LamISIL AT 1 % Topical Gel

WARNINGS

Warnings For external use only

INDICATIONS AND USAGE

Uses • cures most athlete’s foot (tinea pedis) between the toes.

Effectiveness on the bottom or sides of foot is unknown.

• cures most jock itch (tinea cruris) and ringworm (tinea corporis) • relieves itching, burning, cracking and scaling which accompany these conditions

INACTIVE INGREDIENTS

Inactive ingredients benzyl alcohol, butylated hydroxytoluene, carbomer 974 P, ethanol, isopropyl myristate, polysorbate 20, purified water, sodium hydroxide, sorbitan monolaurate

PURPOSE

Purpose Antifungal

KEEP OUT OF REACH OF CHILDREN

Keep Out of Reach of Children If swallowed, get medical help or contact a poison control center right away.

ASK DOCTOR

Ask Doctor before use if you have

DOSAGE AND ADMINISTRATION

Directions • adults and children 12 years and over • use the tip of the cap to break the seal and open the tube • wash the affected skin with soap and water and dry completely before applying • for athlete’s footbetween the toes: apply once a day at bedtime for 1 week or as directed by a doctor.

Wear well-fitting, ventilated shoes.

Change shoes and socks at least once daily 1 week between the toes • for jock itch and ringworm: apply once a day (morning or night) for 1 week or as directed by a doctor.

• wash hands after each use • children under 12 years: ask a doctor image 1

DO NOT USE

Do not use • on nails or scalp • in or near the mouth or eyes • for vaginal yeast infections

STOP USE

Stop use and ask a doctor do not get into eyes.

If eye contact occurs, rinse thoroughly with water.

ACTIVE INGREDIENTS

Active ingredient Terbinafine1%

ASK DOCTOR OR PHARMACIST

Ask a doctor or pharmacist

calcitriol 0.25 MCG Oral Capsule

WARNINGS

Overdosage of any form of vitamin D is dangerous (see OVERDOSAGE ).

Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention.

Chronic hypercalcemia can lead to generalized vascular calcification, nephrocalcinosis and other soft-tissue calcification.

The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70 mg 2 /dL 2 .

Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition.

Calcitriol is the most potent metabolite of vitamin D available.

The administration of calcitriol to patients in excess of their daily requirements can cause hypercalcemia, hypercalciuria, and hyperphosphatemia.

Therefore, pharmacologic doses of vitamin D and its derivatives should be withheld during calcitriol treatment to avoid possible additive effects and hypercalcemia.

If treatment is switched from ergocalciferol (vitamin D 2 ) to calcitriol, it may take several months for the ergocalciferol level in the blood to return to the baseline value (see OVERDOSAGE ).

Calcitriol increases inorganic phosphate levels in serum.

While this is desirable in patients with hypophosphatemia, caution is called for in patients with renal failure because of the danger of ectopic calcification.

A non-aluminum phosphate-binding compound and a low-phosphate diet should be used to control serum phosphorus levels in patients undergoing dialysis.

Magnesium-containing preparations (eg, antacids) and calcitriol should not be used concomitantly in patients on chronic renal dialysis because such use may lead to the development of hypermagnesemia.

Studies in dogs and rats given calcitriol for up to 26 weeks have shown that small increases of calcitriol above endogenous levels can lead to abnormalities of calcium metabolism with the potential for calcification of many tissues in the body.

DRUG INTERACTIONS

Drug Interactions Cholestyramine Cholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins; as such it may impair intestinal absorption of calcitriol (see WARNINGS and PRECAUTIONS : General ).

Phenytoin/Phenobarbital The coadministration of phenytoin or phenobarbital will not affect plasma concentrations of calcitriol, but may reduce endogenous plasma levels of 25(OH)D 3 by accelerating metabolism.

Since blood level of calcitriol will be reduced, higher doses of calcitriol may be necessary if these drugs are administered simultaneously.

Thiazides Thiazides are known to induce hypercalcemia by the reduction of calcium excretion in urine.

Some reports have shown that the concomitant administration of thiazides with calcitriol causes hypercalcemia.

Therefore, precaution should be taken when coadministration is necessary.

Digitalis Calcitriol dosage must be determined with care in patients undergoing treatment with digitalis, as hypercalcemia in such patients may precipitate cardiac arrhythmias (see PRECAUTIONS : General ).

Ketoconazole Ketoconazole may inhibit both synthetic and catabolic enzymes of calcitriol.

Reductions in serum endogenous calcitriol concentrations have been observed following the administration of 300 mg/day to 1200 mg/day ketoconazole for a week to healthy men.

However, in vivo drug interaction studies of ketoconazole with calcitriol have not been investigated.

Corticosteroids A relationship of functional antagonism exists between vitamin D analogues, which promote calcium absorption, and corticosteroids, which inhibit calcium absorption.

Phosphate-Binding Agents Since calcitriol also has an effect on phosphate transport in the intestine, kidneys and bones, the dosage of phosphate-binding agents must be adjusted in accordance with the serum phosphate concentration.

Vitamin D Since calcitriol is the most potent active metabolite of vitamin D3, pharmacological doses of vitamin D and its derivatives should be withheld during treatment with calcitriol to avoid possible additive effects and hypercalcemia (see WARNINGS ).

Calcium Supplements: Uncontrolled intake of additional calcium-containing preparations should be avoided (see PRECAUTIONS : General ).

Magnesium Magnesium-containing preparations (eg, antacids) may cause hypermagnesemia and should therefore not be taken during therapy with calcitriol by patients on chronic renal dialysis.

Carcinogenesis, Mutagenesis and Impairment of Fertility Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of calcitriol.

Calcitriol is not mutagenic in vitro in the Ames Test, nor is it genotoxic in vivo in the Mouse Micronucleus Test.

No significant effects of calcitriol on fertility and/or general reproductive performances were observed in a Segment I study in rats at doses of up to 0.3 mcg/kg (approximately 3 times the maximum recommended dose based on body surface area).

OVERDOSAGE

Administration of calcitriol to patients in excess of their daily requirements can cause hypercalcemia, hypercalciuria and hyperphosphatemia.

Since calcitriol is a derivative of vitamin D, the signs and symptoms of overdose are the same as for an overdose of vitamin D (see ADVERSE REACTIONS ).

High intake of calcium and phosphate concomitant with calcitriol may lead to similar abnormalities.

The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70 mg2/dL2.

High levels of calcium in the dialysate bath may contribute to the hypercalcemia (see WARNINGS ).

Treatment of Hypercalcemia and Overdosage in Dialysis Patients and Hypoparathyroidism Patients General treatment of hypercalcemia (greater than 1 mg/dL above the upper limit of the normal range) consists of immediate discontinuation of calcitriol therapy, institution of a low-calcium diet and withdrawal of calcium supplements.

Serum calcium levels should be determined daily until normocalcemia ensues.

Hypercalcemia frequently resolves in 2 to 7 days.

When serum calcium levels have returned to within normal limits, calcitriol therapy may be reinstituted at a dose of 0.25 mcg/day less than prior therapy.

Serum calcium levels should be obtained at least twice weekly after all dosage changes and subsequent dosage titration.

In dialysis patients, persistent or markedly elevated serum calcium levels may be corrected by dialysis against a calcium-free dialysate.

Treatment of Hypercalcemia and Overdosage in Predialysis Patients If hypercalcemia ensues (greater than 1 mg/dL above the upper limit of the normal range), adjust dosage to achieve normocalcemia by reducing calcitriol therapy from 0.5 mcg to 0.25 mcg daily.

If the patient is receiving a therapy of 0.25 mcg daily, discontinue calcitriol until patient becomes normocalcemic.

Calcium supplements should also be reduced or discontinued.

Serum calcium levels should be determined 1 week after withdrawal of calcium supplements.

If serum calcium levels have returned to normal, calcitriol therapy may be reinstituted at a dosage of 0.25 mcg/day if previous therapy was at a dosage of 0.5 mcg/day.

If calcitriol therapy was previously administered at a dosage of 0.25 mcg/day, calcitriol therapy may be reinstituted at a dosage of 0.25 mcg every other day.

If hypercalcemia is persistent at the reduced dosage, serum PTH should be measured.

If serum PTH is normal, discontinue calcitriol therapy and monitor patient in 3 months’ time.

Treatment of Hyperphosphatemia in Predialysis Patients If serum phosphorus levels exceed 5 mg/dL to 5.5 mg/dL, a calcium-containing phosphate-binding agent (ie, calcium carbonate or calcium acetate) should be taken with meals.

Serum phosphorus levels should be determined as described earlier (see PRECAUTIONS : Laboratory Tests ).

Aluminum-containing gels should be used with caution as phosphate-binding agents because of the risk of slow aluminum accumulation.

Treatment of Accidental Overdosage of Calcitriol The treatment of acute accidental overdosage of calcitriol should consist of general supportive measures.

If drug ingestion is discovered within a relatively short time, induction of emesis or gastric lavage may be of benefit in preventing further absorption.

If the drug has passed through the stomach, the administration of mineral oil may promote its fecal elimination.

Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion and assessment of eIectrocardiographic abnormalities due to hypercalcemia should be obtained.

Such monitoring is critical in patients receiving digitalis.

Discontinuation of supplemental calcium and a low-calcium diet are also indicated in accidental overdosage.

Due to the relatively short duration of the pharmacological action of calcitriol, further measures are probably unnecessary.

Should, however, persistent and markedly elevated serum calcium levels occur, there are a variety of therapeutic alternatives which may be considered, depending on the patient’s underlying condition.

These include the use of drugs such as phosphates and corticosteroids as well as measures to induce an appropriate forced diuresis.

The use of peritoneal dialysis against a calcium-free dialysate has also been reported.

DESCRIPTION

Calcitriol is a synthetic vitamin D analog which is active in the regulation of the absorption of calcium from the gastrointestinal tract and its utilization in the body.

Cacitriol is available as capsules containing 0.25 mcg.

Calcitriol Capsules contain butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) as antioxidants.

The capsules contain a fractionated triglyceride of coconut oil.

Gelatin capsule shells contain gelatin, glycerin (anhydrous), and titanium dioxide, with the following dyes: FD&C Yellow No.

5 and FD&C Yellow No.

6.

In addition to the ingredients listed above, each tablet contains Opacode (Black) monogramming ink, Opacode (Black) contains ammonium hydroxide, iron oxide black, isopropyl alcohol, macrogol, polyvinyl acetate phthalate, propylene glycol, purified water, and SDA 35A alcohol.

Calcitriol is a white, crystalline compound which occurs naturally in humans.

It has a calculated molecular weight of 416.65 and is soluble in organic solvents but relatively insoluble in water.

Chemically, calcitriol is 9,10-seco(5Z,7E)-5,7,10(19)-cholestatriene-1α, 3β, 25-triol and has the following structural formula: The other names frequently used for calcitriol are 1α, 25-dihydroxycholecalciferol, 1,25-dihydroxyvitamin D 3 ,1,25-DHCC, 1,25(OH) 2 D 3 and 1,25-diOHC.

Structural Formula

HOW SUPPLIED

Repackaged by Aphena Pharma Solutions – TN.

See Repackaging Information for available configurations.

Calcitriol Capsules are supplied as oval, soft gelatin capsules.

The 0.25 mcg capsules are imprinted with “547” in black ink.

0054-0007-13 – 0.25 mcg yellow capsule, bottle of 30 0054-0007-25 – 0.25 mcg yellow capsule, bottle of 100 Calcitriol Capsules should be protected from light.

GERIATRIC USE

Geriatric Use Clinical studies of calcitriol did not include sufficient numbers of subjects aged 65 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.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

INDICATIONS AND USAGE

Predialysis Patients Calcitriol Capsules are indicated in the management of secondary hyperparathyroidism and resultant metabolic bone disease in patients with moderate to severe chronic renal failure (Ccr 15 to 55 mL/min) not yet on dialysis.

In children, the creatinine clearance value must be corrected for a surface area of 1.73 square meters.

A serum iPTH level of ≥100 pg/mL is strongly suggestive of secondary hyperparathyroidism.

Dialysis Patients Calcitriol Capsules are indicated in the management of hypocalcemia and the resultant metabolic bone disease in patients undergoing chronic renal dialysis.

In these patients, calcitriol administration enhances calcium absorption, reduces serum alkaline phosphatase levels, and may reduce elevated parathyroid hormone levels and the histological manifestations of osteitis fibrosa cystica and defective mineralization.

Hypoparathyroidism Patients Calcitriol Capsules are also indicated in the management of hypocalcemia and its clinical manifestations in patients with postsurgical hypoparathyroidism, idiopathic hypoparathyroidism, and pseudohypoparathyroidism.

PEDIATRIC USE

Pediatric Use Safety and effectiveness of calcitriol in pediatric patients undergoing dialysis have not been established.

The safety and effectiveness of calcitriol in pediatric predialysis patients is based on evidence from adequate and well-controlled studies of calcitriol in adults with predialysis chronic renal failure and additional supportive data from non-placebo controlled studies in pediatric patients.

Dosing guidelines have not been established for pediatric patients under 1 year of age with hypoparathyroidism or for pediatric patients less than 6 years of age with pseudohypoparathyroidism (see DOSAGE AND ADMINISTRATION : Hypoparathyroidism ).

Oral doses of calcitriol ranging from 10 to 55 ng/kg/day have been shown to improve calcium homeostasis and bone disease in pediatric patients with chronic renal failure for whom hemodialysis is not yet required (predialysis).

Long-term calcitriol therapy is well tolerated by pediatric patients.

The most common safety issues are mild, transient episodes of hypercalcemia, hyperphosphatemia, and increases in the serum calcium times phosphate (Ca x P) product which are managed effectively by dosage adjustment or temporary discontinuation of the vitamin D derivative.

PREGNANCY

Pregnancy Teratogenic Effects Pregnancy Category C Calcitriol has been found to be teratogenic in rabbits when given at doses of 0.08 and 0.3 mcg/kg (approximately 2 and 6 times the maximum recommended dose based on mg/m 2 ).

All 15 fetuses in 3 litters at these doses showed external and skeletal abnormalities.

However, none of the other 23 litters (156 fetuses) showed external and skeletal abnormalities compared with controls.

Teratogenicity studies in rats at doses up to 0.45 mcg/kg (approximately 5 times maximum recommended dose based on mg/m 2 ) showed no evidence of teratogenic potential.

There are no adequate and well-controlled studies in pregnant women.

Calcitriol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects In the rabbit, dosages of 0.3 mcg/kg/day (approximately 6 times maximum recommended dose based on surface area) administered on days 7 to 18 of ges-tation resulted in 19% maternal mortality, a decrease in mean fetal body weight and a reduced number of newborn surviving to 24 hours.

A study of perinatal and postnatal development in rats resulted in hypercalcemia in the offspring of dams given calcitriol at doses of 0.08 or 0.3 mcg/kg/day (approximately 1 and 3 times the maximum recommended dose based on mg/m 2 ), hypercalcemia and hypophosphatemia in dams given calcitriol at a dose of 0.08 or 0.3 mcg/kg/day, and increased serum urea nitrogen in dams given calcitriol at a dose of 0.3 mcg/kg/day.

In another study in rats, maternal weight gain was slightly reduced at a dose of 0.3 mcg/kg/day (approximately 3 times the maximum recommended dose based on mg/m 2 ) administered on days 7 to 15 of gestation.

The offspring of a woman administered 17 mcg/day to 36 mcg/day of calcitriol (approximately 17 to 36 times the maximum recommended dose), during pregnancy manifested mild hypercalcemia in the first 2 days of life which returned to normal at day 3.

Nursing Mothers Calcitriol from ingested calcitriol capsules may be excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from calcitriol in nursing infants, a mother should not nurse while taking calcitriol capsules.

Pediatric Use Safety and effectiveness of calcitriol in pediatric patients undergoing dialysis have not been established.

The safety and effectiveness of calcitriol in pediatric predialysis patients is based on evidence from adequate and well-controlled studies of calcitriol in adults with predialysis chronic renal failure and additional supportive data from non-placebo controlled studies in pediatric patients.

Dosing guidelines have not been established for pediatric patients under 1 year of age with hypoparathyroidism or for pediatric patients less than 6 years of age with pseudohypoparathyroidism (see DOSAGE AND ADMINISTRATION : Hypoparathyroidism ).

Oral doses of calcitriol ranging from 10 to 55 ng/kg/day have been shown to improve calcium homeostasis and bone disease in pediatric patients with chronic renal failure for whom hemodialysis is not yet required (predialysis).

Long-term calcitriol therapy is well tolerated by pediatric patients.

The most common safety issues are mild, transient episodes of hypercalcemia, hyperphosphatemia, and increases in the serum calcium times phosphate (Ca x P) product which are managed effectively by dosage adjustment or temporary discontinuation of the vitamin D derivative.

Geriatric Use Clinical studies of calcitriol did not include sufficient numbers of subjects aged 65 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.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

NUSRING MOTHERS

Nursing Mothers Calcitriol from ingested calcitriol capsules may be excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from calcitriol in nursing infants, a mother should not nurse while taking calcitriol capsules.

INFORMATION FOR PATIENTS

Information for Patients The patient and his or her caregivers should be informed about compliance with dosage instructions, adherence to instructions about diet and calcium supplementation, and avoidance of the use of unapproved nonprescription drugs.

Patients and their caregivers should also be carefully informed about the symptoms of hypercalcemia (see ADVERSE REACTIONS ).

The effectiveness of calcitriol therapy is predicated on the assumption that each patient is receiving an adequate daily intake of calcium.

Patients are advised to have a dietary intake of calcium at a minimum of 600 mg daily.

The U.S.

RDA for calcium in adults is 800 mg to 1200 mg.

DOSAGE AND ADMINISTRATION

The optimal daily dose of calcitriol must be carefully determined for each patient.

Calcitriol Capsules should be administered orally.

Calcitriol therapy should always be started at the lowest possible dose and should not be increased without careful monitoring of serum calcium.

The effectiveness of calcitriol therapy is predicated on the assumption that each patient is receiving an adequate but not excessive daily intake of calcium.

Patients are advised to have a dietary intake of calcium at a minimum of 600 mg daily.

The U.S.

RDA for calcium in adults is 800 mg to 1200 mg.

To ensure that each patient receives an adequate daily intake of calcium, the physician should either prescribe a calcium supplement or instruct the patient in proper dietary measures.

Because of improved calcium absorption from the gastrointestinal tract, some patients on calcitriol may be maintained on a lower calcium intake.

Patients who tend to develop hypercalcemia may require only low doses of calcium or no supplements at all.

During the titration period of treatment with calcitriol, serum calcium levels should be checked at least twice weekly.

When the optimal dosage of calcitriol has been determined, serum calcium levels should be checked every month (or as given below for individual indications).

Samples for serum calcium estimation should be taken without a tourniquet.

Dialysis Patients The recommended initial dose of calcitriol is 0.25 mcg/day.

If a satisfactory response in the biochemical parameters and clinical manifestations of the disease state is not observed, dosage may be increased by 0.25 mcg/day at 4 to 8 week intervals.

During this titration period, serum calcium levels should be obtained at least twice weekly, and if hypercalcemia is noted, the drug should be immediately discontinued until normocalcemia ensues (see PRECAUTIONS : General ).

Phosphorus, magnesium, and alkaline phosphatase should be determined periodically.

Patients with normal or only slightly reduced serum calcium levels may respond to calcitriol doses of 0.25 mcg every other day.

Most patients undergoing hemodialysis respond to doses between 0.5 and 1 mcg/day.

Oral calcitriol may normalize plasma ionized calcium in some uremic patients, yet fail to suppress parathyroid hyperfunction.

In these individuals with autonomous parathyroid hyperfunction, oral calcitriol may be useful to maintain normocalcemia, but has not been shown to be adequate treatment for hyperparathyroidism.

Hypoparathyroidism The recommended initial dosage of calcitriol is 0.25 mcg/day given in the morning.

If a satisfactory response in the biochemical parameters and clinical manifestations of the disease is not observed, the dose may be increased at 2- to 4-week intervals.

During the dosage titration period, serum calcium levels should be obtained at least twice weekly and, if hypercalcemia is noted, calcitriol should be immediately discontinued until normocalcemia ensues (see PRECAUTIONS : General ).

Careful consideration should also be given to lowering the dietary calcium intake.

Serum calcium, phosphorus, and 24-hour urinary calcium should be determined periodically.

Most adult patients and pediatric patients age 6 years and older have responded to dosages in the range of 0.5 mcg to 2 mcg daily.

Pediatric patients in the 1 to 5 year age group with hypoparathyroidism have usually been given 0.25 mcg to 0.75 mcg daily.

The number of treated patients with pseudohypoparathyroidism less than 6 years of age is too small to make dosage recommendations.

Malabsorption is occasionally noted in patients with hypoparathyroidism; hence, larger doses of calcitriol may be needed.

Predialysis Patients The recommended initial dosage of calcitriol is 0.25 mcg/day in adults and pediatric patients 3 years of age and older.

This dosage may be increased if necessary to 0.5 mcg/day.

For pediatric patients less than 3 years of age, the recommended initial dosage of calcitriol is 10 to 15 ng/kg/day.

levETIRAcetam 500 MG in 5 ML Injection

Generic Name: LEVETIRACETAM
Brand Name: Levetiracetam
  • Substance Name(s):
  • LEVETIRACETAM

OVERDOSAGE

10 10.1 Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans The highest known dose of oral Levetiracetam received in the clinical development program was 6000 mg/day.

Other than drowsiness, there were no adverse reactions in the few known cases of overdose in clinical trials.

Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with Levetiracetam overdoses in postmarketing use.

10.2 Management of Overdose There is no specific antidote for overdose with Levetiracetam.

If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions should be observed to maintain airway.

General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient’s clinical status.

A Certified Poison Control Center should be contacted for up to date information on the management of overdose with Levetiracetam.

10.3 Hemodialysis Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose.

Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.

DESCRIPTION

11 Levetiracetam Injection is an antiepileptic drug available as a clear, colorless, sterile solution (100 mg/mL) for intravenous administration.

The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, its molecular formula is C 8 H 14 N 2 O 2 and its molecular weight is 170.21.

Levetiracetam is chemically unrelated to existing antiepileptic drugs (AEDs).

It has the following structural formula: Levetiracetam, USP is a white to off-white crystalline powder with a faint odor and a bitter taste.

It is very soluble in water (104.0 g/100 mL).

It is freely soluble in chloroform (65.3 g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane.

(Solubility limits are expressed as g/100 mL solvent.) Levetiracetam Injection contains 100 mg of levetiracetam per mL.

It is supplied in single-dose 5 mL vials containing 500 mg levetiracetam, water for injection, 45 mg sodium chloride, and buffered at approximately pH 5.5 with glacial acetic acid and 8.2 mg sodium acetate trihydrate.

