108 [95% C.I.

104-112]).

It is not known when during pregnancy cognitive effects in valproate-exposed children occur.

Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed.

Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero can cause decreased IQ in children.

In animal studies, offspring with prenatal exposure to valproate had malformations similar to those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific Populations (8.1) ] .

Women with epilepsy who are pregnant or who plan to become pregnant should not be treated with valproate unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable.

In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks.

5.4 Use in Women of Childbearing Potential Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural tube defects), which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition.

This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine).

Women should use effective contraception while using valproate.

Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients [see Boxed Warning and Use in Specific Populations (8.1) ] .

To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life.

Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population.

It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation.

Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate.

5.5 Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate.

Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death.

Some cases have occurred shortly after initial use as well as after several years of use.

The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate.

In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416 patients, representing 1044 patient-years experience.

Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation.

If pancreatitis is diagnosed, valproate should ordinarily be discontinued.

Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed Warning ] .

5.6 Urea Cycle Disorders (UCD) Valproic acid is contraindicated in patients with known urea cycle disorders.

Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency.

Prior to the initiation of valproate therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD.

Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.11) ] .

5.7 Brain Atrophy There have been postmarketing reports of reversible and irreversible cerebral and cerebellar atrophy temporally associated with the use valproate products; in some cases, patients recovered with permanent sequelae [see Adverse Reactions (6.4) ] .

The motor and cognitive functions of patients on valproate should be routinely monitored and drug should be evaluated for continued use in the presence of suspected or apparent signs of brain atrophy.

Reports of cerebral atrophy have also been reported in children who were exposed in utero to valproate products [see Use in Specific Populations (8.1) ] .

5.8 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including valproic acid capsules, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.

In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.

There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed.

Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.

The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.

The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.

Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

Table 2.

Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing valproic acid capsules or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.

Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.

Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Behaviors of concern should be reported immediately to healthcare providers.

5.9 Thrombocytopenia The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may be dose-related.

In a clinical trial of divalproex sodium as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 × 10 9 /L.

Approximately half of these patients had treatment discontinued, with return of platelet counts to normal.

In the remaining patients, platelet counts normalized with continued treatment.

In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males).

The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects.

Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals.

It is recommended that patients receiving valproic acid capsules be monitored for platelet count and coagulation parameters prior to planned surgery.

Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.

5.10 Hyperammonemia Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests.

In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.

Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and Precautions (5.12) ] .

If ammonia is increased, valproate therapy should be discontinued.

Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6 , 5.11) ] .

Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels.

If the elevation persists, discontinuation of valproate therapy should be considered.

5.11 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone.

Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting.

Hypothermia can also be a manifestation of hyperammonemia [see Warnings and Precautions (5.12) ] .

In most cases, symptoms and signs abated with discontinuation of either drug.

This adverse reaction is not due to a pharmacokinetic interaction.

It is not known if topiramate monotherapy is associated with hyperammonemia.

Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy.

Although not studied, an interaction of topiramate and valproate may exacerbate existing defects or unmask deficiencies in susceptible persons.

In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.6 , 5.10) ] .

5.12 Hypothermia Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia.

This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3) ] .

Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems.

Clinical management and assessment should include examination of blood ammonia levels.

5.13 Multi-Organ Hypersensitivity Reactions Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days).

Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported.

Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement.

Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia.

Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur.

If this reaction is suspected, valproate should be discontinued and an alternative treatment started.

Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.

5.14 Interaction with Carbapenem Antibiotics Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control.

Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy.

Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates [see Drug Interactions (7.1) ] .

5.15 Somnolence in the Elderly In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day.

A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration.

Discontinuations for somnolence were also significantly higher than with placebo.

In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss.

There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN.

In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions.

Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see Dosage and Administration (2.2) ] .

5.16 Monitoring: Drug Plasma Concentration Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see Drug Interactions (7) ] .

5.17 Effect on Ketone and Thyroid Function Tests Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test.

There have been reports of altered thyroid function tests associated with valproate.

The clinical significance of these is unknown.

5.18 Effect on HIV and CMV Viruses Replication There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions.

The clinical consequence, if any, is not known.

Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy.

Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-Approved Medication Guide 17.1 Hepatotoxicity Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.1) ] .

17.2 Pancreatitis Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.5) ] .

17.3 Birth Defects and Decreased IQ Inform pregnant women and women of childbearing potential that use of valproate during pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.

Advise women to use effective contraception while using valproate.

When appropriate, counsel these patients about alternative therapeutic options.

This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death.

Advise patients to read the Medication Guide, which appears as the last section of the labeling [see Warnings and Precautions (5.2 , 5.3 , 5.4) and Use in Specific Populations (8.1) ] .

Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact their doctor immediately if they think they are pregnant.

Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant.

This registry is collecting information about the safety of antiepileptic drugs during pregnancy.

To enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations (8.1) ] .

17.4 Suicidal Thinking and Behavior Counsel patients, their caregivers, and families that AEDs, including valproic acid capsules, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Instruct patients, caregivers, and families to report behaviors of concern immediately to the healthcare providers [see Warnings and Precautions (5.8) ].

17.5 Hyperammonemia Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.10 , 5.11) ] .

17.6 CNS Depression Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug.

17.7 Multi-Organ Hypersensitivity Reactions Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see Warnings and Precautions (5.13) ] .

DOSAGE AND ADMINISTRATION

2 Valproic acid capsules are intended for oral administration.

( 2.1 ) Simple and Complex Absence Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/week until seizure control or limiting side effects ( 2.1 ) Safety of doses above 60 mg/kg/day is not established ( 2.1 , 2.2 ) 2.1 Epilepsy Valproic acid capsules are intended for oral administration.

Valproic acid capsules should be swallowed whole without chewing to avoid local irritation of the mouth and throat.

Patients should be informed to take valproic acid capsules every day as prescribed.

If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose.

If a dose is skipped, the patient should not double the next dose.

Valproic acid capsules are indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures.

As the valproic acid capsules dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2) ] .

Complex Partial Seizures For adults and children 10 years of age or older.

Monotherapy (Initial Therapy) Valproic acid capsules have not been systematically studied as initial therapy.

Patients should initiate therapy at 10 to 15 mg/kg/day.

The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response.

Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day.

If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL).

No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males.

The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

Conversion to Monotherapy Patients should initiate therapy at 10 to 15 mg/kg/day.

The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response.

Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day.

If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL).

No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks.

This reduction may be started at initiation of valproic acid capsules therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction.

The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.

Adjunctive Therapy Valproic acid capsules may be added to the patient’s regimen at a dosage of 10 to 15 mg/kg/day.

The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response.

Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day.

If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL).

No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

If the total daily dose exceeds 250 mg, it should be given in divided doses.

In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to divalproex sodium tablets, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14) ] .

However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7) ] .

Simple and Complex Absence Seizures The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases.

The maximum recommended dosage is 60 mg/kg/day.

If the total daily dose exceeds 250 mg, it should be given in divided doses.

A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect.

However, therapeutic valproate serum concentration for most patients with absence seizures is considered to range from 50 to 100 mcg/mL.

Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3) ].

As the valproic acid capsules dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2) ] .

Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.

The following Table is a guide for the initial daily dose of valproic acid capsules (15 mg/kg/day): Table 1.

Initial Daily Dose Weight Total Daily Dose (mg) Number of Capsules (Kg) (Lb) Dose 1 Dose 2 Dose 3 10 – 24.9 22 – 54.9 250 0 0 1 25 – 39.9 55 – 87.9 500 1 0 1 40 – 59.9 88 – 131.9 750 1 1 1 60 – 74.9 132 – 164.9 1,000 1 1 2 75 – 89.9 165 – 197.9 1,250 2 1 2 2.2 General Dosing Advice Dosing in Elderly Patients Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients.

Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions.

Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence.

The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.15) , Use in Specific Populations (8.5) and Clinical Pharmacology (12.3) ] .

Dose-Related Adverse Reactions The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related.

The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.9) ] .

The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

G.I.

Irritation Patients who experience G.I.

irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.

Bactrim DS 800 MG/ 160 MG Oral Tablet

WARNINGS

FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF SULFONAMIDES, ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, FULMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS, APLASTIC ANEMIA AND OTHER BLOOD DYSCRASIAS.

SULFONAMIDES, INCLUDING SULFONAMIDE-CONTAINING PRODUCTS SUCH AS SULFAMETHOXAZOLE/TRIMETHOPRIM, SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH OR ANY SIGN OF ADVERSE REACTION.

In rare instances, a skin rash may be followed by a more severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, and serious blood disorders (see PRECAUTIONS ).

Clinical signs, such as rash, sore throat, fever, arthralgia, pallor, purpura or jaundice may be early indications of serious reactions.

Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment.

Thrombocytopenia Thrombocytopenia has been reported with both sulfamethoxazole and trimethoprim usage.

A case control study found a 124-fold increased risk of severe thrombocytopenia (platelets <30,000 µL, requiring hospitalization) with sulfamethoxazole and trimethoprim in combination with an incidence of 2 cases per 1000 patient-years of exposure.

6 The incidence of less severe thrombocytopenia may be higher.

Thrombocytopenia caused by sulfamethoxazole and trimethoprim may be immune-mediated.

Drug-induced immune-mediated thrombocytopenia with sulfamethoxazole/trimethoprim is characterized by a drug-dependent antibody that is itself nonreactive, but when soluble drug is present at pharmacologic concentrations, antibody binds tightly to specific platelet membrane glycoproteins, causing platelet destruction.

7 Serologic testing for drug-specific antibody is commercially available and may be useful for identifying the specific cause of thrombocytopenia in individual cases.

Testing is important because a patient with drug-dependent antibodies should not be re-exposed to BACTRIM (see CONTRAINDICATIONS ).

Typically, a patient with immune thrombocytopenia will have taken drug for about 1 week or intermittently over a longer period of time (possibly years) before presenting with petechiae or bruising.

Systemic symptoms, such as lightheadedness, chills, fever, nausea, and vomiting, often may precede bleeding events.

Thrombocytopenia may be severe.

Patients should have risk/benefit re-evaluated in order to continue treatment with BACTRIM.

If the drug is stopped, symptoms usually resolve within 1 or 2 days and platelet count returns to normal in less than 1 week.

If BACTRIM is not stopped, there is a risk of fatal hemorrhage.

The onset of thrombocytopenia may be more rapid upon re-exposure.

Sulfamethoxazole has also been shown to occasionally trigger the production of platelet-specific autoantibodies leading to a clinical picture indistinguishable from spontaneous autoimmune thrombocytopenia.

In such cases, autoantibodies remain present for up to 9 weeks after sulfamethoxazole has been stopped, corresponding with a marked reduction in platelet counts for the same period.