Levetiracetam Injection must be diluted prior to intravenous infusion [see Dosage and Administration ( 2.6 ) ].

chemical structure

CLINICAL STUDIES

14 All clinical studies supporting the efficacy of Levetiracetam Injection utilized oral formulations.

The finding of efficacy of Levetiracetam Injection is based on the results of studies using an oral formulation of Levetiracetam, and on the demonstration of comparable bioavailability of the oral and parenteral formulations [see Clinical Pharmacology ( 12.3 ) ].

14.1 Partial Onset Seizures Effectiveness in Partial-Onset Seizures in Adults The effectiveness of Levetiracetam for the treatment of partial-onset seizures in adults was established in three multicenter, randomized, double-blind, placebo-controlled clinical studies in patients who had refractory partial onset seizures with or without secondary generalization.

The tablet formulation was used in all these studies.

In these studies, 904 patients were randomized to placebo, 1000 mg, 2000 mg, or 3000 mg/day.

Patients enrolled in Study 1 or Study 2 had refractory partial onset seizures for at least two years and had taken two or more classical AEDs.

Patients enrolled in Study 3 had refractory partial onset seizures for at least 1 year and had taken one classical AED.

At the time of the study, patients were taking a stable dose regimen of at least one and could take a maximum of two AEDs.

During the baseline period, patients had to have experienced at least two partial onset seizures during each 4-week period.

Study 1 Study 1 was a double-blind, placebo-controlled, parallel-group study conducted at 41 sites in the United States comparing Levetiracetam 1000 mg/day (N=97), Levetiracetam 3000 mg/day (N=101), and placebo (N=95) given in equally divided doses twice daily.

After a prospective baseline period of 12 weeks, patients were randomized to one of the three treatment groups described above.

The 18-week treatment period consisted of a 6-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant.

The primary measure of effectiveness was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period).

Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency).

The results of the analysis of Study 1 are displayed in Table 10.

Table 10: Reduction In Mean Over Placebo In Weekly Frequency of Partial-Onset Seizures in Study 1 Placebo (N=95) Levetiracetam 1000 mg/day (N=97) Levetiracetam 3000 mg/day (N=101) Percent reduction in partial seizure frequency over placebo – 26.1% statistically significant versus placebo 30.1% The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the three treatment groups (x-axis) is presented in Figure 1.

Figure 1: Responder Rate (≥50% Reduction from Baseline) in Study 1 * statistically significant versus placebo Study 2 Study 2 was a double-blind, placebo-controlled, crossover study conducted at 62 centers in Europe comparing Levetiracetam 1000 mg/day (N=106), Levetiracetam 2000 mg/day (N=105), and placebo (N=111) given in equally divided doses twice daily.

The first period of the study (Period A) was designed to be analyzed as a parallel-group study.

After a prospective baseline period of up to 12 weeks, patients were randomized to one of the three treatment groups described above.

The 16-week treatment period consisted of the 4-week titration period followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant.

The primary measure of effectiveness was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period).

Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency).

The results of the analysis of Period A are displayed in Table 11.

Table 11: Reduction In Mean Over Placebo In Weekly Frequency ofPartial- Onset Seizures in Study 2: Period A Placebo (N=111) Levetiracetam 1000 mg/day (N=106) Levetiracetam 2000 mg/day (N=105) Percent reduction in partial seizure frequency over placebo – 17.1% statistically significant versus placebo 21.4% The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the three treatment groups (x-axis) is presented in Figure 2.

Figure 2: Responder Rate (≥50% Reduction from Baseline) in Study 2: Period A * statistically significant versus placebo The comparison of Levetiracetam 2000 mg/day to Levetiracetam 1000 mg/day for responder rate was statistically significant ( P =0.02).

Analysis of the trial as a cross-over yielded similar results.

Study 3 Study 3 was a double-blind, placebo-controlled, parallel-group study conducted at 47 centers in Europe comparing Levetiracetam 3000 mg/day (N=180) and placebo (N=104) in patients with refractory partial onset seizures, with or without secondary generalization, receiving only one concomitant AED.

Study drug was given in two divided doses.

After a prospective baseline period of 12 weeks, patients were randomized to one of two treatment groups described above.

The 16-week treatment period consisted of a 4-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED doses were held constant.

The primary measure of effectiveness was a between group comparison of the percent reduction in weekly seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period).

Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency).

Table 12 displays the results of the analysis of Study 3.

Table 12: Reduction in Mean Over Placebo in Weekly Frequency of Partial-Onset Seizures in Study 3 Placebo (N=104) Levetiracetam 3000 mg/day (N=180) Percent reduction in partial seizure frequency over placebo – 23.0% statistically significant versus placebo The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 3.

Figure 3: Responder Rate (≥50% Reduction from Baseline) in Study 3 * statistically significant versus placebo Effectiveness in Partial Onset Seizures in Pediatric Patients 4 Years to 16 Years of Age Study 4 was a multicenter, randomized double-blind, placebo-controlled study, in pediatric patients 4 to 16 years of age with partial seizures uncontrolled by standard antiepileptic drugs (AEDs).

Study 4 was conducted at 60 sites in North America.

The study consisted of an 8-week baseline period and 4-week titration period followed by a 10-week evaluation period.

Eligible patients who still experienced, on a stable dose of 1 to 2 AEDs, at least 4 partial onset seizures during the 4 weeks prior to screening, as well as at least 4 partial onset seizures in each of the two 4-week baseline periods, were randomized to receive either Levetiracetam or placebo.

Dosing was initiated at a dose of 20 mg/kg/day in two divided doses.

During the treatment period, Levetiracetam doses were adjusted in 20 mg/kg/day increments, at 2-week intervals to the target dose of 60 mg/kg/day.

The primary measure of efficacy was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire 14-week randomized treatment period (titration + evaluation period).

Secondary outcome variables included the responder rate (incidence of patients with ≥ 50% reduction from baseline in partial onset seizure frequency per week).

The enrolled population included 198 patients (Levetiracetam N=101, placebo N=97) with refractory partial onset seizures, whether or not secondarily generalized.

Table 13 displays the results of Study 4.

Table 13: Reduction in Mean Over Placebo in Weekly Frequency of Partial-Onset Seizures in Study 4 Placebo (N=97) Levetiracetam (N=101) Percent reduction in partial seizure frequency over placebo – 26.8% statistically significant versus placebo The percentage of patients (y-axis) who achieved ≥ 50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 4.

Figure 4: Responder Rate (≥ 50% Reduction from Baseline) in Study 4 *statistically significant versus placebo Effectiveness in Partial Onset Seizures in Pediatric Patients 1 Month to <4 Years of Age Study 5 was a multicenter, randomized double-blind, placebo-controlled study, in pediatric patients 1 month to less than 4 years of age with partial seizures, uncontrolled by standard epileptic drugs (AEDs).

Study 5 was conducted at 62 sites in North America, South America, and Europe.

Study 5 consisted of a 5-day evaluation period, which included a 1-day titration period followed by a 4-day maintenance period.

Eligible patients who experienced, on a stable dose of 1-2 AEDs, at least 2 partial onset seizures during the 48-hour baseline video EEG were randomized to receive either Levetiracetam or placebo.

Randomization was stratified by age range as follows: 1 month to less than 6 months of age (N=4 treated with Levetiracetam), 6 months to less than 1 year of age (N=8 treated with Levetiracetam), 1 year to less than 2 years of age (N=20 treated with Levetiracetam), and 2 years to less than 4 years of age (N=28 treated with Levetiracetam).

Levetiracetam dosing was determined by age and weight as follows: children 1 month to less than 6 months old were randomized to a target dose of 40 mg/kg/day, and children 6 months to less than 4 years old were randomized to a target dose of 50 mg/kg/day.

The primary measure of efficacy was the responder rate (percent of patients with ≥ 50% reduction from baseline in average daily partial onset seizure frequency) assessed by a blinded central reader using a 48-hour video EEG performed during the last two days of the 4-day maintenance period.

The enrolled population included 116 patients (Levetiracetam N=60, placebo N=56) with refractory partial onset seizures, whether or not secondarily generalized.

A total of 109 patients were included in the efficacy analysis.

A statistically significant difference between Levetiracetam and placebo was observed in Study 5 (see Figure 5).

The treatment effect associated with Levetiracetam was consistent across age groups.

Figure 5: Responder Rate for All Patients Ages 1 Month to < 4 Years (≥ 50% Reduction from Baseline) in Study 5 *statistically significant versus placebo Figure 1: Responder Rate (≥50% Reduction from Baseline) in Study 1 Figure 2: Responder Rate (≥50% Reduction from Baseline) in Study 2: Period A Figure 3: Responder Rate (≥50% Reduction from Baseline) in Study 3 Figure 4: Responder Rate (≥ 50% Reduction from Baseline) in Study 4 Figure 5: Responder Rate for All Patients Ages 1 Month to < 4 Years (≥ 50% Reduction from Baseline) in Study 5 14.2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy The effectiveness of Levetiracetam as adjunctive therapy in patients 12 years of age and older with juvenile myoclonic epilepsy (JME) experiencing myoclonic seizures was established in one multicenter, randomized, double-blind, placebo-controlled study (study 6), conducted at 37 sites in 14 countries.

Eligible patients on a stable dose of 1 antiepileptic drug (AED) experiencing one or more myoclonic seizures per day for at least 8 days during the prospective 8-week baseline period were randomized to either Levetiracetam or placebo (Levetiracetam N=60, placebo N=60).

Patients were titrated over 4 weeks to a target dose of 3000 mg/day and treated at a stable dose of 3000 mg/day over 12 weeks (evaluation period).

Study drug was given in 2 divided doses.

The primary measure of efficacy was the proportion of patients with at least 50% reduction in the number of days per week with one or more myoclonic seizures during the treatment period (titration + evaluation periods) as compared to baseline.

Table 14 displays the results for the 113 patients with JME in this study.

Table 14: Responder Rate (≥50% Reduction from Baseline) In Myoclonic Seizure Days per Week in Study 6 Placebo (N=59) Levetiracetam (N=54) Percentage of responders 23.7% 60.4% statistically significant versus placebo 14.3 Primary Generalized Tonic-Clonic Seizures The effectiveness of Levetiracetam as adjunctive therapy in patients 6 years of age and older with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic (PGTC) seizures was established in one multicenter, randomized, double-blind, placebo-controlled study (study 7), conducted at 50 sites in 8 countries.

Eligible patients on a stable dose of 1 or 2 antiepileptic drugs (AEDs) experiencing at least 3 PGTC seizures during the 8-week combined baseline period (at least one PGTC seizure during the 4 weeks prior to the prospective baseline period and at least one PGTC seizure during the 4-week prospective baseline period) were randomized to either Levetiracetam or placebo.

The 8-week combined baseline period is referred to as “baseline” in the remainder of this section.

Patients were titrated over 4 weeks to a target dose of 3000 mg/day for adults or a pediatric target dose of 60 mg/kg/day and treated at a stable dose of 3000 mg/day (or 60 mg/kg/day for children) over 20 weeks (evaluation period).

Study drug was given in 2 equally divided doses per day.

The primary measure of efficacy was the percent reduction from baseline in weekly PGTC seizure frequency for Levetiracetam and placebo treatment groups over the treatment period (titration + evaluation periods).

The population included 164 patients (Levetiracetam N=80, placebo N=84) with idiopathic generalized epilepsy (predominately juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy, or epilepsy with Grand Mal seizures on awakening) experiencing primary generalized tonic-clonic seizures.

Each of these syndromes of idiopathic generalized epilepsy was well represented in this patient population.

There was a statistically significant decrease from baseline in PGTC frequency in the Levetiracetam-treated patients compared to the placebo-treated patients in Study 7 (see Table 15).

Table 15: Median Percent Reduction from Baseline in PGTC Seizure Frequency per Week in Study 7 Placebo (N=84) Levetiracetam (N=78) Percentage reduction in PGTC seizure frequency 44.6% 77.6% statistically significant versus placebo The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in PGTC seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 6.

Figure 6: Responder Rate ( ≥ 50% Reduction from Baseline) in PGTC Seizure Frequency per Week in Study 7 * statistically significant versus placebo Figure 6: Responder Rate (≥50% Reduction from Baseline) in PGTC Seizure Frequency per Week in Study 7

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 How Supplied Levetiracetam Injection 500 mg/5 mL injection is a clear, colorless, sterile solution.

It is supplied in single-dose 5 mL vials, available in cartons of 25 vials (NDC 0143-9574-25).

16.2 Storage Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature].

GERIATRIC USE

8.5 Geriatric Use There were 347 subjects in clinical studies of levetiracetam that were 65 years old and over.

No overall differences in safety were observed between these subjects and younger subjects.

There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of Levetiracetam Injection in these patients.

Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.

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 [see Clinical Pharmacology ( 12.3 ) ].

DOSAGE FORMS AND STRENGTHS

3 One vial of Levetiracetam Injection contains 500 mg levetiracetam (500 mg/5 mL) as a clear, colorless solution..

Injection: 500 mg/5 mL single dose vial ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown.

A saturable and stereoselective neuronal binding site in rat brain tissue has been described for levetiracetam.

Experimental data indicate that this binding site is the synaptic vesicle protein SV2A, thought to be involved in the regulation of vesicle exocytosis.

Although the molecular significance of levetiracetam binding to synaptic vesicle protein SV2A is not understood, levetiracetam and related analogs showed a rank order of affinity for SV2A which correlated with the potency of their antiseizure activity in audiogenic seizure-prone mice.

These findings suggest that the interaction of levetiracetam with the SV2A protein may contribute to the antiepileptic mechanism of action of the drug.

INDICATIONS AND USAGE

1 Levetiracetam Injection is indicated for the treatment of partial-onset seizures in patients 1 month of age and older ( 1.1 ) • Levetiracetam Injection is indicated for adjunctive therapy for the treatment of: Myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy ( 1.2 ) Primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy ( 1.3 ) • Levetiracetam Injection is for intravenous use only as an alternative for patients when oral administration is temporarily not feasible ( 1.4 ) 1.1 Partial-Onset Seizures Levetiracetam Injection is indicated for the treatment of partial-onset seizures in patients 1 month of age and older.

1.2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Levetiracetam Injection is indicated as adjunctive therapy for the treatment of myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy.

1.3 Primary Generalized Tonic-Clonic Seizures Levetiracetam Injection is indicated as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy.

1.4 Limitations of Use Levetiracetam Injection is for intravenous use only as an alternative for patients when oral administration is temporarily not feasible.

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of Levetiracetam Injection for the treatment of partial onset seizures in patients 1 month to 16 years of age have been established [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.1 ) ].

The dosing recommendation in these pediatric patients varies according to age group and is weight-based [see Dosage and Administration ( 2.6 ) ].

The safety and effectiveness of Levetiracetam Injection as adjunctive therapy for the treatment of myoclonic seizures in adolescents 12 years of age and older with juvenile myoclonic epilepsy have been established [see Clinical Studies ( 14.2 ) ].

The safety and effectiveness of Levetiracetam Injection as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in pediatric patients 6 years of age and older with idiopathic generalized epilepsy have been established [see Clinical Studies ( 14.3 ) ].

Safety and effectiveness for the treatment of partial-onset seizures in pediatric patients below the age of 1 month; adjunctive therapy for the treatment of myoclonic seizures in pediatric patients below the age of 12 years; and adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in pediatric patients below the age of 6 years have not been established.

A 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of Levetiracetam Injection as adjunctive therapy in 98 (Levetiracetam Injection N=64, placebo N=34) pediatric patients, ages 4 years to 16 years, with partial seizures that were inadequately controlled.

The target dose was 60 mg/kg/day.

Neurocognitive effects were measured by the Leiter-R Attention and Memory (AM) Battery, which measures various aspects of a child’s memory and attention.

Although no substantive differences were observed between the placebo and drug treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority of the drug and placebo.

The Achenbach Child Behavior Checklist (CBCL/6-18), a standardized validated tool used to assess a child’s competencies and behavioral/emotional problems, was also assessed in this study.

An analysis of the CBCL/6-18 indicated, on average, a worsening in Levetiracetam Injection-treated patients in aggressive behavior, one of the eight syndrome scores [see Warnings and Precautions ( 5.1 ) ].

Juvenile Animal Toxicity Data Studies of levetiracetam in juvenile rats (dosed on postnatal days 4 through 52) and dogs (dosed from postnatal weeks 3 through 7) at doses of up to 1800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric dose of 60 mg/kg/day on a mg/m 2 basis) did not demonstrate adverse effects on postnatal development.

PREGNANCY

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including Levetiracetam Injection, during pregnancy.

Encourage women who are taking Levetiracetam Injection during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.

Risk Summary Prolonged experience with Levetiracetam Injection in pregnant women has not identified a drug-associated risk of major birth defects or miscarriage, based on published literature, which includes data from pregnancy registries, and reflects experience over two decades [see Human Data ].

In animal studies, levetiracetam produced developmental toxicity (increased embryofetal and offspring mortality, increased incidences of fetal structural abnormalities, decreased embryofetal and offspring growth, neurobehavioral alterations in offspring) at doses similar to human therapeutic doses [see Animal Data ].

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

Clinical Considerations Levetiracetam blood levels may decrease during pregnancy [see Warnings and Precautions ( 5.9 ) ].

Physiological changes during pregnancy may affect levetiracetam concentration.

Decrease in levetiracetam plasma concentrations has been observed during pregnancy.

This decrease is more pronounced during the third trimester.

Dose adjustments may be necessary to maintain clinical response.

Data Human Data While available studies cannot definitively establish the absence of risk, data from the published literature and pregnancy registries have not established an association with levetiracetam use during pregnancy and major birth defects or miscarriage.

Animal Data When levetiracetam (0, 400, 1200, or 3600 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, reduced fetal weights and increased incidence of fetal skeletal variations were observed at the highest dose tested.

There was no evidence of maternal toxicity.

The no-effect dose for adverse effects on embryofetal developmental in rats (1200 mg/kg/day) is approximately 4 times the maximum recommended human dose (MRHD) of 3000 mg on a body surface area (mg/m 2 ) basis.

Oral administration of levetiracetam (0, 200, 600, or 1800 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and incidence of fetal skeletal variations at the mid and high dose and decreased fetal weights and increased incidence of fetal malformations at the high dose, which was associated with maternal toxicity.

The no-effect dose for adverse effects on embryofetal development in rabbits (200 mg/kg/day) is approximately equivalent to the MRHD on a mg/m 2 basis.

Oral administration of levetiracetam (0, 70, 350, or 1800 mg/kg/day) to female rats throughout pregnancy and lactation led to an increased incidence of fetal skeletal variations, reduced fetal body weight, and decreased growth in offspring at the mid and high doses and increased pup mortality and neurobehavioral alterations in offspring at the highest dose tested.

There was no evidence of maternal toxicity.

The no-effect dose for adverse effects on pre-and postnatal development in rats (70 mg/kg/day) is less than the MRHD on a mg/m 2 basis.

Oral administration of levetiracetam to rats during the latter part of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m 2 basis).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Behavioral abnormalities including psychotic symptoms, suicidal ideation, irritability, and aggressive behavior have been observed; monitor patients for psychiatric signs and symptoms ( 5.1 ) Monitor for somnolence and fatigue; advise patients not to drive or operate machinery until they have sufficient experience on Levetiracetam Injection ( 5.2 ) Serious Dermatological Reactions: Discontinue Levetiracetam Injection at the first sign of rash unless clearly not drug related ( 5.4 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity: Discontinue if no alternative etiology ( 5.5 ) Coordination Difficulties: Monitor for ataxia, abnormal gait, and incoordination ( 5.6 ) Withdrawal Seizures: Levetiracetam Injection must be gradually withdrawn.

( 5.7 ) 5.1 Behavioral Abnormalities and Psychotic Symptoms Levetiracetam Injection may cause behavioral abnormalities and psychotic symptoms.

Patients treated with Levetiracetam Injection should be monitored for psychiatric signs and symptoms.

Behavioral abnormalities In clinical studies using an oral formulation of Levetiracetam, 13% of adult Levetiracetam-treated patients and 38% of pediatric Levetiracetam-treated patients (4 to 16 years of age), compared to 6% and 19% of adult and pediatric placebo-treated patients, experienced nonpsychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder).

A randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of an oral formulation of Levetiracetam as adjunctive therapy in pediatric patients (4 to 16 years of age).

The results from an exploratory analysis indicated a worsening in Levetiracetam-treated patients on aggressive behavior (one of eight behavior dimensions), as measured in a standardized and systematic way using a validated instrument, the Achenbach Child Behavior Checklist (CBCL/6-18).

In clinical studies in pediatric patients 1 month to < 4 years of age, irritability was reported in 12% of the Levetiracetam-treated patients compared to 0% of placebo-treated patients.

In clinical studies, 1.7% of adult Levetiracetam-treated patients discontinued treatment due to behavioral adverse reactions, compared to 0.2% of placebo-treated patients.

The treatment dose was reduced in 0.8% of adult Levetiracetam-treated patients and in 0.5% of placebo-treated patients.

Overall, 11% of Levetiracetam-treated pediatric patients experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6% of placebo-treated patients.

Psychotic symptoms In clinical studies using an oral formulation of Levetiracetam, 1% of Levetiracetam-treated adult patients, 2% of Levetiracetam-treated pediatric patients 4 to 16 years of age, and 17% of levetiracetam-treated pediatric patients 1 month to <4 years of age experienced psychotic symptoms, compared to 0.2%, 2%, and 5% in the corresponding age groups treated with placebo.

In a controlled study that assessed the neurocognitive and behavioral effects of an oral formulation of Levetiracetam in pediatric patients 4 to 16 years of age, 1.6% of Levetiracetam-treated patients experienced paranoia, compared to 0% of placebo-treated patients.

In the same study, 3.1% of Levetiracetam-treated patients experienced confusional state, compared to 0% of placebo-treated patients [see Use in Specific Populations ( 8.4 ) ].

In clinical studies, two (0.3%) Levetiracetam-treated adult patients were hospitalized, and their treatment was discontinued due to psychosis.

Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation.

There was no difference between drug- and placebo-treated patients in the incidence of the pediatric patients who discontinued treatment due to psychotic and non-psychotic adverse reactions.

5.2 Somnolence and Fatigue Levetiracetam Injection may cause somnolence and fatigue.

Patients should be monitored for somnolence and fatigue, and be advised not to drive or operate machinery until they have gained sufficient experience on Levetiracetam Injection to gauge whether it adversely affects their ability to drive or operate machinery.

Somnolence In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial-onset seizures, 15% of Levetiracetam-treated patients reported somnolence, compared to 8% of placebo-treated patients.

There was no clear dose response up to 3000 mg/day.

In a study in which there was no titration, about 45% of patients receiving levetiracetam 4000 mg/day reported somnolence.

The somnolence was considered serious in 0.3% of Levetiracetam-treated patients, compared to 0% in the placebo group.

About 3% of Levetiracetam-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo-treated patients.

In 1.4% of Levetiracetam-treated patients and 0.9% of placebo-treated patients, the dose was reduced, while 0.3% of the Levetiracetam-treated patients were hospitalized due to somnolence.

Asthenia In controlled clinical studies using an oral formulation of levetiracetam in adult patients with partial onset seizures, 15% of Levetiracetam-treated patients reported asthenia, compared to 9% of placebo-treated patients.

Treatment was discontinued due to asthenia in 0.8% of Levetiracetam-treated patients as compared to 0.5% of placebo-treated patients.

In 0.5% of Levetiracetam-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to asthenia.

Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment.

In general, the incidences of somnolence and fatigue in the pediatric partial onset seizure studies, and in pediatric and adult myoclonic and primary generalized tonic-clonic studies were comparable to those of the adult partial-onset seizure studies.

5.3 Anaphylaxis and Angioedema Levetiracetam Injection can cause anaphylaxis or angioedema after the first dose or at any time during treatment.

Signs and symptoms in cases reported in the postmarketing setting have included hypotension, hives, rash, respiratory distress, and swelling of the face, lip, mouth, eye, tongue, throat, and feet.

In some reported cases, reactions were life-threatening and required emergency treatment.

If a patient develops signs or symptoms of anaphylaxis or angioedema, Levetiracetam Injection should be discontinued and the patient should seek immediate medical attention.

Levetiracetam Injection should be discontinued permanently if a clear alternative etiology for the reaction cannot be established [see Contraindications (4) ].

5.4 Serious Dermatological Reactions Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both pediatric and adult patients treated with Levetiracetam Injection.

The median time of onset is reported to be 14 to 17 days, but cases have been reported at least four months after initiation of treatment.

Recurrence of the serious skin reactions following rechallenge with Levetiracetam Injection has also been reported.

Levetiracetam Injection should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related.

If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

5.5 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including Levetiracetam Injection.

These events can be fatal or life- threatening, particularly if diagnosis and treatment do not occur as early as possible.

Levetiracetam Injection typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection.

Eosinophilia is often present.

Because this disorder is variable in its expression, other organ systems not noted here may be involved.

It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident.

If such signs or symptoms are present, the patient should be evaluated immediately.

Levetiracetam Injection should be discontinued if an alternative etiology for the signs or symptoms cannot be established [see Contraindications (4) ].

5.6 Coordination Difficulties Levetiracetam Injection may cause coordination difficulties.

In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial-onset seizures, 3.4% of Levetiracetam-treated patients experienced coordination difficulties, (reported as ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo-treated patients.

A total of 0.4% of patients in controlled clinical studies discontinued Levetiracetam treatment due to ataxia, compared to 0% of placebo-treated patients.

In 0.7% of Levetiracetam-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to coordination difficulties, while one of the treated patients was hospitalized due to worsening of pre-existing ataxia.

These events occurred most frequently within the first 4 weeks of treatment.

Patients should be monitored for signs and symptoms of coordination difficulties and advised not to drive or operate machinery until they have gained sufficient experience on Levetiracetam Injection to gauge whether it could adversely affect their ability to drive or operate machinery.

5.7 Withdrawal Seizures As with most antiepileptic drugs, Levetiracetam Injection should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus.

But if withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered.

5.8 Hematologic Abnormalities Levetiracetam Injection can cause hematologic abnormalities.

Hematologic abnormalities occurred in clinical trials and included decreases in white blood cell (WBC), neutrophil, and red blood cells counts (RBC); decreases in hemoglobin and hematocrit; and increases in eosinophil counts.

Cases of agranulocytosis, pancytopenia, and thrombocytopenia have been reported in the postmarketing setting.

A complete blood count is recommended in patients experiencing significant weakness, pyrexia, recurrent infections, or coagulation disorders.

Partial-Onset Seizures Adults In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial-onset seizures, minor but statistically significant decreases compared to placebo in total mean RBC (0.03 x 10 6 /mm 3 ), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in Levetiracetam-treated patients.

A total of 3.2% of Levetiracetam-treated and 1.8% of placebo-treated patients had at least one possibly significant (≤2.8 x 10 9 /L) decreased WBC, and 2.4% of Levetiracetam-treated and 1.4% of placebo-treated patients had at least one possibly significant (≤1.0 x 10 9 /L) decreased neutrophil count.

Of the Levetiracetam-treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment.

No patient was discontinued secondary to low neutrophil counts.

Pediatric Patients 4 Years to < 16 Years In a controlled study in pediatric patients age 4 years to <16 years, statistically significant decreases in WBC and neutrophil counts were seen in Levetiracetam-treated patients, as compared to placebo.

The mean decreases from baseline in the Levetiracetam-treated group were -0.4 × 10 9 /L and -0.3 × 10 9 /L, respectively, whereas there were small increases in the placebo group.

Mean relative lymphocyte counts increased by 1.7% in Levetiracetam-treated patients, compared to a decrease of 4% in placebo-treated patients (statistically significant).

More Levetiracetam-treated patients had a possibly clinically significant abnormally low WBC value (3% of Levetiracetam-treated patients versus 0% of placebo-treated patients); however, there was no apparent difference between treatment groups with respect to neutrophil count (5% on Levetiracetam versus 4.2% on placebo).

No patient was discontinued because of low WBC or neutrophil count.

In a randomized, double-blind, placebo-controlled study to assess the neurocognitive and behavioral effects of an oral formulation of Levetiracetam as adjunctive therapy in pediatric patients (4 to 16 years of age), 5 patients (8.6%) in the Levetiracetam-treated group and two patients (6.1%) in the placebo-treated group had high eosinophil count values that were possibly clinically significant (≥10% or ≥0.7X10 9 /L).

5.9 Increase in Blood Pressure In a randomized, placebo-controlled study in patients 1 month to <4 years of age using an oral formulation of Levetiracetam, a significantly higher risk of increased diastolic blood pressure was observed in the Levetiracetam-treated patients (17%), compared to placebo-treated patients (2%).

There was no overall difference in mean diastolic blood pressure between the treatment groups.

This disparity between the Levetiracetam and placebo treatment groups was not observed in the studies of older children or in adults.

Monitor patients 1 month to <4 years of age for increases in diastolic blood pressure.

5.10 Seizure Control During Pregnancy Physiological changes may gradually decrease plasma levels of levetiracetam throughout pregnancy.

This decrease is more pronounced during the third trimester.

It is recommended that patients be monitored carefully during pregnancy.

Close monitoring should continue through the postpartum period especially if the dose was changed during pregnancy.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Psychiatric Reactions and Changes in Behavior Advise patients and their caregivers that Levetiracetam Injection may cause changes in behavior (e.g.

aggression, agitation, anger, anxiety, apathy, depression, hostility, and irritability) and psychotic symptoms [see Warnings and Precautions (5.1) ].

Effects on Driving or Operating Machinery Inform patients that Levetiracetam Injection may cause dizziness and somnolence.

Inform patients not to drive or operate machinery until they have gained sufficient experience on Levetiracetam Injection to gauge whether it adversely affects their ability to drive or operate machinery [see Warnings and Precautions (5.2) ].

Anaphylaxis and Angioedema Advise patients to discontinue Levetiracetam Injection and seek medical care if they develop signs and symptoms of anaphylaxis or angioedema [see Warnings and Precautions (5.3) ].

Dermatological Adverse Reactions Advise patients that serious dermatological adverse reactions have occurred in patients treated with Levetiracetam Injection and instruct them to call their physician immediately if a rash develops [see Warnings and Precautions (5.4) ].

DRESS/Multiorgan Hypersensitivity Instruct patients and caregivers that a fever or rash associated with signs of other organ system involvement (e.g., lymphadenopathy, hepatic dysfunction) may be drug-related and should be reported to their healthcare provider immediately.

Levetiracetam Injection should be discontinued immediately if a serious hypersensitivity reaction is suspected [see Warnings and Precautions (5.5) ].

Withdrawal of Levetiracetam Injection Advise patients and caregivers not to discontinue use of Levetiracetam Injection without consulting with their healthcare provider.

Levetiracetam Injection should normally be gradually withdrawn to reduce the potential of increased seizure frequency and status epilepticus [see Warnings and Precautions (5.7) ].

Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during Levetiracetam Injection therapy.

Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant [see Use In Specific Populations (8.1) ].

Manufactured by: HIKMA FARMACÊUTICA (PORTUGAL) S.A.

Estrada do Rio da Mó, nº8, 8A and 8B – Fervença 2705-906 Terrugem SNT PORTUGAL Distributed by: Hikma Pharmaceuticals USA Inc.

Berkeley Heights, NJ 07922 Novaplus is a registered trademark of Vizient, Inc.

PIN370-NOV/9 Revised: April 2024

DOSAGE AND ADMINISTRATION

2 Levetiracetam Injection is for intravenous use only ( 2.1 ) Partial-Onset Seizures (monotherapy or adjunctive therapy) 1 Month to < 6 Months: 7 mg/kg twice daily; increase by 7 mg/kg twice daily every 2 weeks to recommended dose of 21 mg/kg twice daily ( 2.1 ) 6 Months to < 4 Years: 10 mg/kg twice daily; increase by 10 mg/kg twice daily every 2 weeks to recommended dose of 25 mg/kg twice daily ( 2.1 ) 4 Years to < 16 Years: 10 mg/kg twice daily; increase by 10 mg/kg twice daily every 2 weeks to recommended dose of 30 mg/kg twice daily ( 2.1 ) Adults 16 Years and Older: 500 mg twice daily; increase by 500 mg twice daily every 2 weeks to a recommended dose of 1500 mg twice daily ( 2.1 ) Myoclonic Seizures in Adults and Pediatric Patients 12 Years and Older 500 mg twice daily; increase by 500 mg twice daily every 2 weeks to recommended dose of 1500 mg twice daily ( 2.2 ) Primary Generalized Tonic-Clonic Seizures 6 Years to < 16 Years: 10 mg/kg twice daily; increase by 10 mg/kg twice daily every 2 weeks to recommended dose of 30 mg/kg twice daily ( 2.3 ) Adults 16 Years and Older: 500 mg twice daily; increase by 500 mg twice daily every 2 weeks to recommended dose of 1500 mg twice daily ( 2.3 ) Switching From or To Oral Levetiracetam When switching from or to oral Levetiracetam, the total daily dosage/frequency of Levetiracetam Injection should be equivalent to those of oral Levetiracetam.

( 2.4 , 2.5 ) See full prescribing information for preparation and administration instructions ( 2.6 ) and dosage adjustment in adults with renal impairment ( 2.7 ) 2.1 Dosing for Partial Onset Seizures The recommended dosing for monotherapy and adjunctive therapy is the same as outlined below.

There is no clinical study experience with administration of intravenous levetiracetam for a period longer than 4 days.

Adults 16 Years of Age and Older Initiate treatment with a daily dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily).

Additional dosing increments may be given (1000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3000 mg.

There is no evidence that doses greater than 3000 mg/day confer additional benefit.

Pediatric Patients 1 Month to < 6 Months Initiate treatment with a daily dose of 14 mg/kg in 2 divided doses (7 mg/kg twice daily).

Increase the daily dose every 2 weeks by increments of 14 mg/kg to the recommended daily dose of 42 mg/kg (21 mg/kg twice daily).

In the clinical trial, the mean daily dose was 35 mg/kg in this age group.

6 Months to < 4 Years Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).

Increase the daily dose in 2 weeks by an increment of 20 mg/kg to the recommended daily dose of 50 mg/kg (25 mg/kg twice daily).

If a patient cannot tolerate a daily dose of 50 mg/kg, the daily dose may be reduced.

In the clinical trial, the mean daily dose was 47 mg/kg in this age group.

4 Years to < 16 Years Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).

Increase the daily dose every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily).

If a patient cannot tolerate a daily dose of 60 mg/kg, the daily dose may be reduced.

In the clinical trial, the mean daily dose was 44 mg/kg.

The maximum daily dose was 3000 mg/day.

2.2 Dosing for Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Initiate treatment with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily).

Increase the dosage by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg.

The effectiveness of doses lower than 3000 mg/day has not been studied.

2.3 Dosing for Primary Generalized Tonic-Clonic Seizures Adults 16 Years of Age and Older Initiate treatment with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily).

Increase dosage by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg.

The effectiveness of doses lower than 3000 mg/day has not been adequately studied.

Pediatric Patients 6 to <16 Years of Age Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).

Increase the daily dose every 2 weeks by increments of 20 mg/kg (10 mg/kg twice daily) to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily).

The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied.

2.4 Switching from Oral Dosing When switching from oral Levetiracetam, the initial total daily intravenous dosage of Levetiracetam Injection should be equivalent to the total daily dosage and frequency of oral Levetiracetam.

2.5 Switching to Oral Dosing At the end of the intravenous treatment period, the patient may be switched to Levetiracetam oral administration at the equivalent daily dosage and frequency of the intravenous administration.

2.6 Preparation and Administration Instructions Levetiracetam Injection is for intravenous use only and should be diluted in 100 mL of a compatible diluent prior to administration.

If a smaller volume is required (e.g., pediatric patients), the amount of diluent should be calculated to not exceed a maximum levetiracetam concentration of 15 mg per mL of diluted solution.

Consideration should also be given to the total daily fluid intake of the patient.

Levetiracetam Injection should be administered as a 15-minute IV infusion.

One vial of Levetiracetam Injection contains 500 mg levetiracetam (500 mg/5 mL).

Levetiracetam Injection may be mixed with the following diluents and antiepileptic drugs and may be stored in polyvinyl chloride (PVC) bags.

The diluted solution should not be stored for more than 4 hours at controlled room temperature [15-30⁰C (59-86⁰F)].

Diluents: Sodium chloride (0.9%) injection, USP Lactated Ringer’s injection Dextrose 5% injection, USP Other Antiepileptic Drugs: Lorazepam Diazepam Valproate sodium There are no data to support the physical compatibility of Levetiracetam Injection with antiepileptic drugs that are not listed above.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Product with particulate matter or discoloration should not be used.

Any unused portion of the Levetiracetam Injection vial contents should be discarded.

Adults See Table 1 for the recommended preparation and administration of Levetiracetam Injection for adults to achieve a dose of 500 mg, 1000 mg, or 1500 mg.

Table 1: Preparation and Administration of Levetiracetam Injection for Adults Dose Withdraw Volume Volume of Diluent Infusion Time 500 mg 5 mL (5 mL vial) 100 mL 15 minutes 1000 mg 10 mL (two 5 mL vials) 100 mL 15 minutes 1500 mg 15 mL (three 5 mL vials) 100 mL 15 minutes For example, to prepare a 1000 mg dose, dilute 10 mL of Levetiracetam Injection in 100 mL of a compatible diluent and administer intravenously as a 15-minute infusion.

Pediatric Patients When using Levetiracetam Injection for pediatric patients, dosing is weight-based (mg per kg).

The following calculation should be used to determine the appropriate daily dose of Levetiracetam Injection for pediatric patients: Total daily dose (mL/day) = Daily dose (mg/kg/day) x patient weight (kg) 100 mg/mL 2.7 Dosage Adjustments in Adult Patients with Renal Impairment Levetiracetam Injection dosing must be individualized according to the patient’s renal function status.

Recommended dosage adjustments for adults with renal impairment are shown in Table 2.

Information is unavailable for dosage adjustments in pediatric patients with renal impairment.

In order to calculate the dose recommended for adult patients with renal impairment, creatinine clearance adjusted for body surface area must be calculated.

To do this an estimate of the patient’s creatinine clearance (CLcr) in mL/min must first be calculated using the following formula: CLcr = [140-age (years)] x weight (kg) (x 0.85 for female patients) 72 x serum creatinine (mg/dL) Then CLcr is adjusted for body surface area (BSA) as follows: CLcr (mL/min/1.73m 2 ) = CLcr (mL/min) x 1.73 BSA subject (m 2 ) Table 2: Dosage Adjustment Regimen for Adult Patients with Renal Impairment Group Creatinine Clearance (mL/min/1.73 m 2 ) Dosage (mg) Frequency Normal > 80 500 to 1,500 Every 12 hours Mild 50 – 80 500 to 1,000 Every 12 hours Moderate 30 – 50 250 to 750 Every 12 hours Severe < 30 250 to 500 Every 12 hours ESRD patients using dialysis —– 500 to 1,0001 Following dialysis, a 250 to 500 mg supplemental dose is recommended.

Every 24 hours 2.8 Discontinuation of Levetiracetam Injection Avoid abrupt withdrawal from Levetiracetam Injection in order to reduce the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions ( 5.6 ) ].

amikacin sulfate 500 MG in 2 ML Injection

Generic Name: AMIKACIN SULFATE
Brand Name: Amikacin Sulfate
  • Substance Name(s):
  • AMIKACIN SULFATE

WARNINGS

See box above.

Aminoglycosides can cause fetal harm when administered to a pregnant woman.

Aminoglycosides cross the placenta and there have been several reports of total irreversible, bilateral congenital deafness in children whose mothers received streptomycin during pregnancy.

Although serious side effects to the fetus or newborns have not been reported in the treatment of pregnant women with other aminoglycosides, the potential for harm exists.

Reproduction studies of amikacin have been performed in rats and mice and revealed no evidence of impaired fertility or harm to the fetus due to amikacin.

There are no well controlled studies in pregnant women, but investigational experience does not include any positive evidence of adverse effects to the fetus.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people.

The overall prevalence of sulfite sensitivity in the general population is unknown and probably low.

Sulfite sensitivity is seen more frequently in asthmatic than nonasthmatic people.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Amikacin Sulfate Injection, 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.

Risk of Ototoxicity Due to Mitochondrial DNA Variants Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant.

Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range.

Mitochondrial DNA variants are present in less than 1 % of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown.

In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

OVERDOSAGE

In the event of overdosage or toxic reaction, peritoneal dialysis or hemodialysis will aid in the removal of amikacin from the blood.

In the newborn infant, exchange transfusion may also be considered.

DESCRIPTION

Amikacin sulfate is semi-synthetic aminoglycoside antibiotic derived from kanamycin.

It is C 22 H 43 N 5 O 13 •2H 2 SO 4 • O -3-amino-3-deoxy-α-D-glucopyranosyl-(1→4)- O -[6-amino-6-deoxy-α-D-glucopyranosyl-(1→6)]- N 3 -(4-amino-L-2-hydroxybutyryl)-2-deoxy-L-streptamine sulfate (1:2) M.W.

585.61 The dosage form is supplied as a sterile, colorless to light straw colored solution for intramuscular or intravenous use.

Each mL contains 250 mg amikacin (as the sulfate), 0.66% sodium metabisulfite, 2.5% sodium citrate dihydrate with pH adjusted to 4.5 with sulfuric acid.

chemical structure

HOW SUPPLIED

Amikacin Sulfate Injection, USP is supplied as a colorless solution which requires no refrigeration.

At times the solution may become a very pale yellow; this does not indicate a decrease in potency.

Amikacin Sulfate Injection, USP, 250 mg/mL, is supplied as follows: NDC 0641-6167-10, 2 mL Single Dose Vial packaged in a carton of 10 NDC 0641-6166-10, 4 mL Vial packaged in a carton of 10 Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc.

at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

For Product Inquiry call 1-877-845-0689.

MECHANISM OF ACTION

Mechanism of Action Amikacin, an aminoglycoside, binds to the prokaryotic ribosome, inhibiting protein synthesis in susceptible bacteria.

It is bactericidal in vitro against Gram-positive and Gram-negative bacteria.

INDICATIONS AND USAGE

Amikacin Sulfate Injection is indicated in the short-term treatment of serious infections due to susceptible strains of Gram-negative bacteria, including Pseudomonas species, Escherichia coli , species of indole-positive and indole-negative Proteus , Providencia species, Klebsiella-Enterobacter-Serratia species, and Acinetobacter ( Mima-Herellea ) species.

Clinical studies have shown Amikacin Sulfate Injection to be effective in bacterial septicemia (including neonatal sepsis); in serious infections of the respiratory tract, bones and joints, central nervous system (including meningitis) and skin and soft tissue; intra-abdominal infections (including peritonitis); and in burns and post-operative infections (including post-vascular surgery).

Clinical studies have shown amikacin also to be effective in serious complicated and recurrent urinary tract infections due to these organisms.

Aminoglycosides, including Amikacin Sulfate Injection are not indicated in uncomplicated initial episodes of urinary tract infections unless the causative organisms are not susceptible to antibiotics having less potential toxicity.

Bacteriologic studies should be performed to identify causative organisms and their susceptibilities to amikacin.

Amikacin may be considered as initial therapy in suspected Gram-negative infections and therapy may be instituted before obtaining the results of susceptibility testing.

Clinical trials demonstrated that amikacin was effective in infections caused by gentamicin- and/or tobramycin-resistant strains of Gram-negative organisms, particularly Proteus rettgeri , Providencia stuartii , Serratia marcescens , and Pseudomonas aeruginosa .

The decision to continue therapy with the drug should be based on results of the susceptibility tests, the severity of the infection, the response of the patient and the important additional considerations contained in the WARNINGS box above.

Amikacin has also been shown to be effective in staphylococcal infections and may be considered as initial therapy under certain conditions in the treatment of known or suspected staphylococcal disease such as, severe infections where the causative organism may be either a Gram-negative bacterium or a staphylococcus, infections due to susceptible strains of staphylococci in patients allergic to other antibiotics, and in mixed staphylococci/Gram-negative infections.

In certain severe infections such as neonatal sepsis, concomitant therapy with a penicillin-type drug may be indicated because of the possibility of infections due to Gram-positive organisms such as streptococci or pneumococci.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of amikacin and other antibacterial drugs, amikacin 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.

PEDIATRIC USE

Pediatric Use Aminoglycosides should be used with caution in premature and neonatal infants because of the renal immaturity of these patients and the resulting prolongation of serum half-life of these drugs.

PREGNANCY

Pregnancy Teratogenic Effects; Pregnancy (See WARNINGS section.)

NUSRING MOTHERS

Nursing Mothers It is not known whether amikacin is excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from amikacin, 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

WARNINGS Patients treated with parenteral aminoglycosides should be under close clinical observation because of the potential ototoxicity and nephrotoxicity associated with their use.

Safety for treatment periods which are longer than 14 days has not been established.

Neurotoxicity, manifested as vestibular and permanent bilateral auditory ototoxicity, can occur in patients with preexisting renal damage and in patients with normal renal function treated at higher doses and/or for periods longer than those recommended.

The risk of aminoglycoside-induced ototoxicity is greater in patients with renal damage.

High frequency deafness usually occurs first and can be detected only by audiometric testing.

Vertigo may occur and may be evidence of vestibular injury.

Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching and convulsions.

The risk of hearing loss due to aminoglycosides increases with the degree of exposure to either high peak or high trough serum concentrations.

Patients developing cochlear damage may not have symptoms during therapy to warn them of developing eighth-nerve toxicity, and total or partial irreversible bilateral deafness may occur after the drug has been discontinued.

Aminoglycoside-induced ototoxicity is usually irreversible.

Aminoglycosides are potentially nephrotoxic.