The sulfonamides should not be used for treatment of group A β-hemolytic streptococcal infections.

In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including BACTRIM, and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C.

difficile .

C.

difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing strains of C.

difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibiotic use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C.

difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C.

difficile , and surgical evaluation should be instituted as clinically indicated.

DRUG INTERACTIONS

Drug Interactions: In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported.

It has been reported that BACTRIM may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin.

This interaction should be kept in mind when BACTRIM is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed.

BACTRIM may inhibit the hepatic metabolism of phenytoin.

BACTRIM, given at a common clinical dosage, increased the phenytoin half-life by 39% and decreased the phenytoin metabolic clearance rate by 27%.

When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect.

Sulfonamides can also displace methotrexate from plasma protein binding sites and can compete with the renal transport of methotrexate, thus increasing free methotrexate concentrations.

There have been reports of marked but reversible nephrotoxicity with coadministration of BACTRIM and cyclosporine in renal transplant recipients.

Increased digoxin blood levels can occur with concomitant BACTRIM therapy, especially in elderly patients.

Serum digoxin levels should be monitored.

Increased sulfamethoxazole blood levels may occur in patients who are also receiving indomethacin.

Occasional reports suggest that patients receiving pyrimethamine as malaria prophylaxis in doses exceeding 25 mg weekly may develop megaloblastic anemia if BACTRIM is prescribed.

The efficacy of tricyclic antidepressants can decrease when coadministered with BACTRIM.

Like other sulfonamide-containing drugs, BACTRIM potentiates the effect of oral hypoglycemics.

In the literature, a single case of toxic delirium has been reported after concomitant intake of sulfamethoxazole/trimethoprim and amantadine.

In the literature, three cases of hyperkalemia in elderly patients have been reported after concomitant intake of sulfamethoxazole/trimethoprim and an angiotensin converting enzyme inhibitor.

10,11

OVERDOSAGE

Acute: The amount of a single dose of BACTRIM that is either associated with symptoms of overdosage or is likely to be life-threatening has not been reported.

Signs and symptoms of overdosage reported with sulfonamides include anorexia, colic, nausea, vomiting, dizziness, headache, drowsiness and unconsciousness.

Pyrexia, hematuria and crystalluria may be noted.

Blood dyscrasias and jaundice are potential late manifestations of overdosage.

Signs of acute overdosage with trimethoprim include nausea, vomiting, dizziness, headache, mental depression, confusion and bone marrow depression.

General principles of treatment include the institution of gastric lavage or emesis, forcing oral fluids, and the administration of intravenous fluids if urine output is low and renal function is normal.

Acidification of the urine will increase renal elimination of trimethoprim.

The patient should be monitored with blood counts and appropriate blood chemistries, including electrolytes.

If a significant blood dyscrasia or jaundice occurs, specific therapy should be instituted for these complications.

Peritoneal dialysis is not effective and hemodialysis is only moderately effective in eliminating sulfamethoxazole and trimethoprim.

Chronic: Use of BACTRIM at high doses and/or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia and/or megaloblastic anemia.

If signs of bone marrow depression occur, the patient should be given leucovorin 5 to 15 mg daily until normal hematopoiesis is restored.

DESCRIPTION

BACTRIM (sulfamethoxazole and trimethoprim) is a synthetic antibacterial combination product available in DS (double strength) tablets, each containing 800 mg sulfamethoxazole and 160 mg trimethoprim; in tablets, each containing 400 mg sulfamethoxazole and 80 mg trimethoprim for oral administration.

Sulfamethoxazole is N 1 -(5-methyl-3-isoxazolyl)sulfanilamide; the molecular formula is C 10 H 11 N 3 O 3 S.

It is an almost white, odorless, tasteless compound with a molecular weight of 253.28 and the following structural formula: Trimethoprim is 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine; the molecular formula is C 14 H 18 N 4 O 3 .

It is a white to light yellow, odorless, bitter compound with a molecular weight of 290.3 and the following structural formula: Inactive ingredients: Docusate sodium 85%, sodium benzoate 15%, sodium starch glycolate, magnesium stearate and pregelatinized starch.

Chemical Structure Chemical Structure

HOW SUPPLIED

BACTRIM™ TABLETS are supplied as follows: BACTRIM™ DS (double strength) TABLETS (white, oval shaped, scored) containing 160 mg trimethoprim and 800 mg sulfamethoxazole – bottles of 10 ( NDC 54868-0337-3 ), bottles of 20 ( NDC 54868-0337-0 ), bottles of 30 ( NDC 54868-0337-1 ).

Imprint on tablets (debossed): (front) BACTRIM DS Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature] DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.

GERIATRIC USE

Geriatric Use: Clinical studies of BACTRIM did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

There may be an increased risk of severe adverse reactions in elderly patients, particularly when complicating conditions exist, e.g., impaired kidney and/or liver function, possible folate deficiency, or concomitant use of other drugs.

Severe skin reactions, generalized bone marrow suppression (see WARNINGS and ADVERSE REACTIONS sections), a specific decrease in platelets (with or without purpura), and hyperkalemia are the most frequently reported severe adverse reactions in elderly patients.

In those concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported.

Increased digoxin blood levels can occur with concomitant BACTRIM therapy, especially in elderly patients.

Serum digoxin levels should be monitored.

Hematological changes indicative of folic acid deficiency may occur in elderly patients.

These effects are reversible by folinic acid therapy.

Appropriate dosage adjustments should be made for patients with impaired kidney function and duration of use should be as short as possible to minimize risks of undesired reactions (see DOSAGE AND ADMINISTRATION section).

The trimethoprim component of BACTRIM may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency or when given concomitantly with drugs known to induce hyperkalemia, such as angiotensin converting enzyme inhibitors.

Close monitoring of serum potassium is warranted in these patients.

Discontinuation of BACTRIM treatment is recommended to help lower potassium serum levels.

Bactrim Tablets contain 1.8 mg sodium (0.08 mEq) of sodium per tablet.

Bactrim DS Tablets contain 3.6 mg (0.16 mEq) of sodium per tablet.

Pharmacokinetics parameters for sulfamethoxazole were similar for geriatric subjects and younger adult subjects.

The mean maximum serum trimethoprim concentration was higher and mean renal clearance of trimethoprim was lower in geriatric subjects compared with younger subjects (see CLINICAL PHARMACOLOGY: Geriatric Pharmacokinetics ).

INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Bactrim (sulfamethoxazole and trimethoprim) tablets and other antibacterial drugs, Bactrim (sulfamethoxazole and trimethoprim) tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.

In the absence of such data, local epidemiology and susceptibility patterns may contribute to empiric selection of therapy.

Urinary Tract Infections: For the treatment of urinary tract infections due to susceptible strains of the following organisms: Escherichia coli , Klebsiella species, Enterobacter species, Morganella morganii , Proteus mirabilis and Proteus vulgaris .

It is recommended that initial episodes of uncomplicated urinary tract infections be treated with a single effective antibacterial agent rather than the combination.

Acute Otitis Media: For the treatment of acute otitis media in pediatric patients due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when in the judgment of the physician sulfamethoxazole and trimethoprim offers some advantage over the use of other antimicrobial agents.

To date, there are limited data on the safety of repeated use of BACTRIM in pediatric patients under two years of age.

BACTRIM is not indicated for prophylactic or prolonged administration in otitis media at any age.

Acute Exacerbations of Chronic Bronchitis in Adults: For the treatment of acute exacerbations of chronic bronchitis due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when in the judgment of the physician BACTRIM offers some advantage over the use of a single antimicrobial agent.

Shigellosis: For the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei when antibacterial therapy is indicated.

Pneumocystis Carinii Pneumonia: For the treatment of documented Pneumocystis carinii pneumonia and for prophylaxis against Pneumocystis carinii pneumonia in individuals who are immunosuppressed and considered to be at an increased risk of developing Pneumocystis carinii pneumonia.

Traveler’s Diarrhea in Adults: For the treatment of traveler’s diarrhea due to susceptible strains of enterotoxigenic E.

coli .

PEDIATRIC USE

Pediatric Use: BACTRIM is not recommended for infants younger than 2 months of age (see INDICATIONS and CONTRAINDICATIONS sections).

PREGNANCY

Pregnancy: Teratogenic Effects: Pregnancy Category C.

In rats, oral doses of 533 mg/kg or 200 mg/kg produced teratologic effects manifested mainly as cleft palates.

The highest dose which did not cause cleft palates in rats was 512 mg/kg sulfamethoxazole or 192 mg/kg trimethoprim when administered separately.

In two studies in rats, no teratology was observed when 512 mg/kg of sulfamethoxazole was used in combination with 128 mg/kg of trimethoprim.

In one study, however, cleft palates were observed in one litter out of 9 when 355 mg/kg of sulfamethoxazole was used in combination with 88 mg/kg of trimethoprim.

In some rabbit studies, an overall increase in fetal loss (dead and resorbed and malformed conceptuses) was associated with doses of trimethoprim 6 times the human therapeutic dose.

While there are no large, well-controlled studies on the use of sulfamethoxazole and trimethoprim in pregnant women, Brumfitt and Pursell, 12 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or sulfamethoxazole and trimethoprim.

The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving sulfamethoxazole and trimethoprim.

There were no abnormalities in the 10 children whose mothers received the drug during the first trimester.

In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received oral sulfamethoxazole and trimethoprim at the time of conception or shortly thereafter.

Because sulfamethoxazole and trimethoprim may interfere with folic acid metabolism, BACTRIM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects: See CONTRAINDICATIONS section.

NUSRING MOTHERS

Nursing Mothers: See CONTRAINDICATIONS section.

INFORMATION FOR PATIENTS

Information for Patients: Patients should be counseled that antibacterial drugs including Bactrim (sulfamethoxazole and trimethoprim) tablets should only be used to treat bacterial infections.

They do not treat viral infections (e.g., the common cold).

When Bactrim (sulfamethoxazole and trimethoprim) tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.

Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Bactrim (sulfamethoxazole and trimethoprim) tablets or other antibacterial drugs in the future.

Patients should be instructed to maintain an adequate fluid intake in order to prevent crystalluria and stone formation.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued.

Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic.

If this occurs, patients should contact their physician as soon as possible.

DOSAGE AND ADMINISTRATION

Not recommended for use in pediatric patients less than 2 months of age.

Urinary Tract Infections and Shigellosis in Adults and Pediatric Patients, and Acute Otitis Media in Children: Adults: The usual adult dosage in the treatment of urinary tract infections is 1 BACTRIM DS (double strength) tablet or 2 BACTRIM tablets every 12 hours for 10 to 14 days.