The risk of nephrotoxicity is greater in patients with impaired renal function and in those who receive high doses or prolonged therapy.

Neuromuscular blockade and respiratory paralysis have been reported following parenteral injection, topical instillation (as in orthopedic and abdominal irrigation or in local treatment of empyema), and following oral use of aminoglycosides.

The possibility of these phenomena should be considered if aminoglycosides are administered by any route, especially in patients receiving anesthetics, neuromuscular blocking agents such as tubocurarine, succinylcholine, decamethonium, or in patients receiving massive transfusions of citrate-anticoagulated blood.

If blockage occurs, calcium salts may reverse these phenomena, but mechanical respiratory assistance may be necessary.

Renal and eighth-nerve function should be closely monitored especially in patients with known or suspected renal impairment at the onset of therapy and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy.

Serum concentrations of amikacin should be monitored when feasible to assure adequate levels and to avoid potentially toxic levels and prolonged peak concentrations above 35 micrograms per mL.

Urine should be examined for decreased specific gravity, increased excretion of proteins, and the presence of cells or casts.

Blood urea nitrogen, serum creatinine, or creatinine clearance should be measured periodically.

Serial audiograms should be obtained where feasible in patients old enough to be tested, particularly high risk patients.

Evidence of ototoxicity (dizziness, vertigo, tinnitus, roaring in the ears, and hearing loss) or nephrotoxicity requires discontinuation of the drug or dosage adjustment.

Concurrent and/or sequential systemic, oral or topical use of other neurotoxic or nephrotoxic products, particularly bacitracin, cisplatin, amphotericin B, cephaloridine, paromomycin, viomycin, polymyxin B, colistin, vancomycin, or other aminoglycosides should be avoided.

Other factors that may increase risk of toxicity are advanced age and dehydration.

The concurrent use of amikacin with potent diuretics (ethacrynic acid, or furosemide) should be avoided since diuretics by themselves may cause ototoxicity.

In addition, when administered intravenously, diuretics may enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.

INFORMATION FOR PATIENTS

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

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

When amikacin 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 amikacin 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 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

The patient’s pretreatment body weight should be obtained for calculation of correct dosage.

Amikacin Sulfate Injection may be given intramuscularly or intravenously.

The status of renal function should be estimated by measurement of the serum creatinine concentration or calculation of the endogenous creatinine clearance rate.

The blood urea nitrogen (BUN) is much less reliable for this purpose.

Reassessment of renal function should be made periodically during therapy.

Whenever possible, amikacin concentrations in serum should be measured to assure adequate but not excessive levels.

It is desirable to measure both peak and trough serum concentrations intermittently during therapy.

Peak concentrations (30 to 90 minutes after injection) above 35 micrograms per mL and trough concentrations (just prior to the next dose) above 10 micrograms per mL should be avoided.

Dosage should be adjusted as indicated.

Intramuscular Administration for Patients with Normal Renal Function The recommended dosage for adults, children and older infants (see WARNINGS box) with normal renal function is 15 mg/kg/day divided into 2 or 3 equal doses administered at equally-divided intervals, i.e., 7.5 mg/kg q12h or 5 mg/kg q8h.

Treatment of patients in the heavier weight classes should not exceed 1.5 gram/day.

When amikacin is indicated in newborns (see WARNINGS box), it is recommended that a loading dose of 10 mg/kg be administered initially to be followed with 7.5 mg/kg every 12 hours.

The usual duration of treatment is 7 to 10 days.

It is desirable to limit the duration of treatment to short term whenever feasible.

The total daily dose by all routes of administration should not exceed 15 mg/kg/day.

In difficult and complicated infections where treatment beyond 10 days is considered, the use of amikacin should be reevaluated.

If continued, amikacin serum levels, and renal, auditory, and vestibular functions should be monitored.

At the recommended dosage level, uncomplicated infections due to amikacin-sensitive organisms should respond in 24 to 48 hours.

If definite clinical response does not occur within 3 to 5 days, therapy should be stopped and the antibiotic susceptibility pattern of the invading organism should be rechecked.

Failure of the infection to respond may be due to resistance of the organism or to the presence of septic foci requiring surgical drainage.

When amikacin is indicated in uncomplicated urinary tract infections, a dose of 250 mg twice daily may be used.

DOSAGE GUIDELINES ADULTS AND CHILDREN WITH NORMAL RENAL FUNCTION Patient Weight Dosage lbs kg 7.5 mg/kg q12h OR 5 mg/kg q8h 99 45 337.5 mg 225 mg 110 50 375 mg 250 mg 121 55 412.5 mg 275 mg 132 60 450 mg 300 mg 143 65 487.5 mg 325 mg 154 70 525 mg 350 mg 165 75 562.5 mg 375 mg 176 80 600 mg 400 mg 187 85 637.5 mg 425 mg 198 90 675 mg 450 mg 209 95 712.5 mg 475 mg 220 100 750 mg 500 mg Intramuscular Administration for Patients with Impaired Renal Function Whenever possible, serum amikacin concentrations should be monitored by appropriate assay procedures.

Doses may be adjusted in patients with impaired renal function either by administering normal doses at prolonged intervals or by administering reduced doses at a fixed interval.

Both methods are based on the patient’s creatinine clearance or serum creatinine values since these have been found to correlate with aminoglycoside half-lives in patients with diminished renal function.

These dosage schedules must be used in conjunction with careful clinical and laboratory observations of the patient and should be modified as necessary.

Neither method should be used when dialysis is being performed.

Normal Dosage at Prolonged Intervals If the creatinine clearance rate is not available and the patient’s condition is stable, a dosage interval in hours for the normal dose can be calculated by multiplying the patient’s serum creatinine by 9, e.g., if the serum creatinine concentration is 2 mg/100 mL, the recommended single dose (7.5 mg/kg) should be administered every 18 hours.

Reduced Dosage at Fixed Time Intervals When renal function is impaired and it is desirable to administer amikacin at a fixed time interval, dosage must be reduced.

In these patients, serum amikacin concentrations should be measured to assure accurate administration of amikacin and to avoid concentrations above 35 mcg/mL.

If serum assay determinations are not available and the patient’s condition is stable, serum creatinine and creatinine clearance values are the most readily available indicators of the degree of renal impairment to use as a guide for dosage.

First, initiate therapy by administering a normal dose, 7.5 mg/kg, as a loading dose.

This loading dose is the same as the normally recommended dose which would be calculated for a patient with a normal renal function as described above.

To determine the size of maintenance doses administered every 12 hours, the loading dose should be reduced in proportion to the reduction in the patient’s creatinine clearance rate: Maintenance Dose Every 12 hours = observed CC in mL/min X Calculated loading dose in mg normal CC in mL/min (CC – creatinine clearance rate) An alternate rough guide for determining reduced dosage at 12-hour intervals (for patients whose steady state serum creatinine values are known) is to divide the normally recommended dose by the patient’s serum creatinine.

The above dosage schedules are not intended to be rigid recommendations but are provided as guides to dosage when the measurement of amikacin serum levels is not feasible.

Intravenous Administration The individual dose, the total daily dose, and the total cumulative dose of amikacin sulfate are identical to the dose recommended for intramuscular administration.

The solution for intravenous use is prepared by adding the contents of a 500 mg vial to 100 or 200 mL of sterile diluent such as 0.9% sodium chloride injection or 5% dextrose injection or any of the compatible solutions listed below.

The solution is administered to adults over a 30 to 60 minute period.

The total daily dose should not exceed 15 mg/kg/day and may be divided into either 2 or 3 equally-divided doses at equally-divided intervals.

In pediatric patients the amount of fluid used will depend on the amount of amikacin ordered for the patient.

It should be a sufficient amount to infuse the Amikacin Sulfate Injection over a 30 to 60 minute period.

Infants should receive a 1 to 2 hour infusion.

Amikacin should not be physically premixed with other drugs but should be administered separately according to the recommended dose and route.

Stability in IV Fluids Amikacin sulfate is stable for 24 hours at room temperature at concentrations of 0.25 and 5 mg/mL in the following solutions: 5% Dextrose Injection 5% Dextrose and 0.2% Sodium Chloride Injection 5% Dextrose and 0.45% Sodium Chloride Injection 0.9% Sodium Chloride Injection Lactated Ringer’s Injection Normosol ® M in 5% Dextrose Injection (or Plasma-Lyte 56 Injection in 5% Dextrose in Water) Normosol ® R in 5% Dextrose Injection (or Plasma-Lyte 148 Injection in 5% Dextrose in Water) In the above solutions with Amikacin Sulfate Injection concentrations of 0.25 and 5 mg/mL, solutions aged for 60 days at 4°C and then stored at 25°C had utility times of 24 hours.

At the same concentrations, solutions frozen and aged for 30 days at -15°C, thawed, and stored at 25°C had utility times of 24 hours.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Aminoglycosides administered by any of the above routes should not be physically premixed with other drugs but should be administered separately.

Because of the potential toxicity of aminoglycosides, “fixed dosage” recommendations which are not based upon body weight are not advised.

Rather, it is essential to calculate the dosage to fit the needs of each patient.

Sertraline 100 MG Oral Tablet [Zoloft]

WARNINGS

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 18–24) 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.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of Treatment with ZOLOFT, for a description of the risks of discontinuation of ZOLOFT).

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 health care providers.

Such monitoring should include daily observation by families and caregivers.

Prescriptions for ZOLOFT 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 ZOLOFT is not approved for use in treating bipolar depression.

Cases of serious sometimes fatal reactions have been reported in patients receiving ZOLOFT (sertraline hydrochloride), a selective serotonin reuptake inhibitor (SSRI), in combination with a monoamine oxidase inhibitor (MAOI).

Symptoms of a drug interaction between an SSRI and an MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability, and extreme agitation progressing to delirium and coma.

These reactions have also been reported in patients who have recently discontinued an SSRI and have been started on an MAOI.

Some cases presented with features resembling neuroleptic malignant syndrome.

Therefore, ZOLOFT should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI.

Similarly, at least 14 days should be allowed after stopping ZOLOFT before starting an MAOI.

The concomitant use of Zoloft with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and – Potential for Interaction with Monoamine Oxidase Inhibitors ).

Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome may occur in treatment with SNRIs and SSRIs, including Zoloft, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

If concomitant treatment of SNRIs and SSRIs, including Zoloft, with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see PRECAUTIONS – Drug Interactions ).

The concomitant use of SNRIs and SSRIs, including Zoloft, with serotonin precursors (such as tryptophan) is not recommended (see PRECAUTIONS – Drug Interactions ).

Neuroleptic Malignant Syndrome (NMS) or NMS-Like Reactions Rare instances of neuroleptic malignant syndrome (NMS) or NMS-like reactions have been reported when a selective serotonin reuptake inhibitor (SSRI) drug, such as sertraline, or a serotonin-norepinephrine reuptake inhibitor (SNRI) was added to antipsychotic drug therapy.

Additionally, a small number of such cases have been reported with SSRI’s and SNRI’s in the absence of antipsychotic coadministration.

These serious and sometimes fatal events can include hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.

It is uncertain whether these cases are serotonin syndrome which, in its most severe form, can resemble neuroleptic malignant syndrome.

As these events may result in potentially life-threatening conditions, patients should be monitored for the emergence of NMS-like signs and symptoms, especially if sertraline and an antipsychotic drug are taken concurrently.

Treatment with sertraline and any concomitant antipsychotic agent should be discontinued immediately if such events occur and supportive symptomatic treatment should be initiated.

DRUG INTERACTIONS

Drug Interactions Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins Because sertraline is tightly bound to plasma protein, the administration of ZOLOFT (sertraline hydrochloride) to a patient taking another drug which is tightly bound to protein (e.g., warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect.

Conversely, adverse effects may result from displacement of protein bound ZOLOFT by other tightly bound drugs.

In a study comparing prothrombin time AUC (0–120 hr) following dosing with warfarin (0.75 mg/kg) before and after 21 days of dosing with either ZOLOFT (50–200 mg/day) or placebo, there was a mean increase in prothrombin time of 8% relative to baseline for ZOLOFT compared to a 1% decrease for placebo (p<0.02).

The normalization of prothrombin time for the ZOLOFT group was delayed compared to the placebo group.

The clinical significance of this change is unknown.

Accordingly, prothrombin time should be carefully monitored when ZOLOFT therapy is initiated or stopped.

Cimetidine In a study assessing disposition of ZOLOFT (100 mg) on the second of 8 days of cimetidine administration (800 mg daily), there were significant increases in ZOLOFT mean AUC (50%), Cmax (24%) and half-life (26%) compared to the placebo group.

The clinical significance of these changes is unknown.

CNS Active Drugs In a study comparing the disposition of intravenously administered diazepam before and after 21 days of dosing with either ZOLOFT (50 to 200 mg/day escalating dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the ZOLOFT group compared to a 19% decrease relative to baseline for the placebo group (p<0.03).

There was a 23% increase in Tmax for desmethyldiazepam in the ZOLOFT group compared to a 20% decrease in the placebo group (p<0.03).

The clinical significance of these changes is unknown.

In a placebo-controlled trial in normal volunteers, the administration of two doses of ZOLOFT did not significantly alter steady-state lithium levels or the renal clearance of lithium.

Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following initiation of ZOLOFT therapy with appropriate adjustments to the lithium dose.

In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co-administration to steady state was associated with a mean increase in pimozide AUC and Cmax of about 40%, but was not associated with any changes in EKG.

Since the highest recommended pimozide dose (10 mg) has not been evaluated in combination with sertraline, the effect on QT interval and PK parameters at doses higher than 2 mg at this time are not known.

While the mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide and due to the interaction noted at a low dose of pimozide, concomitant administration of ZOLOFT and pimozide should be contraindicated (see CONTRAINDICATIONS ).

Results of a placebo-controlled trial in normal volunteers suggest that chronic administration of sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism.

Nonetheless, at this time, it is recommended that plasma phenytoin concentrations be monitored following initiation of Zoloft therapy with appropriate adjustments to the phenytoin dose, particularly in patients with multiple underlying medical conditions and/or those receiving multiple concomitant medications.

The effect of Zoloft on valproate levels has not been evaluated in clinical trials.

In the absence of such data, it is recommended that plasma valproate levels be monitored following initiation of Zoloft therapy with appropriate adjustments to the valproate dose.

The risk of using ZOLOFT in combination with other CNS active drugs has not been systematically evaluated.

Consequently, caution is advised if the concomitant administration of ZOLOFT and such drugs is required.

There is limited controlled experience regarding the optimal timing of switching from other drugs effective in the treatment of major depressive disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety disorder to ZOLOFT.

Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents.

The duration of an appropriate washout period which should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to another has not been established.

Monoamine Oxidase Inhibitors See CONTRAINDICATIONS and WARNINGS .

Drugs Metabolized by P450 3A4 In three separate in vivo interaction studies, sertraline was co-administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride under steady-state conditions.

The results of these studies indicated that sertraline did not increase plasma concentrations of terfenadine, carbamazepine, or cisapride.

These data indicate that sertraline’s extent of inhibition of P450 3A4 activity is not likely to be of clinical significance.

Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.) induces the metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%).

Drugs Metabolized by P450 2D6 Many drugs effective in the treatment of major depressive disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in the treatment of major depressive disorder inhibit the biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase the plasma concentrations of co-administered drugs that are metabolized by P450 2D6.

The drugs for which this potential interaction is of greatest concern are those metabolized primarily by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs effective in the treatment of major depressive disorder and the Type 1C antiarrhythmics propafenone and flecainide.

The extent to which this interaction is an important clinical problem depends on the extent of the inhibition of P450 2D6 by the antidepressant and the therapeutic index of the co-administered drug.

There is variability among the drugs effective in the treatment of major depressive disorder in the extent of clinically important 2D6 inhibition, and in fact sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the class.

Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition.

Consequently, concomitant use of a drug metabolized by P450 2D6 with ZOLOFT may require lower doses than usually prescribed for the other drug.

Furthermore, whenever ZOLOFT is withdrawn from co-therapy, an increased dose of the co-administered drug may be required (see Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder under PRECAUTIONS ).

Serotonergic Drugs Based on the mechanism of action of SNRIs and SSRIs, including Zoloft, and the potential for serotonin syndrome, caution is advised when SNRIs and SSRIs, including Zoloft, are coadministered with other drugs that may affect the serotonergic neutrotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St.

John’s Wort (see WARNINGS-Serotonin Syndrome ).

The concomitant use of Zoloft with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS – Drug Interactions ).

Triptans There have been rare post marketing reports of serotonin syndrome with use of an SNRI or an SSRI and a triptan.

If concomitant treatment of SNRIs and SSRIs, including Zoloft, with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS – Serotonin Syndrome ).

Sumatriptan There have been rare post marketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan.

If concomitant treatment with sumatriptan and an SSRI (e.g., citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised.

Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder (TCAs) The extent to which SSRI–TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved.

Nevertheless, caution is indicated in the co-administration of TCAs with ZOLOFT, because sertraline may inhibit TCA metabolism.

Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is co-administered with ZOLOFT (see Drugs Metabolized by P450 2D6 under PRECAUTIONS ).

Hypoglycemic Drugs In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for 22 days (including 200 mg/day for the final 13 days) caused a statistically significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous 1000 mg dose.

ZOLOFT administration did not noticeably change either the plasma protein binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased clearance was due to a change in the metabolism of the drug.

The clinical significance of this decrease in tolbutamide clearance is unknown.

Atenolol ZOLOFT (100 mg) when administered to 10 healthy male subjects had no effect on the beta-adrenergic blocking ability of atenolol.

Digoxin In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for 17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or digoxin renal clearance.

Microsomal Enzyme Induction Preclinical studies have shown ZOLOFT to induce hepatic microsomal enzymes.

In clinical studies, ZOLOFT was shown to induce hepatic enzymes minimally as determined by a small (5%) but statistically significant decrease in antipyrine half-life following administration of 200 mg/day for 21 days.

This small change in antipyrine half-life reflects a clinically insignificant change in hepatic metabolism.

Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.) Serotonin release by platelets plays an important role in hemostasis.

Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding.

These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding.

Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin.

Patients receiving warfarin therapy should be carefully monitored when Zoloft is initiated or discontinued.

Electroconvulsive Therapy There are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and ZOLOFT.

Alcohol Although ZOLOFT did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of ZOLOFT and alcohol is not recommended.

OVERDOSAGE

Human Experience Of 1,027 cases of overdose involving sertraline hydrochloride worldwide, alone or with other drugs, there were 72 deaths (circa 1999).

Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted in fatal outcome, 75 completely recovered, and 27 patients experienced sequelae after overdosage to include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue, insomnia, somnolence and serotonin syndrome.

The remaining 524 cases had an unknown outcome.

The most common signs and symptoms associated with non-fatal sertraline hydrochloride overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor.

The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone and subsequently recovered.

However, another patient who took 2.5 grams of sertraline hydrochloride alone experienced a fatal outcome.

Other important adverse events reported with sertraline hydrochloride overdose (single or multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium, hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval prolongation, serotonin syndrome, stupor and syncope.

Overdose Management Treatment should consist of those general measures employed in the management of overdosage with any antidepressant.

Ensure an adequate airway, oxygenation and ventilation.

Monitor cardiac rhythm and vital signs.

General supportive and symptomatic measures are also recommended.

Induction of emesis is not recommended.

Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.

Activated charcoal should be administered.

Due to large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.

No specific antidotes for sertraline are known.

In managing overdosage, consider the possibility of multiple drug involvement.

The physician should consider contacting a poison control center on the treatment of any overdose.

Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference ® (PDR ® ).

DESCRIPTION

ZOLOFT ® (sertraline hydrochloride) is a selective serotonin reuptake inhibitor (SSRI) for oral administration.

It has a molecular weight of 342.7.

Sertraline hydrochloride has the following chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride.

The empirical formula C 17 H 17 NCl 2 •HCl is represented by the following structural formula: Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and isopropyl alcohol, and sparingly soluble in ethanol.

ZOLOFT is supplied for oral administration as scored tablets containing sertraline hydrochloride equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: dibasic calcium phosphate dihydrate, D & C Yellow #10 aluminum lake (in 25 mg tablet), FD & C Blue #1 aluminum lake (in 25 mg tablet), FD & C Red #40 aluminum lake (in 25 mg tablet), FD & C Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide.

ZOLOFT oral concentrate is available in a multidose 60 mL bottle.

Each mL of solution contains sertraline hydrochloride equivalent to 20 mg of sertraline.

The solution contains the following inactive ingredients: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT).

The oral concentrate must be diluted prior to administration (see PRECAUTIONS, Information for Patients and DOSAGE AND ADMINISTRATION ).

Chemical Structure

CLINICAL STUDIES

Clinical Trials Major Depressive Disorder The efficacy of ZOLOFT as a treatment for major depressive disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III criteria for major depressive disorder.

Study 1 was an 8-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day.

Study 2 was a 6-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.

Overall, these studies demonstrated ZOLOFT to be superior to placebo on the Hamilton Depression Rating Scale and the Clinical Global Impression Severity and Improvement scales.

Study 2 was not readily interpretable regarding a dose response relationship for effectiveness.

Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open treatment phase on ZOLOFT 50–200 mg/day.

These patients (N=295) were randomized to continuation for 44 weeks on double-blind ZOLOFT 50–200 mg/day or placebo.

A statistically significantly lower relapse rate was observed for patients taking ZOLOFT compared to those on placebo.

The mean dose for completers was 70 mg/day.

Analyses for gender effects on outcome did not suggest any differential responsiveness on the basis of sex.

Obsessive-Compulsive Disorder (OCD) The effectiveness of ZOLOFT in the treatment of OCD was demonstrated in three multicenter placebo-controlled studies of adult outpatients (Studies 1–3).

Patients in all studies had moderate to severe OCD (DSM-III or DSM-III-R) with mean baseline ratings on the Yale–Brown Obsessive-Compulsive Scale (YBOCS) total score ranging from 23 to 25.

Study 1 was an 8-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 186 mg/day.

Patients receiving ZOLOFT experienced a mean reduction of approximately 4 points on the YBOCS total score which was significantly greater than the mean reduction of 2 points in placebo-treated patients.

Study 2 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.

Patients receiving ZOLOFT doses of 50 and 200 mg/day experienced mean reductions of approximately 6 points on the YBOCS total score which were significantly greater than the approximately 3 point reduction in placebo-treated patients.

Study 3 was a 12-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 185 mg/day.

Patients receiving ZOLOFT experienced a mean reduction of approximately 7 points on the YBOCS total score which was significantly greater than the mean reduction of approximately 4 points in placebo-treated patients.

Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.

The effectiveness of ZOLOFT for the treatment of OCD was also demonstrated in a 12-week, multicenter, placebo-controlled, parallel group study in a pediatric outpatient population (children and adolescents, ages 6–17).

Patients receiving ZOLOFT in this study were initiated at doses of either 25 mg/day (children, ages 6–12) or 50 mg/day (adolescents, ages 13–17), and then titrated over the next four weeks to a maximum dose of 200 mg/day, as tolerated.

The mean dose for completers was 178 mg/day.

Dosing was once a day in the morning or evening.

Patients in this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the Children’s Yale-Brown Obsessive-Compulsive Scale (CYBOCS) total score of 22.

Patients receiving sertraline experienced a mean reduction of approximately 7 units on the CYBOCS total score which was significantly greater than the 3 unit reduction for placebo patients.

Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.

In a longer-term study, patients meeting DSM-III-R criteria for OCD who had responded during a 52-week single-blind trial on ZOLOFT 50–200 mg/day (n=224) were randomized to continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for discontinuation due to relapse or insufficient clinical response.

Response during the single-blind phase was defined as a decrease in the YBOCS score of ≥ 25% compared to baseline and a CGI-I of 1 (very much improved), 2 (much improved) or 3 (minimally improved).

Relapse during the double-blind phase was defined as the following conditions being met (on three consecutive visits for 1 and 2, and for visit 3 for condition 3): (1) YBOCS score increased by ≥ 5 points, to a minimum of 20, relative to baseline; (2) CGI-I increased by ≥ one point; and (3) worsening of the patient’s condition in the investigator’s judgment, to justify alternative treatment.

Insufficient clinical response indicated a worsening of the patient’s condition that resulted in study discontinuation, as assessed by the investigator.

Patients receiving continued ZOLOFT treatment experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo.

This pattern was demonstrated in male and female subjects.

Panic Disorder The effectiveness of ZOLOFT in the treatment of panic disorder was demonstrated in three double-blind, placebo-controlled studies (Studies 1–3) of adult outpatients who had a primary diagnosis of panic disorder (DSM-III-R), with or without agoraphobia.

Studies 1 and 2 were 10-week flexible dose studies.

ZOLOFT was initiated at 25 mg/day for the first week, and then patients were dosed in a range of 50–200 mg/day on the basis of clinical response and toleration.

The mean ZOLOFT doses for completers to 10 weeks were 131 mg/day and 144 mg/day, respectively, for Studies 1 and 2.

In these studies, ZOLOFT was shown to be significantly more effective than placebo on change from baseline in panic attack frequency and on the Clinical Global Impression Severity of Illness and Global Improvement scores.

The difference between ZOLOFT and placebo in reduction from baseline in the number of full panic attacks was approximately 2 panic attacks per week in both studies.

Study 3 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day.

Patients receiving ZOLOFT experienced a significantly greater reduction in panic attack frequency than patients receiving placebo.

Study 3 was not readily interpretable regarding a dose response relationship for effectiveness.

Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age, race, or gender.

In a longer-term study, patients meeting DSM-III-R criteria for Panic Disorder who had responded during a 52-week open trial on ZOLOFT 50–200 mg/day (n=183) were randomized to continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for discontinuation due to relapse or insufficient clinical response.

Response during the open phase was defined as a CGI-I score of 1 (very much improved) or 2 (much improved).

Relapse during the double-blind phase was defined as the following conditions being met on three consecutive visits: (1) CGI-I ≥ 3; (2) meets DSM-III-R criteria for Panic Disorder; (3) number of panic attacks greater than at baseline.

Insufficient clinical response indicated a worsening of the patient’s condition that resulted in study discontinuation, as assessed by the investigator.

Patients receiving continued ZOLOFT treatment experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo.

This pattern was demonstrated in male and female subjects.

Posttraumatic Stress Disorder (PTSD) The effectiveness of ZOLOFT in the treatment of PTSD was established in two multicenter placebo-controlled studies (Studies 1–2) of adult outpatients who met DSM-III-R criteria for PTSD.

The mean duration of PTSD for these patients was 12 years (Studies 1 and 2 combined) and 44% of patients (169 of the 385 patients treated) had secondary depressive disorder.

Studies 1 and 2 were 12-week flexible dose studies.

ZOLOFT was initiated at 25 mg/day for the first week, and patients were then dosed in the range of 50–200 mg/day on the basis of clinical response and toleration.

The mean ZOLOFT dose for completers was 146 mg/day and 151 mg/day, respectively for Studies 1 and 2.

Study outcome was assessed by the Clinician-Administered PTSD Scale Part 2 (CAPS) which is a multi-item instrument that measures the three PTSD diagnostic symptom clusters of reexperiencing/intrusion, avoidance/numbing, and hyperarousal as well as the patient-rated Impact of Event Scale (IES) which measures intrusion and avoidance symptoms.

ZOLOFT was shown to be significantly more effective than placebo on change from baseline to endpoint on the CAPS, IES and on the Clinical Global Impressions (CGI) Severity of Illness and Global Improvement scores.

In two additional placebo-controlled PTSD trials, the difference in response to treatment between patients receiving ZOLOFT and patients receiving placebo was not statistically significant.

One of these additional studies was conducted in patients similar to those recruited for Studies 1 and 2, while the second additional study was conducted in predominantly male veterans.

As PTSD is a more common disorder in women than men, the majority (76%) of patients in these trials were women (152 and 139 women on sertraline and placebo versus 39 and 55 men on sertraline and placebo; Studies 1 and 2 combined).

Post hoc exploratory analyses revealed a significant difference between ZOLOFT and placebo on the CAPS, IES and CGI in women, regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect in the relatively smaller number of men in these studies.

The clinical significance of this apparent gender interaction is unknown at this time.

There was insufficient information to determine the effect of race or age on outcome.

In a longer-term study, patients meeting DSM-III-R criteria for PTSD who had responded during a 24-week open trial on ZOLOFT 50–200 mg/day (n=96) were randomized to continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for relapse.

Response during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved), and a decrease in the CAPS-2 score of > 30% compared to baseline.

Relapse during the double-blind phase was defined as the following conditions being met on two consecutive visits: (1) CGI-I ≥ 3; (2) CAPS-2 score increased by ≥ 30% and by ≥ 15 points relative to baseline; and (3) worsening of the patient’s condition in the investigator’s judgment.

Patients receiving continued ZOLOFT treatment experienced significantly lower relapse rates over the subsequent 28 weeks compared to those receiving placebo.

This pattern was demonstrated in male and female subjects.

Premenstrual Dysphoric Disorder (PMDD) The effectiveness of ZOLOFT for the treatment of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose trials (Studies 1 and 2) conducted over 3 menstrual cycles.

Patients in Study 1 met DSM-III-R criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as Premenstrual Dysphoric Disorder (PMDD) in DSM-IV.

Patients in Study 2 met DSM-IV criteria for PMDD.

Study 1 utilized daily dosing throughout the study, while Study 2 utilized luteal phase dosing for the 2 weeks prior to the onset of menses.

The mean duration of PMDD symptoms for these patients was approximately 10.5 years in both studies.

Patients on oral contraceptives were excluded from these trials; therefore, the efficacy of sertraline in combination with oral contraceptives for the treatment of PMDD is unknown.

Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and includes assessments for mood, physical symptoms, and other symptoms.

Other efficacy assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.

In Study 1, involving n=251 randomized patients, ZOLOFT treatment was initiated at 50 mg/day and administered daily throughout the menstrual cycle.

In subsequent cycles, patients were dosed in the range of 50–150 mg/day on the basis of clinical response and toleration.

The mean dose for completers was 102 mg/day.

ZOLOFT administered daily throughout the menstrual cycle was significantly more effective than placebo on change from baseline to endpoint on the DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at endpoint.

In Study 2, involving n=281 randomized patients, ZOLOFT treatment was initiated at 50 mg/day in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset of menses.

In subsequent cycles, patients were dosed in the range of 50–100 mg/day in the luteal phase of each cycle, on the basis of clinical response and toleration.

Patients who were titrated to 100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the remainder of the cycle.

The mean ZOLOFT dose for completers was 74 mg/day.

ZOLOFT administered in the late luteal phase of the menstrual cycle was significantly more effective than placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as well as the CGI-I score at endpoint.

There was insufficient information to determine the effect of race or age on outcome in these studies.

Social Anxiety Disorder The effectiveness of ZOLOFT in the treatment of social anxiety disorder (also known as social phobia) was established in two multicenter placebo-controlled studies (Study 1 and 2) of adult outpatients who met DSM-IV criteria for social anxiety disorder.

Study 1 was a 12-week, multicenter, flexible dose study comparing ZOLOFT (50–200 mg/day) to placebo, in which ZOLOFT was initiated at 25 mg/day for the first week.

Study outcome was assessed by (a) the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered instrument that measures fear, anxiety and avoidance of social and performance situations, and by (b) the proportion of responders as defined by the Clinical Global Impression of Improvement (CGI-I) criterion of CGI-I ≤ 2 (very much or much improved).

ZOLOFT was statistically significantly more effective than placebo as measured by the LSAS and the percentage of responders.

Study 2 was a 20-week, multicenter, flexible dose study that compared ZOLOFT (50–200 mg/day) to placebo.

Study outcome was assessed by the (a) Duke Brief Social Phobia Scale (BSPS), a multi-item clinician-rated instrument that measures fear, avoidance and physiologic response to social or performance situations, (b) the Marks Fear Questionnaire Social Phobia Subscale (FQ-SPS), a 5-item patient-rated instrument that measures change in the severity of phobic avoidance and distress, and (c) the CGI-I responder criterion of ≤ 2.

ZOLOFT was shown to be statistically significantly more effective than placebo as measured by the BSPS total score and fear, avoidance and physiologic factor scores, as well as the FQ-SPS total score, and to have significantly more responders than placebo as defined by the CGI-I.

Subgroup analyses did not suggest differences in treatment outcome on the basis of gender.

There was insufficient information to determine the effect of race or age on outcome.

In a longer-term study, patients meeting DSM-IV criteria for social anxiety disorder who had responded while assigned to ZOLOFT (CGI-I of 1 or 2) during a 20-week placebo-controlled trial on ZOLOFT 50–200 mg/day were randomized to continuation of ZOLOFT or to substitution of placebo for up to 24 weeks of observation for relapse.

Relapse was defined as ≥ 2 point increase in the Clinical Global Impression – Severity of Illness (CGI-S) score compared to baseline or study discontinuation due to lack of efficacy.

Patients receiving ZOLOFT continuation treatment experienced a statistically significantly lower relapse rate over this 24-week study than patients randomized to placebo substitution.

HOW SUPPLIED

ZOLOFT (sertraline hydrochloride) capsular-shaped scored tablets, containing sertraline hydrochloride equivalent to 25, 50 and 100 mg of sertraline, are packaged in bottles.

ZOLOFT 25 mg Tablets: light green film coated tablets engraved on one side with ZOLOFT and on the other side scored and engraved with 25 mg.

NDC 0049-4960-30 Bottles of 30 NDC 0049-4960-50 Bottles of 50 ZOLOFT 50 mg Tablets: light blue film coated tablets engraved on one side with ZOLOFT and on the other side scored and engraved with 50 mg.

NDC 0049-4900-30 Bottles of 30 NDC 0049-4900-66 Bottles of 100 NDC 0049-4900-73 Bottles of 500 NDC 0049-4900-94 Bottles of 5000 NDC 0049-4900-41 Unit Dose Packages of 100 ZOLOFT 100 mg Tablets: light yellow film coated tablets engraved on one side with ZOLOFT and on the other side scored and engraved with 100 mg.

NDC 0049-4910-30 Bottles of 30 NDC 0049-4910-66 Bottles of 100 NDC 0049-4910-73 Bottles of 500 NDC 0049-4910-94 Bottles of 5000 NDC 0049-4910-41 Unit Dose Packages of 100 Store at 25°C (77°F); excursions permitted to 15° – 30°C (59° – 86°F)[see USP Controlled Room Temperature].

ZOLOFT Oral Concentrate: ZOLOFT Oral Concentrate is a clear, colorless solution with a menthol scent containing sertraline hydrochloride equivalent to 20 mg of sertraline per mL and 12% alcohol.

It is supplied as a 60 mL bottle with an accompanying calibrated dropper.

NDC 0049-4940-23 Bottles of 60 mL Store at 25°C (77°F); excursions permitted to 15° – 30°C (59° – 86°F) [see USP Controlled Room Temperature].

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GERIATRIC USE

Geriatric Use U.S.

geriatric clinical studies of ZOLOFT in major depressive disorder included 663 ZOLOFT-treated subjects ≥ 65 years of age, of those, 180 were ≥ 75 years of age.

No overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial subjects relative to those reported in younger subjects (see ADVERSE REACTIONS ), and other reported experience has not identified differences in safety patterns between the elderly and younger subjects.

As with all medications, greater sensitivity of some older individuals cannot be ruled out.

There were 947 subjects in placebo-controlled geriatric clinical studies of ZOLOFT in major depressive disorder.

No overall differences in the pattern of efficacy were observed in the geriatric clinical trial subjects relative to those reported in younger subjects.

Other Adverse Events in Geriatric Patients.

In 354 geriatric subjects treated with ZOLOFT in placebo-controlled trials, the overall profile of adverse events was generally similar to that shown in Tables 2 and 3.

Urinary tract infection was the only adverse event not appearing in Tables 2 and 3 and reported at an incidence of at least 2% and at a rate greater than placebo in placebo-controlled trials.

SSRIS and SNRIs, including ZOLOFT, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia ).

INDICATIONS AND USAGE

Major Depressive Disorder ZOLOFT (sertraline hydrochloride) is indicated for the treatment of major depressive disorder in adults.

The efficacy of ZOLOFT in the treatment of a major depressive episode was established in six to eight week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder (see Clinical Trials under CLINICAL PHARMACOLOGY ).

A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.

The antidepressant action of ZOLOFT in hospitalized depressed patients has not been adequately studied.

The efficacy of ZOLOFT in maintaining an antidepressant response for up to 44 weeks following 8 weeks of open-label acute treatment (52 weeks total) was demonstrated in a placebo-controlled trial.

The usefulness of the drug in patients receiving ZOLOFT for extended periods should be reevaluated periodically (see Clinical Trials under CLINICAL PHARMACOLOGY ).

Obsessive-Compulsive Disorder ZOLOFT is indicated for the treatment of obsessions and compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning.

The efficacy of ZOLOFT was established in 12-week trials with obsessive-compulsive outpatients having diagnoses of obsessive-compulsive disorder as defined according to DSM-III or DSM-III-R criteria (see Clinical Trials under CLINICAL PHARMACOLOGY ).

Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable.

The efficacy of ZOLOFT in maintaining a response, in patients with OCD who responded during a 52-week treatment phase while taking ZOLOFT and were then observed for relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials under CLINICAL PHARMACOLOGY ).

Nevertheless, the physician who elects to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).

Panic Disorder ZOLOFT is indicated for the treatment of panic disorder in adults, with or without agoraphobia, as defined in DSM-IV.

Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks.

The efficacy of ZOLOFT was established in three 10–12 week trials in adult panic disorder patients whose diagnoses corresponded to the DSM-III-R category of panic disorder (see Clinical Trials under CLINICAL PHARMACOLOGY ).

Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.

The efficacy of ZOLOFT in maintaining a response, in adult patients with panic disorder who responded during a 52-week treatment phase while taking ZOLOFT and were then observed for relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials under CLINICAL PHARMACOLOGY ).

Nevertheless, the physician who elects to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).

Posttraumatic Stress Disorder (PTSD) ZOLOFT (sertraline hydrochloride) is indicated for the treatment of posttraumatic stress disorder in adults.

The efficacy of ZOLOFT in the treatment of PTSD was established in two 12-week placebo-controlled trials of adult outpatients whose diagnosis met criteria for the DSM-III-R category of PTSD (see Clinical Trials under CLINICAL PHARMACOLOGY ).

PTSD, as defined by DSM-III-R/IV, requires exposure to a traumatic event that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and a response which involves intense fear, helplessness, or horror.

Symptoms that occur as a result of exposure to the traumatic event include reexperiencing of the event in the form of intrusive thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of general responsiveness manifested as diminished interest in significant activities, estrangement from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger.

A PTSD diagnosis requires that the symptoms are present for at least a month and that they cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

The efficacy of ZOLOFT in maintaining a response in adult patients with PTSD for up to 28 weeks following 24 weeks of open-label treatment was demonstrated in a placebo-controlled trial.

Nevertheless, the physician who elects to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).

Premenstrual Dysphoric Disorder (PMDD) ZOLOFT is indicated for the treatment of premenstrual dysphoric disorder (PMDD) in adults.

The efficacy of ZOLOFT in the treatment of PMDD was established in 2 placebo-controlled trials of female adult outpatients treated for 3 menstrual cycles who met criteria for the DSM-III-R/IV category of PMDD (see Clinical Trials under CLINICAL PHARMACOLOGY ).

The essential features of PMDD include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability.

Other features include decreased interest in activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control.

Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating and weight gain.

These symptoms occur regularly during the luteal phase and remit within a few days following onset of menses; the disturbance markedly interferes with work or school or with usual social activities and relationships with others.

In making the diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated by treatment with an antidepressant.

The effectiveness of ZOLOFT in long-term use, that is, for more than 3 menstrual cycles, has not been systematically evaluated in controlled trials.

Therefore, the physician who elects to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).

Social Anxiety Disorder ZOLOFT (sertraline hydrochloride) is indicated for the treatment of social anxiety disorder, also known as social phobia in adults.

The efficacy of ZOLOFT in the treatment of social anxiety disorder was established in two placebo-controlled trials of adult outpatients with a diagnosis of social anxiety disorder as defined by DSM-IV criteria (see Clinical Trials under CLINICAL PHARMACOLOGY ).

Social anxiety disorder, as defined by DSM-IV, is characterized by marked and persistent fear of social or performance situations involving exposure to unfamiliar people or possible scrutiny by others and by fears of acting in a humiliating or embarrassing way.

Exposure to the feared social situation almost always provokes anxiety and feared social or performance situations are avoided or else are endured with intense anxiety or distress.

In addition, patients recognize that the fear is excessive or unreasonable and the avoidance and anticipatory anxiety of the feared situation is associated with functional impairment or marked distress.

The efficacy of ZOLOFT in maintaining a response in adult patients with social anxiety disorder for up to 24 weeks following 20 weeks of ZOLOFT treatment was demonstrated in a placebo-controlled trial.

Physicians who prescribe ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see Clinical Trials under CLINICAL PHARMACOLOGY ).

PEDIATRIC USE

Pediatric Use The efficacy of ZOLOFT for the treatment of obsessive-compulsive disorder was demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6–17 (see Clinical Trials under CLINICAL PHARMACOLOGY ).

Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established (see BOX WARNING and WARNINGS-Clinical Worsening and Suicide Risk) .

Two placebo controlled trials (n=373) in pediatric patients with MDD have been conducted with Zoloft, and the data were not sufficient to support a claim for use in pediatric patients.

Anyone considering the use of Zoloft in a child or adolescent must balance the potential risks with the clinical need.

The safety of ZOLOFT use in children and adolescents with OCD, ages 6–18, was evaluated in a 12-week, multicenter, placebo-controlled study with 187 outpatients, ages 6–17, and in a flexible dose, 52 week open extension study of 137 patients, ages 6–18, who had completed the initial 12-week, double-blind, placebo-controlled study.

ZOLOFT was administered at doses of either 25 mg/day (children, ages 6–12) or 50 mg/day (adolescents, ages 13–18) and then titrated in weekly 25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day based upon clinical response.

The mean dose for completers was 157 mg/day.

In the acute 12 week pediatric study and in the 52 week study, ZOLOFT had an adverse event profile generally similar to that observed in adults.

Sertraline pharmacokinetics were evaluated in 61 pediatric patients between 6 and 17 years of age with major depressive disorder or OCD and revealed similar drug exposures to those of adults when plasma concentration was adjusted for weight (see Pharmacokinetics under CLINICAL PHARMACOLOGY ).

Approximately 600 patients with major depressive disorder or OCD between 6 and 17 years of age have received ZOLOFT in clinical trials, both controlled and uncontrolled.

The adverse event profile observed in these patients was generally similar to that observed in adult studies with ZOLOFT (see ADVERSE REACTIONS ).

As with other SSRIs, decreased appetite and weight loss have been observed in association with the use of ZOLOFT.

In a pooled analysis of two 10-week, double-blind, placebo-controlled, flexible dose (50–200 mg) outpatient trials for major depressive disorder (n=373), there was a difference in weight change between sertraline and placebo of roughly 1 kilogram, for both children (ages 6–11) and adolescents (ages 12–17), in both cases representing a slight weight loss for sertraline compared to a slight gain for placebo.

At baseline the mean weight for children was 39.0 kg for sertraline and 38.5 kg for placebo.

At baseline the mean weight for adolescents was 61.4 kg for sertraline and 62.5 kg for placebo.

There was a bigger difference between sertraline and placebo in the proportion of outliers for clinically important weight loss in children than in adolescents.

For children, about 7% had a weight loss > 7% of body weight compared to none of the placebo patients; for adolescents, about 2% had a weight loss > 7% of body weight compared to about 1% of the placebo patients.

A subset of these patients who completed the randomized controlled trials (sertraline n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label, extension study.

A mean weight loss of approximately 0.5 kg was seen during the first eight weeks of treatment for subjects with first exposure to sertraline during the open-label extension study, similar to mean weight loss observed among sertraline treated subjects during the first eight weeks of the randomized controlled trials.

The subjects continuing in the open label study began gaining weight compared to baseline by week 12 of sertraline treatment.

Those subjects who completed 34 weeks of sertraline treatment (10 weeks in a placebo controlled trial + 24 weeks open label, n=68) had weight gain that was similar to that expected using data from age-adjusted peers.

Regular monitoring of weight and growth is recommended if treatment of a pediatric patient with an SSRI is to be continued long term.

Safety and effectiveness in pediatric patients below the age of 6 have not been established.

The risks, if any, that may be associated with ZOLOFT’s use beyond 1 year in children and adolescents with OCD or major depressive disorder have not been systematically assessed.

The prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for use in children and adolescents derives from clinical studies that were 10 to 52 weeks in duration and from the extrapolation of experience gained with adult patients.

In particular, there are no studies that directly evaluate the effects of long-term sertraline use on the growth, development, and maturation of children and adolescents.

Although there is no affirmative finding to suggest that sertraline possesses a capacity to adversely affect growth, development or maturation, the absence of such findings is not compelling evidence of the absence of the potential of sertraline to have adverse effects in chronic use (see WARNINGS – Clinical Worsening and Suicide Risk ).

PREGNANCY

Pregnancy–Pregnancy Category C Reproduction studies have been performed in rats and rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively.

These doses correspond to approximately 4 times the maximum recommended human dose (MRHD) on a mg/m 2 basis.

There was no evidence of teratogenicity at any dose level.

When pregnant rats and rabbits were given sertraline during the period of organogenesis, delayed ossification was observed in fetuses at doses of 10 mg/kg (0.5 times the MRHD on a mg/m 2 basis) in rats and 40 mg/kg (4 times the MRHD on a mg/m 2 basis) in rabbits.