An identical daily dosage is used for 5 days in the treatment of shigellosis.

Children: The recommended dose for children with urinary tract infections or acute otitis media is 40 mg/kg sulfamethoxazole and 8 mg/kg trimethoprim per 24 hours, given in two divided doses every 12 hours for 10 days.

An identical daily dosage is used for 5 days in the treatment of shigellosis.

The following table is a guideline for the attainment of this dosage: Children 2 months of age or older: Weight Dose–every 12 hours lb kg Tablets 22 10 – 44 20 1 66 30 1½ 88 40 2 or 1 DS tablet For Patients with Impaired Renal Function: When renal function is impaired, a reduced dosage should be employed using the following table: Creatinine Clearance (mL/min) Recommended Dosage Regimen Above 30 Usual standard regimen 15–30 ½ the usual regimen Below 15 Use not recommended Acute Exacerbations of Chronic Bronchitis in Adults: The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is 1 BACTRIM DS (double strength) tablet or 2 BACTRIM tablets every 12 hours for 14 days.

Pneumocystis Carinii Pneumonia: Treatment: Adults and Children: The recommended dosage for treatment of patients with documented Pneumocystis carinii pneumonia is 75 to 100 mg/kg sulfamethoxazole and 15 to 20 mg/kg trimethoprim per 24 hours given in equally divided doses every 6 hours for 14 to 21 days.

13 The following table is a guideline for the upper limit of this dosage: Weight Dose–every 6 hours lb kg Tablets 18 8 – 35 16 1 53 24 1½ 70 32 2 or 1 DS tablet 88 40 2½ 106 48 3 or 1½ DS tablets 141 64 4 or 2 DS tablets 176 80 5 or 2½ DS tablets For the lower limit dose (75 mg/kg sulfamethoxazole and 15 mg/kg trimethoprim per 24 hours) administer 75% of the dose in the above table.

Prophylaxis: Adults: The recommended dosage for prophylaxis in adults is 1 BACTRIM DS (double strength) tablet daily.

14 Children: For children, the recommended dose is 750 mg/m 2 /day sulfamethoxazole with 150 mg/m 2 /day trimethoprim given orally in equally divided doses twice a day, on 3 consecutive days per week.

The total daily dose should not exceed 1600 mg sulfamethoxazole and 320 mg trimethoprim.

15 The following table is a guideline for the attainment of this dosage in children: Body Surface Area Dose–every 12 hours (m 2 ) Tablets 0.26 – 0.53 ½ 1.06 1 Traveler’s Diarrhea in Adults: For the treatment of traveler’s diarrhea, the usual adult dosage is 1 BACTRIM DS (double strength) tablet or 2 BACTRIM tablets every 12 hours for 5 days.

quetiapine 50 MG Oral Tablet

DRUG INTERACTIONS

7 The risks of using quetiapine in combination with other drugs have not been extensively evaluated in systematic studies.

Given the primary CNS effects of quetiapine, caution should be used when it is taken in combination with other centrally acting drugs.

Quetiapine potentiated the cognitive and motor effects of alcohol in a clinical trial in subjects with selected psychotic disorders, and alcoholic beverages should be avoided while taking quetiapine fumarate tablets.

Because of its potential for inducing hypotension, quetiapine may enhance the effects of certain antihypertensive agents.

Quetiapine may antagonize the effects of levodopa and dopamine agonists.

The use of quetiapine should be avoided in combination with drugs known to increase QT interval, and caution should be exercised when quetiapine is used in combination with drugs known to cause electrolyte imbalance [ see Warnings and Precautions (5.12)].

There have been literature reports suggesting false positive results in urine enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine.

Caution should be exercised in the interpretation of positive urine drug screen results for these drugs, and confirmation by alternative analytical technique (e.g.

chromatographic methods) should be considered.

P450 3A Inhibitors: May decrease the clearance of quetiapine.

Lower doses of quetiapine may be required.

( 7.1 ) Hepatic Enzyme Inducers: May increase the clearance of quetiapine.

Higher doses of quetiapine may be required with phenytoin or other inducers.

( 7.1 ) Centrally Acting Drugs: Caution should be used when quetiapine is used in combination with other CNS acting drugs.

( 7 ) Antihypertensive Agents: Quetiapine may add to the hypotensive effects of these agents.

( 7 ) Levodopa and Dopamine Agents: Quetiapine may antagonize the effect of these drugs.

( 7 ) Drugs known to cause electrolyte imbalance or increase QT interval: Caution should be used when quetiapine is used concomitantly with these drugs.

( 7 ) Interference with Urine Drug Screens: False positive urine drug screens using immunoassays for methadone or tricyclic antidepressants (TCAs) in patients taking quetiapine have been reported.

( 7 ).

7.1 The Effect of Other Drugs on Quetiapine Phenytoin: Coadministration of quetiapine (250 mg three times daily) and phenytoin (100 mg three times daily) increased the mean oral clearance of quetiapine by 5-fold.

Increased doses of quetiapine may be required to maintain control of symptoms of schizophrenia in patients receiving quetiapine and phenytoin, or other hepatic enzyme inducers (e.g., carbamazepine, barbiturates, rifampin, glucocorticoids).

Caution should be taken if phenytoin is withdrawn and replaced with a non-inducer (e.g., valproate) [see Dosage and Administration (2)].

Divalproex: Coadministration of quetiapine (150 mg twice daily) and divalproex (500 mg twice daily) increased the mean maximum plasma concentration of quetiapine at steady state by 17% without affecting the extent of absorption or mean oral clearance.

Thioridazine: Thioridazine (200 mg twice daily) increased the oral clearance of quetiapine (300 mg twice daily) by 65%.

Cimetidine: Administration of multiple daily doses of cimetidine (400 mg three times daily for 4 days) resulted in a 20% decrease in the mean oral clearance of quetiapine (150 mg three times daily).

Dosage adjustment for quetiapine is not required when it is given with cimetidine.

P450 3A Inhibitors: Coadministration of ketoconazole (200 mg once daily for 4 days), a potent inhibitor of cytochrome P450 3A, reduced oral clearance of quetiapine by 84%, resulting in a 335% increase in maximum plasma concentration of quetiapine.

Caution (reduced dosage) is indicated when quetiapine is administered with ketoconazole and other inhibitors of cytochrome P450 3A (e.g., itraconazole, fluconazole, erythromycin, and protease inhibitors).

Fluoxetine, Imipramine, Haloperidol, and Risperidone: Coadministration of fluoxetine (60 mg once daily), imipramine (75 mg twice daily), haloperidol (7.5 mg twice daily), or risperidone (3 mg twice daily) with quetiapine (300 mg twice daily) did not alter the steady-state pharmacokinetics of quetiapine.

7.2 Effect of Quetiapine on Other Drugs Lorazepam: The mean oral clearance of lorazepam (2 mg, single dose) was reduced by 20% in the presence of quetiapine administered as 250 mg three times daily dosing.

Divalproex: The mean maximum concentration and extent of absorption of total and free valproic acid at steady state were decreased by 10 to 12% when divalproex (500 mg twice daily) was administered with quetiapine (150 mg twice daily).

The mean oral clearance of total valproic acid (administered as divalproex 500 mg twice daily) was increased by 11% in the presence of quetiapine (150 mg twice daily).

The changes were not significant.

Lithium: Concomitant administration of quetiapine (250 mg three times daily) with lithium had no effect on any of the steady-state pharmacokinetic parameters of lithium.

Antipyrine: Administration of multiple daily doses up to 750 mg/day (on a three times daily schedule) of quetiapine to subjects with selected psychotic disorders had no clinically relevant effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites.

These results indicate that quetiapine does not significantly induce hepatic enzymes responsible for cytochrome P450 mediated metabolism of antipyrine.

OVERDOSAGE

10 10.1 Human Experience In clinical trials, survival has been reported in acute overdoses of up to 30 grams of quetiapine.

Most patients who overdosed experienced no adverse reactions or recovered fully from the reported reactions.

Death has been reported in a clinical trial following an overdose of 13.6 grams of quetiapine alone.

In general, reported signs and symptoms were those resulting from an exaggeration of the drugs known pharmacological effects, ie, drowsiness and sedation, tachycardia and hypotension.

Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose [see Warnings and Precautions (5)].

One case, involving an estimated overdose of 9600 mg, was associated with hypokalemia and first degree heart block.

In post-marketing experience, there were cases reported of QT prolongation with overdose.

There were also very rare reports of overdose of quetiapine alone resulting in death or coma.

10.2 Management of Overdosage In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation.

Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered.

The possibility of obtundation, seizure or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.

Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

If antiarrhythmic therapy is administered, disopyramide, procainamide and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with acute overdosage of quetiapine.

Similarly it is reasonable to expect that the alpha-adrenergic-blocking properties of bretylium might be additive to those of quetiapine, resulting in problematic hypotension.

There is no specific antidote to quetiapine.

Therefore, appropriate supportive measures should be instituted.

The possibility of multiple drug involvement should be considered.

Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of quetiapine-induced alpha blockade).

In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.

Close medical supervision and monitoring should continue until the patient recovers.

DESCRIPTION

11 Quetiapine fumarate is a psychotropic agent belonging to a chemical class, the dibenzothiazepine derivatives.

The chemical designation is 2-[2-(4-dibenzo [b,f] [1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol fumarate (2:1) (salt).

It is present in tablets as the fumarate salt.

All doses and tablet strengths are expressed as milligrams of base, not as fumarate salt.

Its molecular formula is C 42 H 50 N 6 O 4 S 2 •C 4 H 4 O 4 and it has a molecular weight of 883.11 (fumarate salt).

The structural formula is: Quetiapine fumarate is a white to off-white crystalline powder which is moderately soluble in water.

Quetiapine fumarate tablets are supplied for oral administration as 25 mg (round, peach), 50 mg (round, white), 100 mg (round, yellow), 200 mg (round, white), 300 mg (capsule-shaped, white), and 400 mg (capsule-shaped, yellow) tablets.

Inactive ingredients are croscarmellose sodium, colloidal silicon dioxide, fumaric acid, ethylcellulose, magnesium stearate, hypromellose, hydroxylpropyl cellulose, polyethylene glycol, and titanium dioxide.

The 25 mg tablets also contain red ferric oxide and yellow ferric oxide and the 100 mg and 400 mg tablets contain only yellow ferric oxide.

Chemical Structure- Quetiapine Fumarate

CLINICAL STUDIES

14 14.1 Schizophrenia Adults The efficacy of quetiapine in the treatment of schizophrenia was established in 3 short-term (6 week) controlled trials of inpatients with schizophrenia who met DSM III-R criteria for schizophrenia.

Although a single fixed dose haloperidol arm was included as a comparative treatment in one of the three trials, this single haloperidol dose group was inadequate to provide a reliable and valid comparison of quetiapine and haloperidol.

Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia.

The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients.

A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient.

The results of the trials follow: In a 6 week, placebo-controlled trial (n=361) involving 5 fixed doses of quetiapine fumarate (75 mg/day, 150 mg/day, 300 mg/day, 600 mg/day and 750 mg/day given in divided doses three times per day), the 4 highest doses of quetiapine fumarate tablets were generally superior to placebo on the BPRS total score, the BPRS psychosis cluster and the CGI severity score, with the maximal effect seen at 300 mg/day, and the effects of doses of 150 mg/day to 750 mg/day were generally indistinguishable.

In a 6 week, placebo-controlled trial (n=286) involving titration of quetiapine fumarate in high (up to 750 mg/day given in divided doses three times per day) and low (up to 250 mg/day given in divided doses three times per day) doses, only the high dose quetiapine fumarate group (mean dose, 500 mg/day) was superior to placebo on the BPRS total score, the BPRS psychosis cluster, and the CGI severity score.

In a 6 week dose and dose regimen comparison trial (n=618) involving two fixed doses of quetiapine fumarate(450 mg/day given in divided doses both twice daily and three times daily and 50 mg/day given in divided doses twice daily), only the 450 mg/day (225 mg given twice daily) dose group was superior to the 50 mg/day (25 mg given twice daily) quetiapine fumarate dose group on the BPRS total score, the BPRS psychosis cluster, and the CGI severity score.

Examination of population subsets (race, gender, and age) did not reveal any differential responsiveness on the basis of race or gender, with an apparently greater effect in patients under the age of 40 years compared to those older than 40.

The clinical significance of this finding is unknown.

Adolescents (ages 13-17) Clinical trial information in patients (13 to 17 years of age) with schizophrenia is approved for AstraZeneca Pharmaceuticals LP’s quetiapine fumarate drug product labeling.

However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights; this drug product is not labeled for such use in those adolescent patients.

14.2 Bipolar Disorder Manic Episodes Adults The efficacy of quetiapine fumarate in the acute treatment of manic episodes was established in 3 placebo-controlled trials in patients who met DSM-IV criteria for bipolar I disorder with manic episodes.

These trials included patients with or without psychotic features and excluded patients with rapid cycling and mixed episodes.

Of these trials, 2 were monotherapy (12 weeks) and 1 was adjunct therapy (3 weeks) to either lithium or divalproex.

Key outcomes in these trials were change from baseline in the Young Mania Rating Scale (YMRS) score at 3 and 12 weeks for monotherapy and at 3 weeks for adjunct therapy.

Adjunct therapy is defined as the simultaneous initiation or subsequent administration of quetiapine fumarate with lithium or divalproex.

The primary rating instrument used for assessing manic symptoms in these trials was YMRS, an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score).

The results of the trials follow: Monotherapy The efficacy of quetiapine fumarate in the acute treatment of bipolar mania was established in 2 placebo-controlled trials.

In two 12-week trials (n=300, n=299) comparing quetiapine fumarate to placebo, quetiapine fumarate was superior to placebo in the reduction of the YMRS total score at weeks 3 and 12.

The majority of patients in these trials taking quetiapine fumarate were dosed in a range between 400 mg/day and 800 mg per day.

Adjunct Therapy In this 3-week placebo-controlled trial, 170 patients with bipolar mania (YMRS > 20) were randomized to receive quetiapine fumarate or placebo as adjunct treatment to lithium or divalproex.

Patients may or may not have received an adequate treatment course of lithium or divalproex prior to randomization.

Quetiapine fumarate was superior to placebo when added to lithium or divalproex alone in the reduction of YMRS total score.

The majority of patients in this trial taking quetiapine fumarate tablets were dosed in a range between 400 mg/day and 800 mg per day.

In a similarly designed trial (n=200), quetiapine fumarate was associated with an improvement in YMRS scores but did not demonstrate superiority to placebo, possibly due to a higher placebo effect.

Children and Adolescents (ages 10-17) Clinical trial use information in patients (10 to 17 years of age) with bipolar mania is approved for AstraZeneca Pharmaceuticals LP’s quetiapine fumarate drug product labeling.

However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights; this drug product is not labeled for such use in those pediatric patients.

Depressive Episodes Adults The efficacy of quetiapine fumarate for the acute treatment of depressive episodes associated with bipolar disorder was established in 2 identically designed 8-week, randomized, double-blind, placebo-controlled studies (N=1045).

These studies included patients with either bipolar I or II disorder and those with or without a rapid cycling course.

Patients randomized to quetiapine fumarate were administered fixed doses of either 300 mg or 600 mg once daily.

The primary rating instrument used to assess depressive symptoms in these studies was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10 item clinician-rated scale with scores ranging from 0 to 60.

The primary endpoint in both studies was the change from baseline in MADRS score at week 8.

In both studies, quetiapine fumarate was superior to placebo in reduction of MADRS score.

Improvement in symptoms, as measured by change in MADRS score relative to placebo, was seen in both studies at Day 8 (week 1) and onwards.

In these studies, no additional benefit was seen with the 600 mg dose.

For the 300 mg dose group, statistically significant improvements over placebo were seen in overall quality of life and satisfaction related to various areas of functioning, as measured using the Q-LES-Q(SF).

Maintenance Treatment as an Adjunct to Lithium or Divalproex The efficacy of quetiapine fumarate in the maintenance treatment of bipolar I disorder was established in 2 placebo-controlled trials in patients (n=1326) who met DSM-IV criteria for bipolar I disorder.

The trials included patients whose most recent episode was manic, depressed, or mixed, with or without psychotic features.

In the open-label phase, patients were required to be stable on quetiapine fumarate plus lithium or divalproex for at least 12 weeks in order to be randomized.

On average, patients were stabilized for 15 weeks.

In the randomization phase, patients continued treatment with lithium or divalproex and were randomized to receive either quetiapine fumarate (administered twice daily totaling 400 mg/day to 800 mg/day) or placebo.

Approximately 50% of the patients had discontinued from the quetiapine fumarate group by day 280 and 50% of the placebo group had discontinued by day 117 of double-blind treatment.

The primary endpoint in these studies was time to recurrence of a mood event (manic, mixed or depressed episode).

A mood event was defined as medication initiation or hospitalization for a mood episode; YMRS score ≥ 20 or MADRS score ≥ 20 at 2 consecutive assessments; or study discontinuation due to a mood event.

In both studies, quetiapine fumarate was superior to placebo in increasing the time to recurrence of any mood event.

The treatment effect was present for increasing time to recurrence of both manic and depressed episodes.

The effect of quetiapine fumarate was independent of any specific subgroup (assigned mood stabilizer, sex, age, race, most recent bipolar episode, or rapid cycling course).

HOW SUPPLIED

16 /STORAGE AND HANDLING 25 mg Tablets : Peach, round, biconvex, film coated tablets.

Engraved with ‘APO’ on one side and “QUE’ over ‘25’ on the other side.

They are supplied as follows: Bottles of 100 (NDC 60429-371-01) Bottles of 1000 (NDC 60429-371-10) 50 mg Tablets : White, round, biconvex, film coated tablets.

Engraved with ‘APO’ on one side and ‘QUE’ over ‘50’ on the other side.

They are supplied as follows: Bottles of 100 (NDC 60429-372-01) Bottles of 1000 (NDC 60429-372-10) 100 mg Tablets : Yellow, round, biconvex film coated tablets.

Engraved with ‘APO’ on one side and ‘QUE’ over ‘100’ on the other side.

They are supplied as follows: Bottles of 100 (NDC 60429-373-01) Bottles of 1000 (NDC 60429-373-10) 200 mg Tablets : White, round, biconvex, film coated tablets.

Engraved ‘APO’ on one side and ‘QUE’ over ‘200’ on the other side.

They are supplied as follows: Bottles of 100 (NDC 60429-374-01) Bottles of 1000 (NDC 60429-374-10) 300 mg Tablets : White, capsule-shaped, biconvex, film coated tablets.

Engraved ‘APO’ on one side and ‘QUE300’ on the other side.

They are supplied as follows: Bottles of 60 (NDC 60429-375-60) 400 mg Tablets : Yellow, capsule-shaped, biconvex, film coated tablets.

Engraved ‘APO’ on one side and ‘QUE 400’ on the other side.

They are supplied as follows: Bottles of 100 (NDC 60429-376-01) Storage Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15 to 30ºC (59 to 86ºF) [See USP Controlled Room Temperature].

RECENT MAJOR CHANGES

Warnings and Precautions, Hyperglycemia ( 5.4 ), 1/2011 Warnings and Precautions, Hyperlipidemia ( 5.5 ), 1/2011 Warnings and Precautions, Weight Gain ( 5.6 ), 1/2011 Warnings and Precautions, QT Prolongation ( 5.12 ), 6/2011 Warnings and Precautions, Hypothyroidism ( 5.14 ), 1/2011 Warnings and Precautions, Withdrawal ( 5.23 ), 5/2010

GERIATRIC USE

8.5 Geriatric Use Of the approximately 3700 patients in clinical studies with quetiapine, 7% (232) were 65 years of age or over.

In general, there was no indication of any different tolerability of quetiapine in the elderly compared to younger adults.

Nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to quetiapine, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period in the elderly.

The mean plasma clearance of quetiapine was reduced by 30% to 50% in elderly patients when compared to younger patients [ see Clinical Pharmacology (12) and Dosage and Administration (2)].

DOSAGE FORMS AND STRENGTHS

3 25 mg tablets 50 mg tablets 100 mg tablets 200 mg tablets 300 mg tablets 400 mg tablets 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, and 400 mg ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action The mechanism of action of quetiapine, as with other drugs having efficacy in the treatment of schizophrenia and bipolar disorder, is unknown.

However, it has been proposed that the efficacy of quetiapine in schizophrenia and its mood stabilizing properties in bipolar depression and mania are mediated through a combination of dopamine type 2 (D 2 ) and serotonin type 2 (5HT 2 ) antagonism.

Antagonism at receptors other than dopamine and 5HT 2 with similar receptor affinities may explain some of the other effects of quetiapine.

Quetiapine’s antagonism of histamine H 1 receptors may explain the somnolence observed with this drug.

Quetiapine’s antagonism of adrenergic α 1 receptors may explain the orthostatic hypotension observed with this drug.