When female rats received sertraline during the last third of gestation and throughout lactation, there was an increase in the number of stillborn pups and in the number of pups dying during the first 4 days after birth.

Pup body weights were also decreased during the first four days after birth.

These effects occurred at a dose of 20 mg/kg (1 times the MRHD on a mg/m 2 basis).

The no effect dose for rat pup mortality was 10 mg/kg (0.5 times the MRHD on a mg/m 2 basis).

The decrease in pup survival was shown to be due to in utero exposure to sertraline.

The clinical significance of these effects is unknown.

There are no adequate and well-controlled studies in pregnant women.

ZOLOFT (sertraline hydrochloride) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NUSRING MOTHERS

Nursing Mothers It is not known whether, and if so in what amount, sertraline or its metabolites are excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when ZOLOFT is administered to a nursing woman.

BOXED WARNING

Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders.

Anyone considering the use of Zoloft or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need.

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 in risk with antidepressants compared to placebo in adults aged 65 and older.

Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide.

Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior.

Families and caregivers should be advised of the need for close observation and communication with the prescriber.

Zoloft is not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD).

(See Warnings: Clinical Worsening and Suicide Risk , Precautions: Information for Patients , and Precautions: Pediatric Use )

INFORMATION FOR PATIENTS

Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Zoloft 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 ZOLOFT.

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 ZOLOFT.

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.

Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of SNRIs and SSRIs, including Zoloft, and triptans, tramadol, or other serotonergic agents.

Patients should be told that although ZOLOFT has not been shown to impair the ability of normal subjects to perform tasks requiring complex motor and mental skills in laboratory experiments, drugs that act upon the central nervous system may affect some individuals adversely.

Therefore, patients should be told that until they learn how they respond to ZOLOFT they should be careful doing activities when they need to be alert, such as driving a car or operating machinery.

Patients should be cautioned about the concomitant use of Zoloft and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.

Patients should be told that although ZOLOFT has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of ZOLOFT and alcohol is not advised.

Patients should be told that while no adverse interaction of ZOLOFT with over-the-counter (OTC) drug products is known to occur, the potential for interaction exists.

Thus, the use of any OTC product should be initiated cautiously according to the directions of use given for the OTC product.

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Patients should be advised to notify their physician if they are breast feeding an infant.

ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol content of the concentrate.

ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active ingredient and 12% alcohol.

ZOLOFT Oral Concentrate must be diluted before use.

Just before taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice ONLY.

Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed.

The dose should be taken immediately after mixing.

Do not mix in advance.

At times, a slight haze may appear after mixing; this is normal.

Note that caution should be exercised for persons with latex sensitivity, as the dropper dispenser contains dry natural rubber.

DOSAGE AND ADMINISTRATION

Initial Treatment Dosage for Adults Major Depressive Disorder and Obsessive-Compulsive Disorder ZOLOFT treatment should be administered at a dose of 50 mg once daily.

Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder ZOLOFT treatment should be initiated with a dose of 25 mg once daily.

After one week, the dose should be increased to 50 mg once daily.

While a relationship between dose and effect has not been established for major depressive disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range of 50–200 mg/day in the clinical trials demonstrating the effectiveness of ZOLOFT for the treatment of these indications.

Consequently, a dose of 50 mg, administered once daily, is recommended as the initial therapeutic dose.

Patients not responding to a 50 mg dose may benefit from dose increases up to a maximum of 200 mg/day.

Given the 24 hour elimination half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.

Premenstrual Dysphoric Disorder ZOLOFT treatment should be initiated with a dose of 50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the menstrual cycle, depending on physician assessment.

While a relationship between dose and effect has not been established for PMDD, patients were dosed in the range of 50–150 mg/day with dose increases at the onset of each new menstrual cycle (see Clinical Trials under CLINICAL PHARMACOLOGY ).

Patients not responding to a 50 mg/day dose may benefit from dose increases (at 50 mg increments/menstrual cycle) up to 150 mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing during the luteal phase of the menstrual cycle.

If a 100 mg/day dose has been established with luteal phase dosing, a 50 mg/day titration step for three days should be utilized at the beginning of each luteal phase dosing period.

ZOLOFT should be administered once daily, either in the morning or evening.

Dosage for Pediatric Population (Children and Adolescents) Obsessive-Compulsive Disorder ZOLOFT treatment should be initiated with a dose of 25 mg once daily in children (ages 6–12) and at a dose of 50 mg once daily in adolescents (ages 13–17).

While a relationship between dose and effect has not been established for OCD, patients were dosed in a range of 25–200 mg/day in the clinical trials demonstrating the effectiveness of ZOLOFT for pediatric patients (6–17 years) with OCD.

Patients not responding to an initial dose of 25 or 50 mg/day may benefit from dose increases up to a maximum of 200 mg/day.

For children with OCD, their generally lower body weights compared to adults should be taken into consideration in advancing the dose, in order to avoid excess dosing.

Given the 24 hour elimination half-life of ZOLOFT, dose changes should not occur at intervals of less than 1 week.

ZOLOFT should be administered once daily, either in the morning or evening.

Maintenance/Continuation/Extended Treatment Major Depressive Disorder It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy beyond response to the acute episode.

Systematic evaluation of ZOLOFT has demonstrated that its antidepressant efficacy is maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a dose of 50–200 mg/day (mean dose of 70 mg/day) (see Clinical Trials under CLINICAL PHARMACOLOGY ).

It is not known whether the dose of ZOLOFT needed for maintenance treatment is identical to the dose needed to achieve an initial response.

Patients should be periodically reassessed to determine the need for maintenance treatment.

Posttraumatic Stress Disorder It is generally agreed that PTSD requires several months or longer of sustained pharmacological therapy beyond response to initial treatment.

Systematic evaluation of ZOLOFT has demonstrated that its efficacy in PTSD is maintained for periods of up to 28 weeks following 24 weeks of treatment at a dose of 50–200 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY ).

It is not known whether the dose of ZOLOFT needed for maintenance treatment is identical to the dose needed to achieve an initial response.

Patients should be periodically reassessed to determine the need for maintenance treatment.

Social Anxiety Disorder Social anxiety disorder is a chronic condition that may require several months or longer of sustained pharmacological therapy beyond response to initial treatment.

Systematic evaluation of ZOLOFT has demonstrated that its efficacy in social anxiety disorder is maintained for periods of up to 24 weeks following 20 weeks of treatment at a dose of 50–200 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY ).

Dosage adjustments should be made to maintain patients on the lowest effective dose and patients should be periodically reassessed to determine the need for long-term treatment.

Obsessive-Compulsive Disorder and Panic Disorder It is generally agreed that OCD and Panic Disorder require several months or longer of sustained pharmacological therapy beyond response to initial treatment.

Systematic evaluation of continuing ZOLOFT for periods of up to 28 weeks in patients with OCD and Panic Disorder who have responded while taking ZOLOFT during initial treatment phases of 24 to 52 weeks of treatment at a dose range of 50–200 mg/day has demonstrated a benefit of such maintenance treatment (see Clinical Trials under CLINICAL PHARMACOLOGY ).

It is not known whether the dose of ZOLOFT needed for maintenance treatment is identical to the dose needed to achieve an initial response.

Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.

Premenstrual Dysphoric Disorder The effectiveness of ZOLOFT in long-term use, that is, for more than 3 menstrual cycles, has not been systematically evaluated in controlled trials.

However, as women commonly report that symptoms worsen with age until relieved by the onset of menopause, it is reasonable to consider continuation of a responding patient.

Dosage adjustments, which may include changes between dosage regimens (e.g., daily throughout the menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to maintain the patient on the lowest effective dosage and patients should be periodically reassessed to determine the need for continued treatment.

Switching Patients to or from a Monoamine Oxidase Inhibitor At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with ZOLOFT.

In addition, at least 14 days should be allowed after stopping ZOLOFT before starting an MAOI (see CONTRAINDICATIONS and WARNINGS ).

Special Populations Dosage for Hepatically Impaired Patients The use of sertraline in patients with liver disease should be approached with caution.

The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied.

If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used (see CLINICAL PHARMACOLOGY and PRECAUTIONS ).

Treatment of Pregnant Women During the Third Trimester Neonates exposed to ZOLOFT and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS ).

When treating pregnant women with ZOLOFT during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

The physician may consider tapering ZOLOFT in the third trimester.

Discontinuation of Treatment with Zoloft Symptoms associated with discontinuation of ZOLOFT and other SSRIs and SNRIs, have been reported (see PRECAUTIONS ).

Patients should be monitored for these symptoms when discontinuing treatment.

A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.

If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.

Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

ZOLOFT Oral Concentrate ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active ingredient and 12% alcohol.

ZOLOFT Oral Concentrate must be diluted before use.

Just before taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice ONLY.

Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed.

The dose should be taken immediately after mixing.

Do not mix in advance.

At times, a slight haze may appear after mixing; this is normal.

Note that caution should be exercised for patients with latex sensitivity, as the dropper dispenser contains dry natural rubber.

ZOLOFT Oral Concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol content of the concentrate.

Nimodipine 30 MG Oral Capsule

WARNINGS

DEATH DUE TO INADVERTENT INTRAVENOUS ADMINISTRATION: DO NOT ADMINISTER NIMODIPINE INTRAVENOUSLY OR BY OTHER PARENTERAL ROUTES.

DEATHS AND SERIOUS, LIFE THREATENING ADVERSE EVENTS, INCLUDING CARDIAC ARREST, CARDIOVASCULAR COLLAPSE, HYPOTENSION, AND BRADYCARDIA, HAVE OCCURRED WHEN THE CONTENTS OF NIMODIPINE CAPSULES HAVE BEEN INJECTED PARENTERALLY (SEE DOSAGE AND ADMINISTRATION ).

Reduced Efficacy with CYP3A4 Inducers: Concomitant use of strong CYP3A4 inducers (e.g.

rifampin, phenobarbital, phenytoin, carbamazepine, St John’s wort) and nimodipine should generally be avoided, as nimodipine plasma concentration and efficacy may be very significantly reduced (see PRECAUTIONS, Drug Interactions ).

Moderate and weak inducers of CYP3A4 may also reduce the efficacy of nimodipine to a lesser extent.

Patients on these should be closely monitored for lack of effectiveness, and a nimodipine dosage increase may be required.

Moderate and weak CYP3A4 inhibitors include, for example: amprenavir, aprepitant, armodafinil, bosentan, efavirenz, etravirine, echinacea, modafinil, nafcillin, pioglitazone, prednisone and rufinamide.

OVERDOSAGE

There have been no reports of overdosage from the oral administration of nimodipine.

Symptoms of overdosage would be expected to be related to cardiovascular effects such as excessive peripheral vasodilation with marked systemic hypotension.

Clinically significant hypotension due to nimodipine overdosage may require active cardiovascular support with pressor agents.

Specific treatments for calcium channel blocker overdose should also be given promptly.

Since nimodipine is highly protein-bound, dialysis is not likely to be of benefit.

DESCRIPTION

Nimodipine belongs to the class of pharmacological agents known as calcium channel blockers.

Nimodipine is isopropyl 2 -methoxyethyl 1,4 –dihydro -2,6 –dimethyl -4-(m-nitrophenyl) -3,5-pyridinedicarboxylate.

It has a molecular weight of 418.5 and a molecular formula of C 21 H 26 N 2 O 7 .

The structural formula is: Nimodipine is a yellow crystalline substance, practically insoluble in water.

Nimodipine capsules are formulated as soft gelatin capsules for oral administration.

Each liquid filled capsule contains 30 mg of nimodipine.

In addition the capsules contain the following inactive ingredients: gelatin, glycerin, hypromellose, iron oxide black, kosher glycerin, mannitol, peppermint oil, polyethylene glycol, propylene glycol, sorbitol, sorbitol anhydrides and titanium dioxide.

6fb8ce9c-figure-01

HOW SUPPLIED

Nimodipine Capsules 30 mg – Oblong, white opaque, soft gelatin capsules in Overbagged with 10 capsules per bag NDC 55154-4184-0 • Printed H108 in black ink.

The capsules should be stored in the manufacturer’s original package.

Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].

Capsules should be protected from light and freezing.

Manufactured for: Heritage Pharmaceuticals Inc.

Eatontown, NJ 07724 Manufactured by: Banner Pharmacaps, Inc.

High Point, NC 27265 Distributed by: Cardinal Health Dublin, OH 43017 L51227260318 Iss.

02/2014

MECHANISM OF ACTION

Mechanism of Action Nimodipine is a calcium channel blocker.

The contractile processes of smooth muscle cells are dependent upon calcium ions, which enter these cells during depolarization as slow ionic transmembrane currents.

Nimodipine inhibits calcium ion transfer into these cells and thus inhibits contractions of vascular smooth muscle.

In animal experiments, nimodipine had a greater effect on cerebral arteries than on arteries elsewhere in the body perhaps because it is highly lipophilic, allowing it to cross the blood-brain barrier; concentrations of nimodipine as high as 12.5 ng/mL have been detected in the cerebrospinal fluid of nimodipine-treated subarachnoid hemorrhage (SAH) patients.

The precise mechanism of action of nimodipine in humans is unknown.

Although the clinical studies described below demonstrate a favorable effect of nimodipine on the severity of neurological deficits caused by cerebral vasospasm following SAH, there is no arteriographic evidence that the drug either prevents or relieves the spasm of these arteries.

However, whether or not the arteriographic methodology utilized was adequate to detect a clinically meaningful effect, if any, on vasospasm is unknown.

INDICATIONS AND USAGE

Nimodipine is indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition (i.e., Hunt and Hess Grades I-V).

BOXED WARNING

DO NOT ADMINISTER NIMODIPINE INTRAVENOUSLY OR BY OTHER PARENTERAL ROUTES.

DEATHS AND SERIOUS, LIFE THREATENING ADVERSE EVENTS HAVE OCCURRED WHEN THE CONTENTS OF NIMODIPINE CAPSULES HAVE BEEN INJECTED PARENTERALLY (See WARNINGS and DOSAGE AND ADMINISTRATION ).

DOSAGE AND ADMINISTRATION

DO NOT ADMINISTER NIMODIPINE CAPSULES INTRAVENOUSLY OR BY OTHER PARENTERAL ROUTES (see WARNINGS ).

If Nimodipine is inadvertently administered intravenously, clinically significant hypotension may require cardiovascular support with pressor agents.

Specific treatments for calcium channel blocker overdose should also be given promptly.

Nimodipine is given orally in the form of soft gelatin 30 mg capsules for subarachnoid hemorrhage.

The recommended oral dose is 60 mg (two 30 mg capsules) every 4 hours for 21 consecutive days.

In general, the capsules should be swallowed whole with a little liquid, preferably not less than one hour before or two hours after meals.

Grapefruit juice is to be avoided (See PRECAUTIONS, Drug Interactions ).

Oral nimodipine therapy should commence as soon as possible within 96 hours of the onset of subarachnoid hemorrhage.

If the capsule cannot be swallowed, e.g., at the time of surgery, or if the patient is unconscious, a hole should be made in both ends of the capsule with an 18 gauge needle, and the contents of the capsule extracted into a syringe.

A parenteral syringe can be used to extract the liquid inside the capsule, but the liquid should always be transferred to a syringe that cannot accept a needle and that is designed for administration orally or via a naso-gastric tube or PEG.

To help minimize administration errors, it is recommended that the syringe used for administration be labeled “Not for IV Use”.

The contents should then be emptied into the patient’s in situ naso-gastric tube and washed down the tube with 30 mL of normal saline (0.9%).

Severely disturbed liver function, particularly liver cirrhosis, may result in an increased bioavailability of nimodipine due to a decreased first pass capacity and a reduced metabolic clearance.

The reduction in blood pressure and other adverse effects may be more pronounced in these patients.

Dosage should be reduced to one 30 mg capsule every 4 hours with close monitoring of blood pressure and heart rate; if necessary, discontinuation of the treatment should be considered.

Strong inhibitors of CYP3A4 should not be administered concomitantly with nimodipine (See CONTRAINDICATIONS ).

Strong inducers of CYP3A4 should generally not be administered with nimodipine (See WARNINGS ).

Patients on moderate and weak inducers of CYP3A4 should be closely monitored for lack of effectiveness, and a nimodipine dose increase may be required.

Patients on moderate and weak CYP3A4 inhibitors may require a nimodipine dose reduction in case of hypotension (See PRECAUTIONS, Drug Interactions )

fluticasone propionate 250 MCG/INHAL Dry Powder Inhaler, 60 Blisters

Generic Name: FLUTICASONE PROPIONATE
Brand Name: FLOVENT DISKUS
  • Substance Name(s):
  • FLUTICASONE PROPIONATE

DRUG INTERACTIONS

7 Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): Use not recommended.

May increase risk of systemic corticosteroid effects.

( 7.1 ) 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone propionate is a substrate of CYP3A4.

The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with FLOVENT DISKUS is not recommended because increased systemic corticosteroid adverse effects may occur.

Ritonavir A drug interaction trial with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations [see Clinical Pharmacology (12.3)] .

During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.

Ketoconazole Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol.

OVERDOSAGE

10 Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.5)] .

Inhalation by healthy volunteers of a single dose of 4,000 mcg of fluticasone propionate inhalation powder or single doses of 1,760 or 3,520 mcg of fluticasone propionate CFC inhalation aerosol was well tolerated.

Fluticasone propionate given by inhalation aerosol at dosages of 1,320 mcg twice daily for 7 to 15 days to healthy human volunteers was also well tolerated.

Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in subjects were well tolerated.

Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups.

DESCRIPTION

11 FLOVENT DISKUS inhalation powder is a dry powder inhaler for oral inhalation.

The active component of FLOVENT DISKUS 50 mcg, FLOVENT DISKUS 100 mcg, and FLOVENT DISKUS 250 mcg is fluticasone propionate, a corticosteroid having the chemical name S- (fluoromethyl) 6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate and the following chemical structure: Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C 25 H 31 F 3 O 5 S.

It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.

FLOVENT DISKUS is an orange plastic inhaler containing a foil blister strip.

Each blister on the strip contains a white powder mix of micronized fluticasone propionate (50, 100, or 250 mcg) in 12.5 mg of formulation containing lactose monohydrate (which contains milk proteins).

After the inhaler is activated, the powder is dispersed into the airstream created by the patient inhaling through the mouthpiece.

Under standardized in vitro test conditions, FLOVENT DISKUS delivers 46, 94, and 229 mcg of fluticasone propionate from FLOVENT DISKUS 50 mcg, FLOVENT DISKUS 100 mcg, and FLOVENT DISKUS 250 mcg, respectively, when tested at a flow rate of 60 L/min for 2 seconds.

In adult subjects with obstructive lung disease and severely compromised lung function (mean FEV 1 20% to 30% of predicted), mean peak inspiratory flow (PIF) through the DISKUS inhaler was 82.4 L/min (range: 46.1 to 115.3 L/min).

In children with asthma aged 4 and 8 years, mean PIF through FLOVENT DISKUS was 70 and 104 L/min, respectively (range: 48 to 123 L/min).

The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile.

Chemical structure

CLINICAL STUDIES

14 14.1 Adult and Adolescent Subjects Aged 12 Years and Older Four randomized, double-blind, parallel-group, placebo-controlled, U.S.

clinical trials were conducted in 1,036 adult and adolescent subjects (aged 12 years and older) with asthma to assess the efficacy and safety of FLOVENT DISKUS in the treatment of asthma.

Fixed dosages of 100, 250, and 500 mcg twice daily were compared with placebo to provide information about appropriate dosing to cover a range of asthma severity.

Subjects in these trials included those inadequately controlled with bronchodilators alone and those already maintained on daily ICS.

All doses were delivered by inhalation of the contents of 1 or 2 blisters from FLOVENT DISKUS twice daily.

Figures 1 through 4 display results of pulmonary function tests (mean percent change from baseline in FEV 1 prior to AM dose) for 3 recommended dosages of FLOVENT DISKUS (100, 250, and 500 mcg twice daily) and placebo from the four 12-week trials in adolescents and adults.

These trials used predetermined criteria for lack of efficacy (indicators of worsening asthma), resulting in withdrawal of more patients in the placebo group.

Therefore, pulmonary function results at Endpoint (the last evaluable FEV 1 result, including most patients’ lung function data) are also displayed.

Pulmonary function, as determined by percent change from baseline in FEV 1 at recommended dosages of FLOVENT DISKUS improved significantly compared with placebo by the first week of treatment, and improvement was maintained for up to 1 year or more.

Figure 1.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Bronchodilators Alone Figure 2.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids Figure 3.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 250 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone Figure 4.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 500 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone In all 4 efficacy trials, measures of pulmonary function (FEV 1 ) were statistically significantly improved as compared with placebo at all twice-daily doses.

Subjects on all dosages of FLOVENT DISKUS were also less likely to discontinue study participation due to asthma deterioration (as defined by predetermined criteria for lack of efficacy including lung function and subject-recorded variables such as AM PEF, albuterol use, and nighttime awakenings due to asthma) compared with placebo.

In a clinical trial of 111 subjects with severe asthma requiring chronic oral prednisone therapy (average baseline daily prednisone dose was 14 mg), fluticasone propionate given by inhalation powder at doses of 500 and 1,000 mcg twice daily was evaluated.

Both doses enabled a statistically significantly larger percentage of subjects to wean from oral prednisone as compared with placebo (75% of the subjects on 500 mcg twice daily and 89% of the subjects on 1,000 mcg twice daily as compared with 9% of subjects on placebo).

Accompanying the reduction in oral corticosteroid use, subjects treated with fluticasone propionate had significantly improved lung function and fewer asthma symptoms as compared with the placebo group.

Figure 1.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Bronchodilators Alone Figure 2.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids Figure 3.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 250 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone Figure 4.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 500 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone 14.2 Pediatric Subjects Aged 4 to 11 Years A 12-week, placebo-controlled clinical trial was conducted in 437 pediatric subjects (177 received FLOVENT DISKUS), approximately half of whom were receiving ICS at baseline.

In this trial, doses of fluticasone propionate inhalation powder 50 and 100 mcg twice daily significantly improved FEV 1 (15% and 18% change from baseline at Endpoint, respectively) compared with placebo (7% change).

AM PEF was also significantly improved with doses of fluticasone propionate 50 and 100 mcg twice daily (26% and 27% change from baseline at Endpoint, respectively) compared with placebo (14% change).

In this trial, subjects on active treatment were significantly less likely to discontinue treatment due to asthma deterioration (as defined by predetermined criteria for lack of efficacy including lung function and subject-recorded variables such as AM PEF, albuterol use, and nighttime awakenings due to asthma).

Two other 12-week placebo-controlled clinical trials were conducted in 504 pediatric subjects with asthma, approximately half of whom were receiving ICS at baseline.

In these trials, FLOVENT DISKUS was efficacious at doses of 50 and 100 mcg twice daily when compared with placebo on major endpoints including lung function and symptom scores.