INDICATIONS AND USAGE

1 Quetiapine Fumarate Tablets is an atypical antipsychotic indicated for the: Treatment of schizophrenia ( 1.1 ) • Adults: Efficacy was established in three 6 week clinical trials in patients with schizophrenia ( 14.1 ) Acute treatment of manic episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or divalproex ( 1.2 ) Adults: Efficacy was established in two 12 week monotherapy trials and in one 3 week adjunctive trial in patients with manic episodes associated with bipolar I disorder ( 14.2 ) Acute treatment of depressive episodes associated with bipolar disorder ( 1.2 ) Adults: Efficacy was established in two 8 week trials in patients with bipolar I or II disorder ( 14.2 ) Maintenance treatment of bipolar I disorder as an adjunct to lithium or divalproex ( 1.2 ) Adults: Efficacy was established in two maintenance trials in adults ( 14.2 ) 1.1 Schizophrenia Quetiapine fumarate tablets are indicated for the treatment of schizophrenia.

The efficacy of quetiapine fumarate tablets in schizophrenia was established in three 6 week trials in adults.

The effectiveness of quetiapine fumarate tablets for the maintenance treatment of schizophrenia has not been systematically evaluated in controlled clinical trials [see Clinical Studies (14.1)].

Pediatric use information in patients (13 to 17 years of age) with schizophrenia is approved for AstraZeneca Pharmaceuticals LP’s quetiapine fumarate drug product labeling.

However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights; this drug product is not labeled for use in those adolescent patients.

1.2 Bipolar Disorder Quetiapine fumarate tablets are indicated for the acute treatment of manic episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or divalproex.

Efficacy was established in two 12 week monotherapy trials in adults, in one 3 week adjunctive trial in adults [ see Clinical Studies (14.2)].

Quetiapine fumarate tablets are indicated as monotherapy for the acute treatment of depressive episodes associated with bipolar disorder.

Efficacy was established in two 8 week monotherapy trials in adult patients with bipolar I and bipolar II disorder [ see Clinical Studies (14.2)].

Quetiapine fumarate tablets are indicated for the maintenance treatment of bipolar I disorder, as an adjunct to lithium or divalproex.

Efficacy was established in two maintenance trials in adults.

The effectiveness of quetiapine fumarate tablets as monotherapy for the maintenance treatment of bipolar disorder has not been systematically evaluated in controlled clinical trials [ see Clinical Studies (14.2)].

Pediatric use information in patients (10 to 17 years of age) with bipolar mania is approved for AstraZeneca Pharmaceuticals LP’s quetiapine fumarate drug product labeling.

However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights; this drug product is not labeled for use in those pediatric patients.

1.3 Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder Pediatric use information in patients (13 to 17 years of age) with schizophrenia, and patients (10 to 17 years of age) with bipolar mania is approved for AstraZeneca Pharmaceuticals LP’s quetiapine fumarate drug product labeling.

However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights; this drug product is not labeled for use in those patients.

PEDIATRIC USE

8.4 Pediatric Use In general, the adverse reactions observed in children and adolescents during the clinical trials were similar to those in the adult population with few exceptions.

Increases in systolic and diastolic blood pressure occurred in children and adolescents and did not occur in adults.

Orthostatic hypotension occurred more frequently in adults (4 to 7%) compared to children and adolescents (< 1%).

Schizophrenia Safety and effectiveness of quetiapine in pediatric patients less than 13 years of age with schizophrenia have not been established.

Maintenance The safety and effectiveness of quetiapine in the maintenance treatment of bipolar disorder has not been established in pediatric patients less than 18 years of age.

The safety and effectiveness of quetiapine in the maintenance treatment of schizophrenia has not been established in any patient population, including pediatric patients.

Bipolar Mania Safety and effectiveness of quetiapine in pediatric patients less than 10 years of age with bipolar mania have not been established.

Bipolar Depression Safety and effectiveness of quetiapine in pediatric patients less than 18 years of age with bipolar depression have not been established.

Pediatric use information in patients (13 to 17 years of age) with schizophrenia, and patients (10 to 17 years of age) with bipolar mania is approved for AstraZeneca Pharmaceuticals LP’s quetiapine fumarate drug product labeling.

However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights; this drug product is not labeled for such use in those patients.

PREGNANCY

8.1 Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of quetiapine use in pregnant women.

In limited published literature, there were no major malformations associated with quetiapine exposure during pregnancy.

In animal studies, embryo-fetal toxicity occurred.

Quetiapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

There are limited published data on the use of quetiapine for treatment of schizophrenia and other psychiatric disorders during pregnancy.

In a prospective observational study, 21 women exposed to quetiapine and other psychoactive medications during pregnancy delivered infants with no major malformations.

Among 42 other infants born to pregnant women who used quetiapine during pregnancy, there were no major malformations reported (one study of 36 women, 6 case reports).

Due to the limited number of exposed pregnancies, these postmarketing data do not reliably estimate the frequency or absence of adverse outcomes.

When pregnant rats and rabbits were exposed to quetiapine during organogenesis, there was no increase in the incidence of major malformations in fetuses at doses up to 2.4 times the maximum recommended human dose for schizophrenia (MRHD, 800 mg/day on a mg/m 2 basis); however, there was evidence of embryo-fetal toxicity.

In rats, delays in skeletal ossification occurred at 0.6 and 2.4 times the MRHD and in rabbits at 1.2 and 2.4 times the MRHD.

At 2.4 times the MRHD, there was an increased incidence of carpal/tarsal flexure (minor soft tissue anomaly) in rabbit fetuses and decreased fetal weights in both species.

Maternal toxicity (decreased body weights and/or death) occurred at 2.4 times the MRHD in rats and at 0.6 to 2.4 times the MRHD (all doses) in rabbits.

In a peri/postnatal reproductive study in rats, no drug-related effects were observed when pregnant dams were treated with quetiapine at doses 0.01, 0.12, and 0.24 times the MRHD.

However, in a preliminary peri/postnatal study, there were increases in fetal and pup death, and decreases in mean litter weight at 3.0 times the MRHD.

Non-Teratogenic Effects Neonates exposed to antipsychotic drugs (including quetiapine), during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.

There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates.

These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

Quetiapine fumarate tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NUSRING MOTHERS

8.3 Nursing Mothers Quetiapine was excreted into human milk.

It is recommended that women receiving quetiapine fumarate tablets should not breastfeed.

In published case reports, the level of quetiapine in breast milk ranged from undetectable to 170 μg/L.

The estimated infant dose ranged from 0.09% to 0.43% of the weight-adjusted maternal dose.

Based on a limited number (N=8) of mother/infant pairs, calculated infant daily doses range from less than 0.01 mg/kg (at a maternal daily dose up to 100 mg quetiapine) to 0.1 mg/kg (at a maternal daily dose of 400 mg).

BOXED WARNING

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks) largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients.

Over the course of a typical 10 week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.

Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality.

The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

Quetiapine fumarate tablets are not approved for the treatment of patients with dementia-related psychosis [ see Warnings and Precautions (5.1)].

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See Full Prescribing Information for complete boxed warning.

Antipsychotic drugs are associated with an increased risk of death ( 5.1 ) Quetiapine is not approved for elderly patients with Dementia-Related Psychosis ( 5.1 )

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Atypical antipsychotic drugs, including quetiapine, are associated with an increased risk of death; causes of death are variable.

( 5.1 ) Suicidality and Antidepressant Drugs: Increased the risk of suicidal thinking and behavior in children, adolescents and young adults taking antidepressants for major depressive disorder and other psychiatric disorders.

( 5.2 ) Neuroleptic Malignant Syndrome (NMS): Manage with immediate discontinuation and close monitoring.

( 5.3 ) Hyperglycemia and Diabetes Mellitus (DM): Ketoacidosis, hyperosmolar coma and death have been reported in patients treated with atypical antipsychotics, including quetiapine.

Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.

When starting treatment, patients with diabetes or risk factors for diabetes should undergo blood glucose testing before and during treatment.

( 5.4 ) Hyperlipidemia: Undesirable alterations in lipids have been observed.

Increases in total cholesterol, LDL-cholesterol and triglycerides and decreases in HDL-cholesterol have been reported in clinical trials.

Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically during treatment.

( 5.5 ) Weight Gain: Patients should receive regular monitoring of weight.

( 5.6 ) Tardive Dyskinesia: Discontinue if clinically appropriate.

( 5.7 ) Orthostatic Hypotension: Associated dizziness, tachycardia and syncope may occur especially during the initial dose titration period.

( 5.8 ) Increased Blood Pressure in Children and Adolescents: Blood pressure should be measured at the beginning of, and periodically during treatment in children and adolescents.

( 5.9 ) Leukopenia, Neutropenia and Agranulocytosis have been reported with atypical antipsychotics including quetiapine fumarate tablets.

Patients with a pre-existing low white cell count (WBC) or a history of leukopenia/neutropenia should have complete blood count (CBC) monitored frequently during the first few months of treatment and should discontinue quetiapine fumarate at the first sign of a decline in WBC in absence of other causative factors.

( 5.10 ) Cataracts: Lens changes have been observed in patients during long-term quetiapine treatment.

Lens examination is recommended when starting treatment and at 6 month intervals during chronic treatment.

( 5.11 ) • QT Prolongation: Post-marketing case show increases in QT interval in patients who overdosed on quetiapine, in patients with concomitant illness, and in patients taking medicines know to cause electrolyte imbalance or increase QT interval.

Avoid use with drugs that increase the QT interval and in patients with risk factors for prolonged QT interval.

( 5.12 ) Suicide: The possibility of a suicide attempt is inherent in schizophrenia and bipolar disorder, and close supervision of high risk patients should accompany drug therapy.

( 5.21 ) See Full Prescribing Information for additional WARNINGS and PRECAUTIONS .

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Quetiapine fumarate tablets are not approved for the treatment of patients with dementia-related psychosis ( see Boxed Warning ).

5.2 Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.

Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.

Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients.

The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.

There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.

There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.

The risk differences (drug vs.

placebo), however, were relatively stable within age strata and across indications.

These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1: Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18–24 5 additional cases Decreases Compared to Placebo 25–64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials.

There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.

However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.

Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers.

Such monitoring should include daily observation by families and caregivers.

Prescriptions for quetiapine fumarate tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder.

It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder.

Whether any of the symptoms described above represent such a conversion is unknown.

However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

It should be noted that quetiapine fumarate tablets are approved for use in treating adult bipolar depression.

5.3 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including quetiapine fumarate.

Rare cases of NMS have been reported with quetiapine fumarate.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).

Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated.

In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).

Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available.

There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.

The patient should be carefully monitored since recurrences of NMS have been reported.

5.4 Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including quetiapine.

Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population.

Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood.

However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control.

Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment.

Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.

Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing.

In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose and lipids was observed in clinical studies.

Changes in these parameters should be managed as clinically appropriate.

Adults: Table 2: Fasting Glucose — Proportion of Patients Shifting to ≥ 126 mg/dL in Short-Term (≤ 12 weeks) Placebo-Controlled Studies Laboratory Analyte Category Change (At Least Once) from Baseline Treatment Arm N Patients n (%) Fasting Glucose Normal to High (<100 mg/dL to ≥ 126 mg/dL) Quetiapine 2907 71 (2.4%) Placebo 1346 19 (1.4%) Borderline to High (≥ 100 mg/dL and < 126 mg/dL to ≥ 126 mg/dL) Quetiapine 572 67 (11.7%) Placebo 279 33 (11.8%) In a 24 week trial (active-controlled, 115 patients treated with quetiapine fumarate) designed to evaluate glycemic status with oral glucose tolerance testing of all patients, at week 24 the incidence of a treatment-emergent post-glucose challenge glucose level ≥ 200 mg/dL was 1.7% and the incidence of a fasting treatment-emergent blood glucose level ≥ 126 mg/dL was 2.6%.

The mean change in fasting glucose from baseline was 3.2 mg/dL and mean change in 2 hour glucose from baseline was -1.8 mg/dL for quetiapine.

In 2 long-term placebo-controlled randomized withdrawal clinical trials for bipolar maintenance, mean exposure of 213 days for quetiapine (646 patients) and 152 days for placebo (680 patients), the mean change in glucose from baseline was +5.0 mg/dL for quetiapine and –0.05 mg/dL for placebo.

The exposure-adjusted rate of any increased blood glucose level (≥ 126 mg/dL) for patients more than 8 hours since a meal (however, some patients may not have been precluded from calorie intake from fluids during fasting period) was 18.0 per 100 patient years for quetiapine (10.7% of patients; n=556) and 9.5 for placebo per 100 patient years (4.6% of patients; n=581).

Children and Adolescents: In a placebo-controlled quetiapine monotherapy study of adolescent patients (13 to 17 years of age) with schizophrenia (6 weeks duration), the mean change in fasting glucose levels for quetiapine (n=138) compared to placebo (n=67) was -0.75 mg/dL versus -1.70 mg/dL.

In a placebo controlled quetiapine monotherapy study of children and adolescent patients (10 to 17 years of age) with bipolar mania (3 weeks duration), the mean change in fasting glucose level for quetiapine (n=170) compared to placebo (n=81) was 3.62 mg/dL versus -1.17 mg/dL.

No patient in either study with a baseline normal fasting glucose level (<100 mg/dL) or a baseline borderline fasting glucose level (≥100 mg/dL and <126 mg/dL) had a treatment-emergent blood glucose level of ≥126 mg/dL.

5.5 Hyperlipidemia Undesirable alterations in lipids have been observed with quetiapine use.

Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using quetiapine is recommended.

In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose and lipids was observed in clinical studies.

Changes in these parameters should be managed as clinically appropriate.

Adults: Table 3 shows the percentage of adult patients with changes in total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline by indication in clinical trials with quetiapine fumarate.

Table 3: Percentage of Adult Patients with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels by Indication Laboratory Analyte Indication Treatment Arm N Patients n (%) Total Cholesterol ≥ 240 mg/dL Schizophrenia 6 weeks duration Quetiapine Fumarate 137 24 (18%) Placebo 92 6 (7%) Bipolar Depression 8 weeks duration Quetiapine Fumarate 463 41 (9%) Placebo 250 15 (6%) Triglycerides ≥200 mg/dL Schizophrenia Quetiapine Fumarate 120 26 (22%) Placebo 70 11 (16%) Bipolar Depression Quetiapine Fumarate 436 59 (14%) Placebo 232 20 (9%) LDL-Cholesterol ≥ 160 mg/dL Schizophrenia Quetiapine Fumarate na Parameters not measured in the quetiapine fumarate registration studies for schizophrenia.

Lipid parameters also were not measured in the bipolar mania registration studies.

na Placebo na na Bipolar Depression Quetiapine Fumarate 465 29 (6%) Placebo 256 12 (5%) HDL-Cholesterol ≤ 40 mg/dL Schizophrenia Quetiapine Fumarate na na Placebo na na Bipolar Depression Quetiapine Fumarate 393 56 (14%) Placebo 214 29 (14%) Children and Adolescents: Table 4 shows the percentage of children and adolescents with changes in total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline in clinical trials with quetiapine fumarate.

Table 4: Percentage of Children and Adolescents with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels Laboratory Analyte Indication Treatment Arm N Patients n (%) Total Cholesterol ≥ 200 mg/dL Schizophrenia 13-17 years, 6 weeks duration Quetiapine Fumarate 107 13 (12%) Placebo 56 1 (2%) Bipolar Mania 10-17 years, 3 weeks duration Quetiapine Fumarate 159 16 (10%) Placebo 66 2 (3%) Triglycerides ≥150 mg/dL Schizophrenia Quetiapine Fumarate 103 17 (17%) Placebo 51 4 (8%) Bipolar Mania Quetiapine Fumarate 149 32 (22%) Placebo 60 8 (13%) LDL-Cholesterol ≥ 130 mg/dL Schizophrenia Quetiapine Fumarate 112 4 (4%) Placebo 60 1 (2%) Bipolar Mania Quetiapine Fumarate 169 13 (8%) Placebo 74 4 (5%) HDL-Cholesterol ≤ 40 mg/dL Schizophrenia Quetiapine Fumarate 104 16 (15%) Placebo 54 10 (19%) Bipolar Mania Quetiapine Fumarate 154 16 (10%) Placebo 61 4 (7%) 5.6 Weight Gain Increases in weight have been observed in clinical trials.

Patients receiving quetiapine should receive regular monitoring of weight [ see Patient Counseling Information (17)].

In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose and lipids was observed in clinical studies.

Changes in these parameters should be managed as clinically appropriate.

Adults: In clinical trials with quetiapine fumarate the following increases in weight have been reported.

Table 5: Proportion of Patients with Weight Gain ≥7% of Body Weight (Adults) Vital Sign Indication Treatment Arm N Patients n (%) Weight Gain ≥7% of Body Weight Schizophrenia up to 6 weeks duration Quetiapine Fumarate 391 89 (23%) Placebo 206 11 (6%) Bipolar Mania (monotherapy) up to 12 weeks duration Quetiapine Fumarate 209 44 (21%) Placebo 198 13 (7%) Bipolar Mania (adjunct therapy) up to 3 weeks duration Quetiapine Fumarate 196 25 (13%) Placebo 203 8 (4%) Bipolar Depression up to 8 weeks duration Quetiapine Fumarate 554 47 (8%) Placebo 295 7 (2%) Children and Adolescents: In two clinical trials with quetiapine fumarate, one in bipolar mania and one in schizophrenia, reported increases in weight are included in the table below.

Table 6: Proportion of Patients with Weight Gain ≥7% of Body Weight (Children and Adolescents) Vital Sign Indication Treatment Arm N Patients n (%) Weight Gain ≥7% of Body Weight Schizophrenia : 6 weeks duration Quetiapine Fumarate 111 23 (21%) Placebo 44 3 (7%) Bipolar Mania : 3 weeks duration Quetiapine Fumarate 157 18 (12%) Placebo 68 0 (0%) The mean change in body weight in the schizophrenia trial was 2.0 kg in the quetiapine fumarate group and -0.4 kg in the placebo group and in the bipolar mania trial it was 1.7 kg in the quetiapine fumarate group and 0.4 kg in the placebo group.

In an open-label study that enrolled patients from the above two pediatric trials, 63% of patients (241/380) completed 26 weeks of therapy with quetiapine fumarate.

After 26 weeks of treatment, the mean increase in body weight was 4.4 kg.

Forty-five percent of the patients gained ≥ 7% of their body weight, not adjusted for normal growth.

In order to adjust for normal growth over 26 weeks an increase of at least 0.5 standard deviation from baseline in BMI was used as a measure of a clinically significant change; 18.3% of patients on Quetiapine fumarate met this criterion after 26 weeks of treatment.

When treating pediatric patients with quetiapine fumarate for any indication, weight gain should be assessed against that expected for normal growth.

5.7 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including quetiapine.

Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome.

Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase.

However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process.

The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, quetiapine fumarate should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.

Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.

In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought.

The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on quetiapine fumarate, drug discontinuation should be considered.

However, some patients may require treatment with quetiapine fumarate despite the presence of the syndrome.

5.8 Orthostatic Hypotension Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α1-adrenergic antagonist properties.

Syncope was reported in 1% (28/3265) of the patients treated with quetiapine fumarate, compared with 0.2% (2/954) on placebo and about 0.4% (2/527) on active control drugs.

Orthostatic hypotension, dizziness, and syncope may lead to falls.

Quetiapine fumarate should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolemia and treatment with antihypertensive medications) [ see Adverse Reactions (6.2)].

The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 25 mg twice daily [ see Dosage and Administration (2)].

If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate.

5.9 Increases in Blood Pressure in Children and Adolescents In placebo-controlled trials in children and adolescents with schizophrenia (6 week duration) or bipolar mania (3 week duration), the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 15.2% (51/335) for quetiapine fumarate and 5.5% (9/163) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 40.6% (136/335) for quetiapine fumarate and 24.5% (40/163) for placebo.

In the 26 week open-label clinical trial, one child with a reported history of hypertension experienced a hypertensive crisis.

Blood pressure in children and adolescents should be measured at the beginning of, and periodically during treatment.

5.10 Leukopenia, Neutropenia and Agranulocytosis In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to atypical antipsychotic agents, including quetiapine fumarate.

Agranulocytosis (including fatal cases) has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white cell count (WBC) and history of drug induced leukopenia/neutropenia.

Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue quetiapine fumarate at the first sign of a decline in WBC in absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur.

Patients with severe neutropenia (absolute neutrophil count <1000/mm 3 ) should discontinue quetiapine fumarate and have their WBC followed until recovery [ see Adverse Reactions (6.2)].

5.11 Cataracts The development of cataracts was observed in association with quetiapine treatment in chronic dog studies [ see Nonclinical Toxicology, Animal Toxicology (13.2)].

Lens changes have also been observed in adults, children and adolescents during long-term quetiapine treatment, but a causal relationship to quetiapine use has not been established.

Nevertheless, the possibility of lenticular changes cannot be excluded at this time.