Pulmonary function improved significantly compared with placebo by the first week of treatment, and subjects treated with FLOVENT DISKUS were also less likely to discontinue trial participation due to asthma deterioration.

One hundred ninety-two (192) subjects received FLOVENT DISKUS for up to 1 year during an open-label extension.

Data from this open-label extension suggested that lung function improvements could be maintained up to 1 year.

HOW SUPPLIED

16 /STORAGE AND HANDLING FLOVENT DISKUS 50 mcg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters.

The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 0173-0600-02).

FLOVENT DISKUS 100 mcg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters.

The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 0173-0602-02).

FLOVENT DISKUS 250 mcg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters.

The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 0173-0601-02).

Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C) [See USP Controlled Room Temperature].

Store in a dry place away from direct heat or sunlight.

Keep out of reach of children.

FLOVENT DISKUS should be stored inside the unopened moisture-protective foil pouch and only removed from the pouch immediately before initial use.

Discard FLOVENT DISKUS 6 weeks (50-mcg strength) or 2 months (100- and 250-mcg strengths) after opening the foil pouch or when the counter reads “0” (after all blisters have been used), whichever comes first.

The inhaler is not reusable.

Do not attempt to take the inhaler apart.

GERIATRIC USE

8.5 Geriatric Use Safety data have been collected on 280 subjects (FLOVENT DISKUS n = 83, FLOVENT ROTADISK n = 197) aged 65 years and older and 33 subjects (FLOVENT DISKUS n = 14, FLOVENT ROTADISK n = 19) aged 75 years and older who have been treated with fluticasone propionate inhalation powder in U.S.

and non-U.S.

clinical trials.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

DOSAGE FORMS AND STRENGTHS

3 Inhalation powder: Inhaler containing a foil blister strip of powder formulation for oral inhalation.

The strip contains fluticasone propionate 50, 100, or 250 mcg per blister.

Inhalation powder: Inhaler containing fluticasone propionate (50, 100, or 250 mcg) as a powder formulation for oral inhalation.

( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity.

Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide.

Data from the McKenzie vasoconstrictor assay in man are consistent with these results.

The clinical significance of these findings is unknown.

Inflammation is an important component in the pathogenesis of asthma.

Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation.

These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.

Though effective for the treatment of asthma, corticosteroids do not affect asthma symptoms immediately.

Individual patients will experience a variable time to onset and degree of symptom relief.

Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment.

When corticosteroids are discontinued, asthma stability may persist for several days or longer.

Trials in subjects with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of orally inhaled fluticasone propionate.

This is explained by a combination of a relatively high local anti-inflammatory effect, negligible oral systemic bioavailability (<1%), and the minimal pharmacological activity of the only metabolite detected in man.

INDICATIONS AND USAGE

1 FLOVENT DISKUS is indicated for the maintenance treatment of asthma as prophylactic therapy in patients aged 4 years and older.

Important Limitation of Use FLOVENT DISKUS is NOT indicated for the relief of acute bronchospasm.

FLOVENT DISKUS is an inhaled corticosteroid (ICS) indicated for: • Maintenance treatment of asthma as prophylactic therapy in patients aged 4 years and older.

( 1 ) Important limitation: • Not indicated for relief of acute bronchospasm.

( 1 )

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of FLOVENT DISKUS in children aged 4 years and older have been established [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)] .

The safety and effectiveness of FLOVENT DISKUS in children younger than 4 years have not been established.

Effects on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients.

A reduction of growth velocity in children or teenagers may occur as a result of poorly controlled asthma or from use of corticosteroids, including ICS.

The effects of long-term treatment of children and adolescents with ICS, including fluticasone propionate, on final adult height are not known.

Controlled clinical trials have shown that ICS may cause a reduction in growth in pediatric patients.

In these trials, the mean reduction in growth velocity was approximately 1 cm/year (range: 0.3 to 1.8 cm/year) and appeared to depend upon dose and duration of exposure.

This effect was observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function.

The long‑term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown.

The potential for “catch-up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied.

The effects on growth velocity of treatment with orally inhaled corticosteroids for over 1 year, including the impact on final adult height, are unknown.

The growth of children and adolescents receiving orally inhaled corticosteroids, including FLOVENT DISKUS, should be monitored routinely (e.g., via stadiometry).

The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies.

To minimize the systemic effects of orally inhaled corticosteroids, including FLOVENT DISKUS, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.

A 52-week placebo-controlled trial to assess the potential growth effects of fluticasone propionate inhalation powder (FLOVENT ROTADISK) at 50 and 100 mcg twice daily was conducted in the U.S.

in 325 prepubescent children (244 males and 81 females) aged 4 to 11 years.

The mean growth velocities at 52 weeks observed in the intent-to-treat population were 6.32 cm/year in the placebo group (n = 76), 6.07 cm/year in the 50-mcg group (n = 98), and 5.66 cm/year in the 100‑mcg group (n = 89).

An imbalance in the proportion of children entering puberty between groups and a higher dropout rate in the placebo group due to poorly controlled asthma may be confounding factors in interpreting these data.

A separate subset analysis of children who remained prepubertal during the trial revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n = 57), 5.91 cm/year in the 50-mcg group (n = 74), and 5.67 cm/year in the 100‑mcg group (n = 79).

In children aged 8.5 years, the mean age of children in this trial, the range for expected growth velocity is: boys – 3 rd percentile = 3.8 cm/year, 50 th percentile = 5.4 cm/year, and 97 th percentile = 7.0 cm/year; girls – 3 rd percentile = 4.2 cm/year, 50 th percentile = 5.7 cm/year, and 97 th percentile = 7.3 cm/year.

The clinical relevance of these growth data is not certain.

PREGNANCY

8.1 Pregnancy Risk Summary There are insufficient data on the use of FLOVENT DISKUS in pregnant women.

There are clinical considerations with the use of FLOVENT DISKUS in pregnant women.

(See Clinical Considerations.) In animals, teratogenicity characteristic of corticosteroids, decreased fetal body weight, and/or skeletal variations in rats, mice, and rabbits were observed with subcutaneously administered maternal toxic doses of fluticasone propionate less than the maximum recommended human daily inhaled dose (MRHDID) on a mcg/m 2 basis.

(See Data.) However, fluticasone propionate administered via inhalation to rats decreased fetal body weight, but did not induce teratogenicity at a maternal toxic dose less than the MRHDID on a mcg/m 2 basis.

(See Data.) Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.

The estimated risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S.

general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate.

Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.

Data Human Data: Following inhaled administration, fluticasone propionate was detected in the neonatal cord blood after delivery.

Animal Data: In embryofetal development studies with pregnant rats and mice dosed by the subcutaneous route throughout the period of organogenesis, fluticasone propionate was teratogenic in both species.

Omphalocele, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, at a dose approximately 0.5 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 100 mcg/kg/day).

The rat no observed adverse effect level (NOAEL) was observed at approximately 0.15 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 30 mcg/kg/day).

Cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately 0.1 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 45 mcg/kg/day).

The mouse NOAEL was observed with a dose approximately 0.04 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 15 mcg/kg/day).

In an embryofetal development study with pregnant rats dosed by the inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately 0.13 times the MRHDID (on a mcg/m 2 basis with a maternal inhalation dose of 25.7 mcg/kg/day); however, there was no evidence of teratogenicity.

The NOAEL was observed with a dose approximately 0.03 times the MRHDID (on a mcg/m 2 basis with a maternal inhalation dose of 5.5 mcg/kg/day).

In an embryofetal development study in pregnant rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate produced reductions of fetal body weights, in the presence of maternal toxicity, at doses approximately 0.006 times the MRHDID and higher (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.57 mcg/kg/day).

Teratogenicity was evident based upon a finding of cleft palate for 1 fetus at a dose approximately 0.04 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 4 mcg/kg/day).

The NOAEL was observed in rabbit fetuses with a dose approximately 0.001 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.08 mcg/kg/day).

Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits.

In a pre- and post-natal development study in pregnant rats dosed from late gestation through delivery and lactation (Gestation Day 17 to Postpartum Day 22), fluticasone propionate was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to 0.2 times the MRHDID (on a mcg/m 2 basis with maternal subcutaneous doses up to 50 mcg/kg/day).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Candida albicans infection of the mouth and pharynx may occur.

Monitor patients periodically.

Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk.

( 5.1 ) • Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infection; ocular herpes simplex).

Use with caution in patients with these infections.

More serious or even fatal course of chickenpox or measles can occur in susceptible patients.

( 5.3 ) • Risk of impaired adrenal function when transferring from systemic corticosteroids.

Taper patients slowly from systemic corticosteroids if transferring to FLOVENT DISKUS.

( 5.4 ) • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals.

If such changes occur, discontinue FLOVENT DISKUS slowly.

( 5.5 ) • Assess for decrease in bone mineral density initially and periodically thereafter.

( 5.7 ) • Monitor growth of pediatric patients.

( 5.8 ) • Glaucoma and cataracts may occur with long-term use of ICS.

Consider referral to an ophthalmologist in patients who develop ocular symptoms or use FLOVENT DISKUS long term.

( 5.9 ) 5.1 Local Effects of Inhaled Corticosteroids In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with FLOVENT DISKUS.

When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with FLOVENT DISKUS continues, but at times therapy with FLOVENT DISKUS may need to be interrupted.

Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

5.2 Acute Asthma Episodes FLOVENT DISKUS is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm.

Patients should be instructed to contact their physicians immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with FLOVENT DISKUS.

During such episodes, patients may require therapy with oral corticosteroids.

5.3 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals.

Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids.

In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure.

How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known.

The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known.

If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated.

If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated.

(See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

ICS should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

5.4 Transferring Patients from Systemic Corticosteroid Therapy Particular care is needed for patients who have been transferred from systemically active corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available ICS.

After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.

During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss.

Although FLOVENT DISKUS may control asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction.

These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to FLOVENT DISKUS.

Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with FLOVENT DISKUS.

Lung function (mean forced expiratory volume in 1 second [FEV 1 ] or morning peak expiratory flow [AM PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids.

In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

Transfer of patients from systemic corticosteroid therapy to FLOVENT DISKUS may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).

During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.

5.5 Hypercorticism and Adrenal Suppression Fluticasone propionate will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone.

Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of FLOVENT DISKUS in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose.

A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate inhalation aerosol.

Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing FLOVENT DISKUS.

Because of the possibility of significant systemic absorption of ICS in sensitive patients, patients treated with FLOVENT DISKUS should be observed carefully for any evidence of systemic corticosteroid effects.

Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects.

If such effects occur, FLOVENT DISKUS should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of asthma symptoms should be considered.

5.6 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of FLOVENT DISKUS.

There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not use FLOVENT DISKUS [see Contraindications (4)] .

5.7 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS.

The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown.

Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids), should be monitored and treated with established standards of care.

A 2-year trial in 160 subjects (females aged 18 to 40 years, males 18 to 50) with asthma receiving chlorofluorocarbon (CFC)-propelled fluticasone propionate inhalation aerosol 88 or 440 mcg twice daily demonstrated no statistically significant changes in BMD at any time point (24, 52, 76, and 104 weeks of double-blind treatment) as assessed by dual-energy x-ray absorptiometry at lumbar regions L1 through L4.

5.8 Effect on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients .

Monitor the growth of pediatric patients receiving FLOVENT DISKUS routinely (e.g., via stadiometry).

To minimize the systemic effects of orally inhaled corticosteroids, including FLOVENT DISKUS, titrate each patient’s dosage to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration (2.2), Use in Specific Populations (8.4)] .

5.9 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long-term administration of ICS, including fluticasone propionate.

Consider referral to an ophthalmologist in patients who develop ocular symptoms or use FLOVENT DISKUS long term.

5.10 Paradoxical Bronchospasm As with other inhaled medicines, bronchospasm may occur with an immediate increase in wheezing after dosing.

If bronchospasm occurs following dosing with FLOVENT DISKUS, it should be treated immediately with an inhaled, short-acting bronchodilator; FLOVENT DISKUS should be discontinued immediately; and alternative therapy should be instituted.

5.11 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with FLOVENT DISKUS is not recommended because increased systemic corticosteroid adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)] .

5.12 Eosinophilic Conditions and Churg-Strauss Syndrome In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions.

Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy.

These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate.

Cases of serious eosinophilic conditions have also been reported with other ICS in this clinical setting.

Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients.

A causal relationship between fluticasone propionate and these underlying conditions has not been established.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Local Effects Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients.

If oropharyngeal candidiasis develops, treat it with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with FLOVENT DISKUS, but at times therapy with FLOVENT DISKUS may need to be temporarily interrupted under close medical supervision.

Advise patients to rinse the mouth with water without swallowing after inhalation to help reduce the risk of thrush.

Status Asthmaticus and Acute Asthma Symptoms Inform patients that FLOVENT DISKUS is not a bronchodilator and is not intended for use as rescue medicine for acute asthma exacerbations.

Advise patients to treat acute asthma symptoms with an inhaled, short-acting beta 2 -agonist such as albuterol.

Instruct patients to contact their physicians immediately if there is deterioration of their asthma.

Immunosuppression Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay.

Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Hypercorticism and Adrenal Suppression Advise patients that FLOVENT DISKUS may cause systemic corticosteroid effects of hypercorticism and adrenal suppression.

Additionally, inform patients that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids.

Patients should taper slowly from systemic corticosteroids if transferring to FLOVENT DISKUS.

Immediate Hypersensitivity Reactions Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of FLOVENT DISKUS.

Patients should discontinue FLOVENT DISKUS if such reactions occur.

There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not take FLOVENT DISKUS.

Reduction in Bone Mineral Density Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk.

Reduced Growth Velocity Inform patients that orally inhaled corticosteroids, including FLOVENT DISKUS, may cause a reduction in growth velocity when administered to pediatric patients.

Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route.

Glaucoma and Cataracts Advise patients that long-term use of ICS may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations.

Use Daily for Best Effect Patients should use FLOVENT DISKUS at regular intervals as directed.

Individual patients will experience a variable time to onset and degree of symptom relief and the full benefit may not be achieved until treatment has been administered for 1 to 2 weeks or longer.

Patients should not increase the prescribed dosage but should contact their physicians if symptoms do not improve or if the condition worsens.

Instruct patients not to stop use of FLOVENT DISKUS abruptly.

Patients should contact their physicians immediately if they discontinue use of FLOVENT DISKUS.

Trademarks are owned by or licensed to the GSK group of companies.

GlaxoSmithKline Durham, NC 27701 ©2023 GSK group of companies or its licensor.

FLD:16PI

DOSAGE AND ADMINISTRATION

2 • For oral inhalation only.

( 2.1 ) • Starting dosage is based on prior asthma therapy and disease severity.

( 2.2 ) • Treatment of asthma in patients aged 12 years and older: 100 mcg twice daily up to a maximum recommended dosage of 1,000 mcg twice daily.

( 2.2 ) • Treatment of asthma in patients aged 4 to 11 years: 50 mcg twice daily up to a maximum recommended dosage of 100 mcg twice daily.

( 2.2 ) 2.1 Administration Information FLOVENT DISKUS should be administered by the orally inhaled route in patients aged 4 years and older.

After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis.

2.2 Recommended Dosage Adult and Adolescent Patients Aged 12 Years and Older The starting dosage is based on previous asthma therapy and asthma severity, including consideration of patients’ current control of asthma symptoms and risk of future exacerbation.

The recommended starting dosage for patients aged 12 years and older who are not on an inhaled corticosteroid (ICS) is 100 mcg twice daily, approximately 12 hours apart.

For other patients, and for patients who do not respond adequately to the starting dosage after 2 weeks of therapy, higher dosages may provide additional asthma control.

The maximum recommended dosage for patients aged 12 years and older is 1,000 mcg twice daily.

Pediatric Patients Aged 4 to 11 Years The starting dosage is based on previous asthma therapy and asthma severity, including consideration of patients’ current control of asthma symptoms and risk of future exacerbation.

For patients aged 4 to 11 years not on an ICS, the recommended starting dosage is 50 mcg twice daily, approximately 12 hours apart.

For other patients, and for patients who do not respond adequately to the starting dosage after 2 weeks of therapy, increasing the dosage to 100 mcg twice daily may provide additional asthma control.

The maximum recommended dosage for patients aged 4 to 11 years is 100 mcg twice daily.

General Dosing Recommendations If symptoms arise between doses, an inhaled short-acting beta 2 -agonist should be used for immediate relief.

Individual patients will experience a variable time to onset and degree of symptom relief.

Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment.

If a dosage regimen fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options, e.g., replacing the current strength with a higher strength, initiating an ICS and long-acting beta2-agonist (LABA) combination product, or initiating oral corticosteroids, should be considered.

After asthma stability has been achieved, titrate to the lowest effective dosage to reduce the possibility of side effects.

rizatriptan 10 MG (as rizatriptan benzoate 14.53 MG) Oral Tablet

Generic Name: RIZATRIPTAN BENZOATE
Brand Name: Rizatriptan Benzoate
  • Substance Name(s):
  • RIZATRIPTAN BENZOATE

DRUG INTERACTIONS

7 7.1 Propranolol The dose of rizatriptan benzoate tablets should be adjusted in propranolol-treated patients, as propranolol has been shown to increase the plasma AUC of rizatriptan by 70% [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] .

7.2 Ergot-Containing Drugs Ergot-containing drugs have been reported to cause prolonged vasospastic reactions.

Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and rizatriptan benzoate tablets within 24 hours is contraindicated [see Contraindications (4) ] .

7.3 Other 5-HT 1 Agonists Because their vasospastic effects may be additive, co-administration of rizatriptan benzoate tablets and other 5-HT 1 agonists within 24 hours of each other is contraindicated [see Contraindications (4) ] .

7.4 SSRIs/SNRIs and Serotonin Syndrome Cases of serotonin syndrome have been reported during co-administration of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.7) ] .

7.5 Monoamine Oxidase Inhibitors Rizatriptan benzoate tablets is contraindicated in patients taking MAO-A inhibitors and non-selective MAO inhibitors.

A specific MAO-A inhibitor increased the systemic exposure of rizatriptan and its metabolite [see Contraindications (4) and Clinical Pharmacology (12.3) ] .

OVERDOSAGE

10 No overdoses of rizatriptan benzoate tablets were reported during clinical trials in adults.

Some adult patients who received 40 mg of rizatriptan benzoate tablets either a single dose or as two doses with a 2-hour interdose interval had dizziness and somnolence.

In a clinical pharmacology study in which 12 adult subjects received rizatriptan benzoate tablets, at total cumulative doses of 80 mg (given within four hours), two of the subjects experienced syncope, dizziness, bradycardia including third degree AV block, vomiting, and/or incontinence.

In the long-term, open label study, involving 606 treated pediatric migraineurs 12 to 17 years of age (of which 432 were treated for at least 12 months), 151 patients (25%) took two 10-mg doses of rizatriptan benzoate orally disintegrating tablets within a 24-hour period.

Adverse reactions for 3 of these patients included abdominal discomfort, fatigue, and dyspnea.

In addition, based on the pharmacology of rizatriptan benzoate tablets, hypertension or myocardial ischemia could occur after overdosage.

Gastrointestinal decontamination, (i.e., gastric lavage followed by activated charcoal) should be considered in patients suspected of an overdose with rizatriptan benzoate tablets.

Clinical and electrocardiographic monitoring should be continued for at least 12 hours, even if clinical symptoms are not observed.

The effects of hemo- or peritoneal dialysis on serum concentrations of rizatriptan are unknown.

DESCRIPTION

11 Rizatriptan benzoate tablet, USP contains rizatriptan benzoate, a selective 5-hydroxytryptamine 1B/1D (5-HT 1B/1D ) receptor agonist.

Rizatriptan benzoate is described chemically as: N,N -dimethyl-5-(1 H -1,2,4-triazol-1-ylmethyl)-1 H -indole-3-ethanamine monobenzoate and its structural formula is: Its empirical formula is C 15 H 19 N 5 •C 7 H 6 O 2 , representing a molecular weight of the free base of 269.4.

Rizatriptan benzoate is a white to off-white, crystalline solid that is soluble in water at about 42 mg per mL (expressed as free base) at 25°C.

Rizatriptan benzoate Tablets, USP are available for oral administration in strengths of 5 and 10 mg (corresponding to 7.265 mg or 14.53 mg of the benzoate salt, respectively).

Each compressed tablet contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch (maize), and magnesium stearate.

rizatriptan-Structure

CLINICAL STUDIES

14 14.1 Adults The efficacy of rizatriptan benzoate tablets was established in four multicenter, randomized, placebo-controlled trials.

Patients enrolled in these studies were primarily female (84%) and Caucasian (88%), with a mean age of 40 years (range of 18 to 71).

Patients were instructed to treat a moderate to severe headache.

Headache response, defined as a reduction of moderate or severe headache pain to no or mild headache pain, was assessed for up to 2 hours (Study 1) or up to 4 hours after dosing (Studies 2, 3 and 4).

Associated symptoms of nausea, photophobia, and phonophobia and maintenance of response up to 24 hours post-dose were evaluated.

A second dose of rizatriptan benzoate tablets was allowed 2 to 24 hours after dosing for treatment of recurrent headache in Studies 1 and 2.

Additional analgesics and/or antiemetics were allowed 2 hours after initial treatment for rescue in all four studies.

In all studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater in patients who received either rizatriptan benzoate tablets 5 or 10 mg compared to those who received placebo.

In a separate study, doses of 2.5 mg were not different from placebo.

Doses greater than 10 mg were associated with an increased incidence of adverse effects.

The results from the four controlled studies are summarized in Table 2.

Table 2: Response Rates 2 Hours Following Treatment of Initial Headache in Studies 1, 2, 3, and 4 *p-value <0.05 in comparison with placebo.

† p-value <0.05 in comparison with 5 mg.

‡ Results for initial headache only.

Study Placebo Rizatriptan Benzoate Tablets 5 mg Rizatriptan Benzoate Tablets 10 mg 1 35% (n=304) 62%* (n=458) 71%* ,† (n=456) 2 ‡ 37% (n=82) — 77%* (n=320) 3 23% (n=80) 63%* (n=352) — 4 40% (n=159) 60%* (n=164) 67%* (n=385) Comparisons of drug performance based upon results obtained in different clinical trials may not be reliable.

Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study.

The estimated probability of achieving an initial headache response within 2 hours following treatment in pooled Studies 1, 2, 3, and 4 is depicted in Figure 1.

Figure 1: Estimated Probability of Achieving an Initial Headache Response by 2 Hours in Pooled Studies 1, 2, 3, and 4 * * Figure 1 shows the Kaplan-Meier plot of the probability over time of obtaining headache response (no or mild pain) following treatment with rizatriptan benzoate tablets or placebo.

The averages displayed are based on pooled data from 4 placebo-controlled, outpatient trials providing evidence of efficacy (Studies 1, 2, 3, and 4).

Patients taking additional treatment or not achieving headache response prior to 2 hours were censored at 2 hours.