Therefore, examination of the lens by methods adequate to detect cataract formation, such as slit lamp exam or other appropriately sensitive methods, is recommended at initiation of treatment or shortly thereafter, and at 6-month intervals during chronic treatment.

5.12 QT Prolongation In clinical trials quetiapine was not associated with a persistent increase in QT intervals.

However, the QT effect was not systematically evaluated in a thorough QT study.

In post marketing experience, there were cases reported of QT prolongation in patients who overdosed on quetiapine [see Overdosage (10.1)], in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval [see Drug Interactions (7)].

The use of quetiapine should be avoided in combination with other drugs that are known to prolong QTc including Class 1A antiarrythmics (e.g., quinidine, procainamide) or Class III antiarrythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone).

Quetiapine should also be avoided in circumstances that may increase the risk of occurrence of torsade de pointes and/or sudden death including (1) a history of cardiac arrhythmias such as bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

Caution should also be exercised when quetiapine is prescribed in patients with increased risk of QT prolongation (e.g.

cardiovascular disease, family history of QT prolongation, the elderly, congestive heart failure and heart hypertrophy).

5.13 Seizures During clinical trials, seizures occurred in 0.5% (20/3490) of patients treated with quetiapine fumarate compared to 0.2% (2/954) on placebo and 0.7% (4/527) on active control drugs.

As with other antipsychotics, quetiapine fumarate should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia.

Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

5.14 Hypothyroidism Adults: Clinical trials with quetiapine demonstrated a dose-related decreases in thyroid hormone levels.

The reduction in total and free thyroxine (T4) of approximately 20% at the higher end of the therapeutic dose range was maximal in the first six weeks of treatment and maintained without adaptation or progression during more chronic therapy.

In nearly all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T4, irrespective of the duration of treatment.

About 0.7% (26/3489) of quetiapine patients did experience TSH increases in monotherapy studies.

Some patients with TSH increases needed replacement thyroid treatment.

In the mania adjunct studies, where quetiapine was added to lithium or divalproex, 12% (24/196) of quetiapine-treated patients compared to 7% (15/203) of placebo-treated patients had elevated TSH levels.

Of the quetiatpine-treated patients with elevated TSH levels, 3 had simultaneous low free T4 levels.

In all quetiapine trials, the incidence of potentially clinically significant shifts in thyroid hormones and TSH were*: decrease in free T4, 2.0% (357/17513); decrease in total T4, 4.0% (75/1861); decrease in free T3, 0.4% (53/13766); decrease in total T3, 2.0% (26/1312), and increase in TSH, 4.9% (956/19412).

In eight patients, where TBG was measured, levels of TBG were unchanged.

Table 7 shows the incidence of these shifts in short-term placebo-controlled clinical trials.

Table 7: Incidence of potentially clinically significant shifts in thyroid hormone levels and TSH in short term placebo-controlled clinical trials Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline.

Shifts in total T 4 , free T 4 , total T 3 and free T 3 are defined as 5 mIU/L at any time.

Total T 4 Free T 4 Total T 3 Free T 3 TSH Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo 3.4 % (37/1097) 0.6% (4/651) 0.7% (52/7218) 0.1% (4/3668) 0.5% (2/369) 0.0% (0/113) 0.2% (11/5673) 0.0% (1/2679) 3.2% (240/7587) 2.7% (105/3912) In short-term placebo-controlled monotherapy trials, the incidence of reciprocal, potentially clinically significant shifts in T 3 and TSH was 0.0 % for both quetiapine (1/4800) and placebo (0/2190) and for T 4 and TSH the shifts were 0.1% (7/6154) for quetiapine versus 0.0% (1/3007) for placebo.

Generally, these changes in thyroid hormone levels were of no clinical significance.

Children and Adolescents: In acute placebo-controlled trials in children and adolescent patients with schizophrenia (6 week duration) or bipolar mania (3 week duration), the incidence of shifts to potentially clinically important thyroid function values at any time for quetiapine treated patients and placebo-treated patients for elevated TSH was 2.9% (8/280) vs.

0.7% (1/138), respectively and for decreased total thyroxine was 2.8% (8/289) vs.

0% (0/145, respectively).

Of the quetiapine treated patients with elevated TSH levels, 1 had simultaneous low free T4 level at end of treatment.

5.15 Hyperprolactinemia Adults: During clinical trials with quetiapine, the incidence of shifts in prolactin levels to a clinically significant value occurred in 3.6% (158/4416) of patients treated with quetiapine compared to 2.6% (51/1968) on placebo.

Children and Adolescents: In acute placebo-controlled trials in children and adolescent patients with bipolar mania (3 week duration) or schizophrenia (6 week duration), the incidence of shifts in prolactin levels to a clinically significant value (>20 µg/L males; > 26 µg/L females at any time) was 13.4% (18/134) for quetiapine compared to 4% (3/75) for placebo in males and 8.7% (9/104) for quetiapine compared to 0% (0/39) for placebo in females.

Like other drugs that antagonize dopamine D2 receptors, quetiapine elevates prolactin levels in some patients and the elevation may persist during chronic administration.

Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion.

This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients.

Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.

Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro , a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer.

As is common with compounds which increase prolactin release, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in carcinogenicity studies conducted in mice and rats.

Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive [ see Carcinogenesis, Mutagenesis, Impairment of Fertility (13.1)].

5.16 Transaminase Elevations Asymptomatic, transient and reversible elevations in serum transaminases (primarily ALT) have been reported.

In schizophrenia trials in adults, the proportions of patients with transaminase elevations of > 3 times the upper limits of the normal reference range in a pool of 3 to 6 week placebo-controlled trials were approximately 6% (29/483) for quetiapine fumarate compared to 1% (3/194) for placebo.

In acute bipolar mania trials in adults, the proportions of patients with transaminase elevations of > 3 times the upper limits of the normal reference range in a pool of 3 to 12 week placebo-controlled trials were approximately 1% for both quetiapine fumarate (3/560) and placebo (3/294).

These hepatic enzyme elevations usually occurred within the first 3 weeks of drug treatment and promptly returned to pre-study levels with ongoing treatment with quetiapine fumarate.

In bipolar depression trials, the proportions of patients with transaminase elevations of > 3 times the upper limits of the normal reference range in two 8 week placebo-controlled trials was 1% (5/698) for quetiapine fumarate and 2% (6/347) for placebo.

5.17 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse event reported in patients treated with quetiapine fumarate especially during the 3-5 day period of initial dose-titration.

In schizophrenia trials, somnolence was reported in 18% (89/510) of patients on quetiapine fumarate compared to 11% (22/206) of placebo patients.

In acute bipolar mania trials using quetiapine fumarate as monotherapy, somnolence was reported in 16% (34/209) of patients on quetiapine fumarate compared to 4% of placebo patients.

In acute bipolar mania trials using quetiapine fumarate as adjunct therapy, somnolence was reported in 34% (66/196) of patients on quetiapine fumarate compared to 9% (19/203) of placebo patients.

In bipolar depression trials, somnolence was reported in 57% (398/698) of patients on quetiapine fumarate compared to 15% (51/347) of placebo patients.

Since quetiapine fumarate has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that quetiapine fumarate therapy does not affect them adversely.

Somnolence may lead to falls.

5.18 Priapism One case of priapism in a patient receiving quetiapine fumarate has been reported prior to market introduction.

While a causal relationship to use of quetiapine fumarate has not been established, other drugs with alpha-adrenergic blocking effects have been reported to induce priapism, and it is possible that quetiapine fumarate may share this capacity.

Severe priapism may require surgical intervention.

5.19 Body Temperature Regulation Although not reported with quetiapine fumarate, disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents.

Appropriate care is advised when prescribing quetiapine fumarate tablets for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

5.20 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.

Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia.

Quetiapine fumarate and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

5.21 Suicide The possibility of a suicide attempt is inherent in bipolar disorder and schizophrenia; close supervision of high risk patients should accompany drug therapy.

Prescriptions for quetiapine fumarate should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.

In two 8 week clinical studies in patients with bipolar depression (N=1048), the incidence of treatment emergent suicidal ideation or suicide attempt was low and similar to placebo (quetiapine fumarate 300 mg, 6/350, 1.7%; quetiapine fumarate 600 mg, 9/348, 2.6%; Placebo, 7/347, 2.0%).

5.22 Use in Patients with Concomitant Illness Clinical experience with quetiapine fumarate in patients with certain concomitant systemic illnesses is limited [ see Pharmacokinetics (12.3)].

Quetiapine fumarate has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease.

Patients with these diagnoses were excluded from premarketing clinical studies.

Because of the risk of orthostatic hypotension with quetiapine fumarate, caution should be observed in cardiac patients [ see Warnings and Precautions (5.8)].

5.23 Withdrawal Acute withdrawal symptoms, such as insomnia, nausea, and vomiting have been described after abrupt cessation of atypical antipsychotic drugs, including quetiapine fumarate.

In short-term placebo-controlled, monotherapy clinical trials with quetiapine fumarate extended-release tablets that included a discontinuation phase which evaluated discontinuation symptoms, the aggregated incidence of patients experiencing one or more discontinuation symptoms after abrupt cessation was 12.1% (241/1993) for quetiapine fumarate extended-release tablets and 6.7% (71/1065) for placebo.

The incidence of the individual adverse events (i.e., insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability) did not exceed 5.3% in any treatment group and usually resolved after 1 week post-discontinuation.

Gradual withdrawal is advised.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION [see Medication Guide] Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with quetiapine fumarate tablets and should counsel them in its appropriate use.

A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for quetiapine fumarate tablets.

The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents.

Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.

The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking quetiapine fumarate tablets.

Increased Mortality in Elderly Patients with Dementia-Related Psychosis Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at increased risk of death compared with placebo.

Quetiapine is not approved for elderly patients with dementia-related psychosis [ see Warnings and Precautions (5.1)].

Clinical Worsening and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down.

Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt.

Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [ see Warnings and Precautions (5.2)].

Neuroleptic Malignant Syndrome (NMS) Patients should be advised to report to their physician any signs or symptoms that may be related to NMS.

These may include muscle stiffness and high fever [ see Warnings and Precautions (5.3)].

Hyperglycemia and Diabetes Mellitus Patients should be aware of the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus.

Patients who are diagnosed with diabetes, those with risk factors for diabetes, or those that develop these symptoms during treatment should have their blood glucose monitored at the beginning of and periodically during treatment [ see Warnings and Precautions (5.4)].

Hyperlipidemia Patients should be advised that elevations in total cholesterol, LDL–cholesterol and triglycerides and decreases in HDL-cholesterol may occur.

Patients should have their lipid profile monitored at the beginning of and periodically during treatment [ see Warnings and Precautions (5.5)].

Weight Gain Patients should be advised that they may experience weight gain.

Patients should have their weight monitored regularly [ see Warnings and Precautions (5.6)].

Orthostatic Hypotension Patients should be advised of the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing, which may lead to falls), especially during the period of initial dose titration, and also at times of re-initiating treatment or increases in dose [ see Warnings and Precautions (5.8)].

Increased Blood Pressure in Children and Adolescents Blood pressure should be measured at the beginning of, and periodically during, treatment [ see Warnings and Precautions (5.9)].

Leukopenia/Neutropenia Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should be advised that they should have their CBC monitored while taking quetiapine fumarate tablets [see Warnings and Precautions (5.10)].

Interference with Cognitive and Motor Performance Patients should be advised of the risk of somnolence or sedation (which may lead to falls), especially during the period of initial dose titration.

Patients should be cautioned about performing any activity requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating machinery, until they are reasonably certain quetiapine therapy does not affect them adversely.

Patients should limit consumption of alcohol during treatment with quetiapine [see Warnings and Precautions (5.17)].

Heat Exposure and Dehydration Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.19).] Concomitant Medication As with other medications, patients should be advised to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs [see Warnings and Precautions (5.22)] Pregnancy and Nursing Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Patients should be advised not to breast feed if they are taking quetiapine [ see Use in Specific Populations (8.1) and (8.3)].

Need for Comprehensive Treatment Program Pediatric use information in patients (13 to 17 years of age) with schizophrenia, and patients (10 to 17 years of age) with bipolar mania is approved for AstraZeneca Pharmaceuticals LP’s quetiapine fumarate drug product labeling.

However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights; this drug product is not labeled for such use in those patients.

Manufactured by: Apotex Inc.

Toronto, Ontario Canada M9L 1T9 Manufactured for: Apotex Corp.

Weston, Florida USA 33326 Marketed/Packaged by: GSMS Inc.

Camarillo, CA 93012 Revised: July 2011

DOSAGE AND ADMINISTRATION

2 Quetiapine fumarate tablets can be taken with or without food.

Quetiapine fumarate tablets can be taken with or without food.

Indication Dosing Instructions After initial dosing, adjustments can be made upwards or downwards, if necessary, within the dose range depending upon the clinical response and tolerance of the patient.

Recommended Dose/Dose Range Schizophrenia-Adults (2.1) Day 1: 25 mg twice daily.

Increase in increments of 25 mg to 50 mg divided two or three times on Days 2 and 3 to range of 300 to 400 mg by Day 4.

Further adjustments can be made in increments of 25 to 50 mg twice a day, in intervals of not less than 2 days.

150 to 750 mg/day Bipolar Mania- Adults Monotherapy or as an adjunct to lithium or divalproex (2.2) Day 1: Twice daily dosing totaling 100 mg.

Day 2: Twice daily dosing totaling 200 mg.

Day 3: Twice daily dosing totaling 300 mg.

Day 4: Twice daily dosing totaling 400 mg.

Further dosage adjustments up to 800 mg/day by Day 6 should be in increments of no greater than 200 mg/day.

400 to 800 mg/day Bipolar Depression- Adults Administer once daily at bedtime.

Day 1: 50 mg.

Day 2: 100 mg.

Day 3: 200 mg.

Day 4: 300 mg.

300 mg/day Bipolar I Disorder Maintenance Therapy- Adults Administer twice daily totaling 400 to 800 mg/day as adjunct to lithium or divalproex.

Generally, in the maintenance phase, patients continued on the same dose on which they were stabilized.

2.1 Schizophrenia Adults Dose Selection—Quetiapine fumarate tablets should generally be administered with an initial dose of 25 mg twice daily, with increases in total daily dose of 25 mg to 50 mg divided in two or three doses on the second and third day, as tolerated, to a total dose range of 300 mg to 400 mg daily by the fourth day.

Further dosage adjustments, if indicated, should generally occur at intervals of not less than 2 days, as steady-state for quetiapine fumarate tablets would not be achieved for approximately 1 to 2 days in the typical patient.

When dosage adjustments are necessary, dose increments/decrements of 25 mg to 50 mg divided twice daily are recommended.

Most efficacy data with quetiapine fumarate tablets were obtained using three times daily dosing regimens, but in one controlled trial 225 mg given twice per day was also effective.

Efficacy in schizophrenia was demonstrated in a dose range of 150 mg/day to 750 mg/day in the clinical trials supporting the effectiveness of quetiapine fumarate tablets.

In a dose response study, doses above 300 mg/day were not demonstrated to be more efficacious than the 300 mg/day dose.

In other studies, however, doses in the range of 400 mg/day to 500 mg/day appeared to be needed.

The safety of doses above 800 mg/day has not been evaluated in clinical trials.

Maintenance Treatment —The effectiveness of quetiapine fumarate tablets for longer than 6 weeks has not been evaluated in controlled clinical trials.

While there is no body of evidence available to answer the question of how long the patient treated with quetiapine fumarate tablets should be maintained, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission.

Patients should be periodically reassessed to determine the need for maintenance treatment.

Adolescents (13-17 years) Pediatric dosing information in patients (13 to 17 years of age) with schizophrenia is approved for AstraZeneca Pharmaceuticals LP’s quetiapine fumarate drug product labeling.

However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights; this drug product is not labeled for such use in those adolescent patients.

2.2 Bipolar Disorder Adults Acute Treatment of Manic Episodes in Bipolar I Disorder Dose Selection —When used as monotherapy or adjunct therapy (with lithium or divalproex), quetiapine fumarate tablets should be initiated in twice daily doses totaling 100 mg/day on Day 1, increased to 400 mg/day on Day 4 in increments of up to 100 mg/day in twice daily divided doses.

Further dosage adjustments up to 800 mg/day by Day 6 should be in increments of no greater than 200 mg/day.

Data indicate that the majority of patients responded between 400 mg/day to 800 mg/day.

The safety of doses above 800 mg/day has not been evaluated in clinical trials.

Acute Treatment of Depressive Episodes in Bipolar Disorder Dose Selection —Quetiapine fumarate tablets should be administered once daily at bedtime to reach 300 mg/day by Day 4.

Recommended Dosing Schedule Day Day 1 Day 2 Day 3 Day 4 Quetiapine Fumarate Tablets 50 mg 100 mg 200 mg 300 mg In the clinical trials supporting effectiveness, the dosing schedule was 50 mg, 100 mg, 200 mg and 300 mg/day for Days 1 to 4 respectively.

Patients receiving 600 mg increased to 400 mg on Day 5 and 600 mg on Day 8 (Week 1).

Antidepressant efficacy was demonstrated with quetiapine fumarate tablets at both 300 mg and 600 mg; however, no additional benefit was seen in the 600 mg group.

Maintenance Treatment of Bipolar I Disorder Maintenance of efficacy in bipolar I disorder was demonstrated with quetiapine fumarate tablets (administered twice daily totaling 400 to 800 mg per day) as adjunct therapy to lithium or divalproex.

Generally, in the maintenance phase, patients continued on the same dose on which they were stabilized during the stabilization phase Children and Adolescents (10 to 17 years) Pediatric dosing information in patients (10 to 17 years of age) with bipolar mania is approved for AstraZeneca Pharmaceuticals LP’s quetiapine fumarate drug product labeling.

However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights; this drug product is not labeled for such use in those pediatric patients.

2.3 Dosing in Special Populations Consideration should be given to a slower rate of dose titration and a lower target dose in the elderly and in patients who are debilitated or who have a predisposition to hypotensive reactions [ see Clinical Pharmacology (12)].

When indicated, dose escalation should be performed with caution in these patients.

Patients with hepatic impairment should be started on 25 mg/day.

The dose should be increased daily in increments of 25 mg/day to 50 mg/day to an effective dose, depending on the clinical response and tolerability of the patient.

2.4 Reinitiation of Treatment in Patients Previously Discontinued Although there are no data to specifically address reinitiation of treatment, it is recommended that when restarting patients who have had an interval of less than one week off quetiapine fumarate tablets, titration of quetiapine fumarate tablets is not required and the maintenance dose may be reinitiated.

When restarting therapy of patients who have been off quetiapine fumarate tablets for more than one week, the initial titration schedule should be followed.

2.5 Switching from Antipsychotics There are no systematically collected data to specifically address switching patients with schizophrenia from antipsychotics to quetiapine fumarate tablets, or concerning concomitant administration with antipsychotics.

While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others.

In all cases, the period of overlapping antipsychotic administration should be minimized.

When switching patients with schizophrenia from depot antipsychotics, if medically appropriate, initiate quetiapine fumarate tablets therapy in place of the next scheduled injection.

The need for continuing existing EPS medication should be re-evaluated periodically.

codeine phosphate 10 MG / guaifenesin 100 MG per 5 ML Oral Solution

WARNINGS

Warnings

INDICATIONS AND USAGE

Uses temporarily relieves cough due to minor throat and bronchial irritation as may occur with a cold helps loosen phlegm (mucus) and thin bronchial secretions to make coughs more productive calms the cough control center and relieves coughing

INACTIVE INGREDIENTS

Inactive ingredients alcohol, caramel, citric acid, FD&C red #40, flavor, glycerin, menthol racemic, purified water, saccharin sodium, sodium benzoate, sorbitol solution

PURPOSE

Purpose Cough suppressant Expectorant

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

ASK DOCTOR

Ask a doctor before use if you have cough that occurs with excessive phlegm (mucus) cough that lasts or is chronic such as occurs with smoking, asthma, chronic bronchitis, or emphysema

DOSAGE AND ADMINISTRATION

Directions take every 4 hours do not take more than 6 doses in any 24-hour period adults and children 12 years and over take 10 mL (2 tsp) children 6 years to under 12 years take 5 mL (1 tsp) children 2 years to under 6 years consult a doctor children under 2 years do not use Attention: A special measuring device should be used to give an accurate dose of this product to children under 6 years of age.

Giving a higher dose than recommended by a doctor could result in serious side effects for your child.

PREGNANCY AND BREAST FEEDING

If pregnant or breast-feeding, ask a health professional before use.

DO NOT USE

Do not use in a child under 2 years of age if you or your child has a chronic pulmonary disease or shortness of breath if your child is taking other drugs, unless directed by a doctor

STOP USE

Stop use and ask a doctor if cough lasts more than 7 days, comes back or is accompanied by fever, rash, or persistent headache.

These could be signs of a serious condition.

ACTIVE INGREDIENTS

Active ingredients (in each 5 mL = 1 tsp) Codeine phosphate, USP 10 mg Guaifenesin, USP 100 mg