For patients with migraine-associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of rizatriptan benzoate tablets compared to placebo.

Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain response in the form of a second dose of study treatment or other medication.

The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.

Figure 2: Estimated Probability of Patients Taking a Second Dose of Rizatriptan benzoate Tablets, USP or Other Medication for Migraines Over the 24 Hours Following the Initial Dose of Study Treatment in Pooled Studies 1, 2, 3, and 4 * * This Kaplan-Meier plot is based on data obtained in 4 placebo-controlled outpatient clinical trials (Studies 1, 2, 3, and 4).

Patients not using additional treatments were censored at 24 hours.

The plot includes both patients who had headache response at 2 hours and those who had no response to the initial dose.

Remedication was not allowed within 2 hours post- dose.

Efficacy was unaffected by the presence of aura; by the gender, or age of the patient; or by concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants) or oral contraceptives.

In two additional similar studies, efficacy was unaffected by relationship to menses.

There were insufficient data to assess the impact of race on efficacy.

rizatriptan-Fig-1 rizatriptan-Fig-2 14.2 Pediatric Patients 6 to 17 Years of Age The efficacy of rizatriptan benzoate orally disintegrating tablets in pediatric patients 6 to 17 years was evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial (Study 7).

Patients had to have at least a 6-month history of migraine attacks (with or without aura) usually lasting 3 hours or more (when untreated).

The patient population was historically non-responsive to NSAIDs and acetaminophen therapy.

Patients were instructed to treat a single migraine attack with headache pain of moderate to severe intensity.

The treatment phase of the study had two stages.

Stage 1 was used to identify placebo non-responders, who then entered into Stage 2, in which patients were randomized to rizatriptan benzoate orally disintegrating tablets or placebo.

Using a weight-based dosing strategy, patients 20 kg to <40 kg (44 lb to <88 lb) received rizatriptan benzoate orally disintegrating tablets 5 mg or placebo, and patients ≥40 kg (88 lb) received rizatriptan benzoate orally disintegrating tablets10 mg or placebo.

The mean age for the studied patient population was 13 years.

Sixty-one percent of the patients were Caucasian, and fifty-six percent of the patients were female.

The percentage of patients achieving the primary efficacy endpoint of no headache pain at 2 hours after treatment was significantly greater in patients who received rizatriptan benzoate orally disintegrating tablets, compared with those who received placebo (33% vs.

24%).

Study 7 results are summarized in Table 4.

Table 4: Response Rates 2 Hours Following Treatment of Initial Headache in Pediatric Patients 6 to 17 Years of Age in Study 7 Endpoint Placebo Rizatriptan benzoate orally disintegrating tablets p-Value No headache pain at 2 hours post-dose 24% (n/m=94/388) 33% (n/m=126/382) 0.01 n = Number of evaluable patients with no headache pain at 2 hours post-dose.

m = Number of evaluable patients in population.

The observed percentage of pediatric patients achieving no headache pain within 2 hours following initial treatment with rizatriptan benzoate orally disintegrating tablets is shown in Figure 5.

Figure 5: Observed Percentage of Patients Reporting No Headache Pain by 2 Hours Post-Dose in Study 7 The prevalence of the exploratory endpoints of absence of migraine-associated symptoms (nausea, photophobia, and phonophobia) at 2 hours after taking the dose was not statistically significantly different between patients who received rizatriptan benzoate orally disintegrating tablets and those who received placebo.

rizatriptan-Fig-5

HOW SUPPLIED

16 /STORAGE AND HANDLING Rizatriptan benzoate tablets, USP 5 mg, are white to off-white, capsule-shaped, compressed tablets debossed “ RZT” on one side and “5” on other side.

They are supplied as follows: NDC 67877-261-30, bottle of 30 tablets.

NDC 67877-261-01, bottle of 100 tablets.

NDC 67877-261-05, bottle of 500 tablets.

NDC 67877-261-18, carton of 18 tablets NDC 67877-261-25, carton of 12 tablets Rizatriptan benzoate tablets, USP 10 mg, are white to off-white, capsule-shaped, compressed tablets debossed “RZT” on one side and “10” on other side.

They are supplied as follows: NDC 67877-262-30, bottle of 30 tablets.

NDC 67877-262-01, bottle of 100 tablets.

NDC 67877-262-05, bottle of 500 tablets.

NDC 67877-262-18, carton of 18 tablets NDC 67877-262-25, carton of 12 tablets Storage Store rizatriptan benzoate tablets, USP at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

GERIATRIC USE

8.5 Geriatric Use Clinical studies of rizatriptan benzoate tablets did not include sufficient numbers of subjects aged 65 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.

Although the pharmacokinetics of rizatriptan were similar in elderly (aged ≥65 years) and in younger adults (n=17), in general, dose selection for an elderly patient should be cautious, starting at the low end of the dosing range.

This reflects the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) should have a cardiovascular evaluation prior to receiving rizatriptan benzoate tablets [see Warnings and Precautions (5.1) ] .

DOSAGE FORMS AND STRENGTHS

3 Rizatriptan benzoate Tablets, USP 5 mg tablets are white to off-white, capsule-shaped, compressed tablets debossed “RZT” on one side and “5” on other side.

10 mg tablets are white to off-white, capsule-shaped, compressed tablets debossed “RZT” on one side and “10” on other side.

Rizatriptan Benzoate Tablets, USP: 5 and 10 mg ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Rizatriptan binds with high affinity to human cloned 5-HT 1B/1D receptors.

Rizatriptan benzoate tablets presumably exerts its therapeutic effects in the treatment of migraine headache by binding to 5-HT 1B/1D receptors located on intracranial blood vessels and sensory nerves of the trigeminal system.

INDICATIONS AND USAGE

1 Rizatriptan benzoate tablets are indicated for the acute treatment of migraine with or without aura in adults and in pediatric patients 6 to 17 years old.

Limitations of Use Rizatriptan benzoate tablets should only be used where a clear diagnosis of migraine has been established.

If a patient has no response for the first migraine attack treated with rizatriptan benzoate tablets, the diagnosis of migraine should be reconsidered before rizatriptan benzoate tablets are administered to treat any subsequent attacks.

Rizatriptan benzoate tablets are not indicated for use in the management of hemiplegic or basilar migraine [see Contraindications (4) ] .

Rizatriptan benzoate tablets are not indicated for the prevention of migraine attacks.

Safety and effectiveness of rizatriptan benzoate tablets have not been established for cluster headache.

Rizatriptan benzoate tablets are a serotonin (5-HT) 1B/1D receptor agonist (triptan) indicated for the acute treatment of migraine with or without aura in adults and in pediatric patients 6 to 17 years of age( 1 ) Limitations of Use : Use only after clear diagnosis of migraine has been established ( 1 ) Not indicated for the prophylactic therapy of migraine ( 1 ) Not indicated for the treatment of cluster headache ( 1 )

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness in pediatric patients under 6 years of age have not been established.

The efficacy and safety of rizatriptan benzoate tablets in the acute treatment of migraine in patients aged 6 to 17 years was established in an adequate and well-controlled study [see Clinical Studies ( 14.2) ] .

The incidence of adverse reactions reported for pediatric patients in the acute clinical trial was similar in patients who received rizatriptan benzoate tablets to those who received placebo.

The adverse reaction pattern in pediatric patients is expected to be similar to that in adults.

PREGNANCY

8.1 Pregnancy Risk Summary Available human data on the use of rizatriptan benzoate tablets in pregnant women are not sufficient to draw conclusions about drug-associated risk for major birth defects and miscarriage.

In animal studies, developmental toxicity was observed following oral administration of rizatriptan during pregnancy (decreased fetal body weight in rats) or throughout pregnancy and lactation (increased mortality, decreased body weight, and neurobehavioral impairment in rat offspring) at maternal plasma exposures greater than that expected at therapeutic doses in humans [see Animal Data].

In the U.S.

general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

The reported rate of major birth defects among deliveries to women with migraine range from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which are similar to rates reported in women without migraine.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk In women with migraine, there is an increased risk of adverse perinatal outcomes in the mother, including pre-eclampsia and gestational hypertension.

Data Human Data The Pregnancy Registry for rizatriptan benzoate tablets did not identify any pattern of congenital anomalies or other adverse birth outcomes over the period of 1998 to 2018.

However, the lack of identification of any pattern should be viewed with caution, as the number of prospective reports with outcome information was low and did not provide sufficient power to detect an increased risk of individual birth defects associated with the use of rizatriptan benzoate tablets.

Additionally, there was significant loss to follow-up in the prospective pregnancy reports, further complicating this assessment of an association between rizatriptan benzoate tablets and any pattern of congenital anomalies or other adverse birth outcomes.

In a study using data from the Swedish Medical Birth Register, live births to women who reported using triptans or ergots during pregnancy were compared with those of women who did not.

Of the 157 births with first-trimester exposure to rizatriptan, 7 infants were born with malformations (relative risk 1.01 [95% CI: 0.40 to 2.08]).

A study using linked data from the Medical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for triptans before pregnancy only, compared with a population control group.

Of the 310 women who redeemed prescriptions for rizatriptan during the first trimester, 10 had infants with major congenital malformations (OR 1.03 [95% CI: 0.55 to 1.93]), while for the 271 women who redeemed prescriptions for rizatriptan before, but not during, pregnancy, 12 had infants with major congenital malformations (OR 1.48 [95% CI: 0.83 to 2.64]), each compared with the population comparison group.

Animal Data When rizatriptan (0, 2, 10, or 100 mg/kg/day) was administered orally to pregnant rats throughout organogenesis, a decrease in fetal body weight was observed at the highest doses tested.

At the mid dose (10 mg/kg/day), which was a no-effect dose for adverse effects on embryofetal development, plasma exposure (AUC) was approximately 15 times that in humans at the maximum recommended human dose (MRHD) of 30 mg/day.

When rizatriptan (0, 5, 10, or 50 mg/kg/day) was administered orally to pregnant rabbits throughout organogenesis, no adverse fetal effects were observed.

Plasma exposure (AUC) at the highest dose tested was 115 times that in humans at the MRHD.

Placental transfer of drug to the fetus was demonstrated in both species.

Oral administration of rizatriptan (0, 2, 10, or 100 mg/kg/day) to female rats prior to and during mating and continuing throughout gestation and lactation resulted in reduced body weight in offspring from birth and throughout lactation at all but the lowest dose tested (2 mg/kg/day).

Plasma exposure (AUC) at the no-effect dose (2 mg/kg/day) for adverse effects on postnatal development was similar to that in humans at the MRHD.

Oral administration of rizatriptan (0, 5, 100, or 250 mg/kg/day) throughout organogenesis and lactation resulted in neonatal mortality, reduced body weight (which persisted into adulthood), and impaired neurobehavioral function in offspring at all but the lowest dose tested.

Plasma exposure (AUC) at the no-effect dose for adverse effects on postnatal development (5 mg/kg/day) was approximately 8 times that in humans at the MRHD.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Myocardial ischemia, myocardial infarction, and Prinzmetal’s angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors ( 5.1 ) Arrhythmias: Discontinue dosing if occurs ( 5.2 ) Chest/throat/neck/jaw pain, tightness, pressure, or heaviness; Generally not associated with myocardial ischemia; Evaluate patients at high risk ( 5.3 ) Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue dosing if occurs ( 5.4 ) Gastrointestinal ischemic events, peripheral vasospastic reactions: Discontinue dosing if occurs ( 5.5 ) Medication overuse headache: Detoxification may be necessary ( 5.6 ) Serotonin syndrome: Discontinue dosing if occurs ( 5.7 ) 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina Rizatriptan benzoate tablets should not be given to patients with ischemic or vasospastic coronary artery disease.

There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of rizatriptan benzoate tablets.

Some of these reactions occurred in patients without known coronary artery disease (CAD).

5-HT 1 agonists, including rizatriptan benzoate tablets may cause coronary artery vasospasm (Prinzmetal’s Angina), even in patients without a history of CAD.

Triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) should have a cardiovascular evaluation prior to receiving rizatriptan benzoate tablets.

If there is evidence of CAD or coronary artery vasospasm, rizatriptan benzoate tablets should not be administered [see Contraindications (4) ] .

For patients who have a negative cardiovascular evaluation, consideration should be given to administration of the first rizatriptan benzoate tablets dose in a medically supervised setting and performing an electrocardiogram (ECG) immediately following rizatriptan benzoate tablets administration.

Periodic cardiovascular evaluation should be considered in intermittent long-term users of rizatriptan benzoate tablets who have cardiovascular risk factors.

5.2 Arrhythmias Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT 1 agonists.

Discontinue rizatriptan benzoate tablets if these disturbances occur.

5.3 Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure As with other 5-HT 1 agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck and jaw commonly occur after treatment with rizatriptan benzoate tablets and are usually non­-cardiac in origin.

However, if a cardiac origin is suspected, patients should be evaluated.

Patients shown to have CAD and those with Prinzmetal’s variant angina should not receive 5-HT 1 agonists.

5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT 1 agonists, and some have resulted in fatalities.

In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT 1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not.

Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack).

Discontinue rizatriptan benzoate tablets, USP if a cerebrovascular event occurs.

As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions.

Rizatriptan benzoate tablets should not be administered to patients with a history of stroke or transient ischemic attack [see Contraindications (4) ] .

5.5 Other Vasospasm Reactions 5-HT 1 agonists, including rizatriptan benzoate tablets, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome.

In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT 1 agonist, the suspected vasospasm reaction should be ruled out before receiving additional rizatriptan benzoate tablets doses.

Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT 1 agonists.

Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT 1 agonists have not been clearly established.

5.6 Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or a combination of drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache).

Medication overuse headache may present as migraine-like daily headaches, or as a marked increase in frequency of migraine attacks.

Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.

5.7 Serotonin Syndrome Serotonin syndrome may occur with triptans, including rizatriptan benzoate tablets particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see Drug Interactions (7.5) ] .

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The onset of symptoms can occur within minutes to hours of receiving a new or a greater dose of a serotonergic medication.

Rizatriptan benzoate tablets treatment should be discontinued if serotonin syndrome is suspected [see Drug Interactions (7.4) and Patient Counseling Information (17) ] .

5.8 Increase in Blood Pressure Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients with and without a history of hypertension receiving 5-HT 1 agonists, including rizatriptan benzoate tablets.

In healthy young adult male and female patients who received maximal doses of rizatriptan benzoate tablets (10 mg every 2 hours for 3 doses), slight increases in blood pressure (approximately 2-3 mmHg) were observed.

Rizatriptan benzoate tablets is contraindicated in patients with uncontrolled hypertension [see Contraindications (4) ] .

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).

Risk of Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospasm-Related Events, and Cerebrovascular Events Inform patients that rizatriptan benzoate tablets, USP may cause serious cardiovascular side effects such as myocardial infarction or stroke.

Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms.

Patients should be apprised of the importance of this follow-up [see Warnings and Precautions (5.1 , 5.2 , 5.4 , 5.5 )] .

Serotonin Syndrome Patients should be cautioned about the risk of serotonin syndrome with the use of rizatriptan benzoate tablets or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.7) , Drug Interactions (7.4) , and Clinical Pharmacology (12.3) ] .

Pregnancy Inform patients that rizatriptan benzoate tablets should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1) ] .

Lactation Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations ( 8.2 )].

Ability to Perform Complex Tasks Since migraines or treatment with rizatriptan benzoate tablets may cause somnolence and dizziness, instruct patients to evaluate their ability to perform complex tasks during migraine attacks and after administration of rizatriptan benzoate tablets, USP.

Medication Overuse Headache Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [see Warnings and Precautions (5.6) ] .

Manufactured by: Alkem Laboratories Ltd., INDIA.

Distributed by: Ascend Laboratories, LLC Parsippany, NJ 07054 Revised: November, 2021 Patient Information RIZATRIPTAN BENZOATE TABLETS, USP 5 mg and 10 mg Read this Patient Information before you start taking rizatriptan benzoate tablets and each time you get a refill.

There may be new information.

This information does not take the place of talking to your doctor about your medical condition or your treatment.

Unless otherwise stated, the information in this Patient Information leaflet applies to both rizatriptan benzoate tablets and to rizatriptan benzoate orally disintegrating tablets.

What is rizatriptan benzoate , USP ? Rizatriptan benzoate tablets, USP is a prescription medicine that belongs to a class of medicines called Triptans.

Rizatriptan benzoate tablets is available as a traditional tablet and as an orally disintegrating tablet.

Rizatriptan benzoate tablet are used to treat migraine attacks with or without aura in adults and in children 6 to 17 years of age.

Rizatriptan benzoate tablets is not to be used to prevent migraine attacks.

Rizatriptan benzoate tablets is not for the treatment of hemiplegic or basilar migraines.

It is not known if rizatriptan benzoate tablets is safe and effective for the treatment of cluster headaches.

It is not known if taking more than 1 dose of rizatriptan benzoate tablet in 24 hours is safe and effective in children 6 to 17 years of age.

It is not known if rizatriptan benzoate tablet is safe and effective in children under 6 years of age.

Who should not take rizatriptan benzoate tablets? Do not take rizatriptan benzoate tablets if you: have or have had heart problems have or have had a stroke or a transient ischemic attack (TIA) have or have had blood vessel problems including ischemic bowel disease have uncontrolled high blood pressure have taken other Triptan medicines in the last 24 hours have taken ergot-containing medicines in the last 24 hours have hemiplegic or basilar migraines take monoamine oxidase (MAO) inhibitor or have taken a MAO inhibitor within the last 2 weeks are allergic to rizatriptan benzoate or any of the ingredients in rizatriptan benzoate tablets, USP.

See the end of this leaflet for a complete list of ingredients in rizatriptan benzoate tablets.

Talk to your doctor before taking this medicine if you have any of the conditions listed above or if you are not sure if you take any of these medicines.

What should I tell my doctor before taking rizatriptan benzoate tablets? Before you take rizatriptan benzoate tablets, tell your doctor if you: have or have had heart problems, high blood pressure, chest pain, or shortness of breath have any risk factors for heart problems or blood vessel problems such as: high blood pressure high cholesterol smoking obesity diabetes family history of heart problems you are post menopausal you are a male over 40 have kidney or liver problems have any other medical condition are pregnant or plan to become pregnant.

It is not known if rizatriptan benzoate tablets will harm your unborn baby.

If you become pregnant while taking rizatriptan benzoate tablets, talk to your healthcare provider.

are breastfeeding or plan to breastfeed.

It is not known if rizatriptan benzoate passes into your breast milk.

Talk to your doctor about the best way to feed your baby if you take rizatriptan benzoate tablets.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.

Rizatriptan benzoate tablets and other medicines may affect each other causing side effects.

Rizatriptan benzoate tablets may affect the way other medicines work, and other medicines may affect how rizatriptan benzoate tablets works.

Especially tell your doctor if you take: propranolol containing medicines such as Inderal ® , Inderal ® LA, or Innopran ® XL medicines used to treat mood disorders, including selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).

Ask your doctor or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take.

Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take rizatriptan benzoate tablets? Take rizatriptan benzoate tablets exactly as your doctor tells you to take it.

Your doctor will tell you how much rizatriptan benzoate tablets to take and when to take it.

If your headache comes back after your first rizatriptan benzoate tablets dose: For adults: a second dose may be taken 2 hours after the first dose.

Do not take more than 30 mg of rizatriptan benzoate tablets in a 24-hour period (for example, do not take more than 3 10-mg tablets in a 24-hour period).

For children 6 to 17 years of age: It is not known if taking more than 1 dose of rizatriptan benzoate tablets in 24 hours is safe and effective.

Talk to your doctor about what to do if your headache does not go away or comes back.

If you take too much rizatriptan benzoate tablets, call your doctor or go to the nearest hospital emergency room right away.

What should I avoid while taking rizatriptan benzoate tablets ? Rizatriptan benzoate tablets may cause dizziness, weakness, or fainting.

If you have these symptoms, do not drive a car, use machinery, or do anything that needs you to be alert.

What are the possible side effects of rizatriptan benzoate tablets? Rizatriptan benzoate tablets may cause serious side effects .

Call your doctor or go to the nearest hospital emergency room right away if you think you are having any of the serious side effects of rizatriptan benzoate tablets including: heart attack .

Symptoms of a heart attack may include: chest discomfort in the center of your chest that lasts for more than a few minutes or that goes away and comes back chest discomfort that feels like uncomfortable pressure, squeezing, fullness or pain pain or discomfort in your arms, back, neck, jaw or stomach shortness of breath with or without chest discomfort breaking out in a cold sweat nausea or vomiting feeling lightheaded stroke .

Symptoms of a stroke may include the following sudden symptoms: numbness or weakness in your face, arm or leg, especially on one side of your body confusion, problems speaking or understanding problems seeing in 1 or both of your eyes problems walking, dizziness, loss of balance or coordination severe headache with no known cause blood vessel problems .

Symptoms of blood vessel problems may include: stomach pain bloody diarrhea vision problems coldness and numbness of hands and feet serotonin syndrome .

A condition called serotonin syndrome can happen when Triptan medicines such as rizatriptan benzoate tablets are taken with certain other medicines.

Symptoms of serotonin syndrome may include: agitation hallucinations coma fast heartbeat fast changes in your blood pressure increased body temperature muscle spasm loss of coordination nausea, vomiting or diarrhea increased blood pressure.

The most common side effects of rizatriptan benzoate tablets in adults include: feeling sleepy or tired pain or pressure in your chest or throat dizziness Tell your doctor if you have any side effect that bothers you or that does not go away.

If you take rizatriptan benzoate tablets too often, this may result in you getting chronic headaches.

In such cases, you should contact your doctor, as you may have to stop taking rizatriptan benzoate tablets.

These are not all the possible side effects of rizatriptan benzoate tablets.

For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects.

You may report side effects to FDA at 1-800-FDA-1088.

How should I store rizatriptan benzoate tablets? Store rizatriptan benzoate tablets at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Safely throw away medicine that is out of date or no longer needed.

Keep rizatriptan benzoate tablets and all medicines out of the reach of children.

General Information about the safe and effective use of rizatriptan benzoate tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.

Do not use rizatriptan benzoate tablets for a condition for which it was not prescribed.

Do not give rizatriptan benzoate tablets to other people, even if they have the same symptoms that you have.

It may harm them.

This Patient Information leaflet summarizes the most important information about rizatriptan benzoate tablets.

If you would like more information, talk to your doctor.

You can ask your pharmacist or doctor for information about rizatriptan benzoate tablets that is written for health professionals.

For more information contact Ascend Laboratories, LLC at 1-877-ASC-RX01 (877-272-7901) What are the ingredients in rizatriptan benzoate tablets ? Active ingredient in rizatriptan benzoate tablets: rizatriptan benzoate.

Inactive ingredients in rizatriptan benzoate tablets: lactose monohydrate, microcrystalline cellulose, pregelatinized starch (maize), and magnesium stearate.

The brands listed are the trademarks of their respective owners.

This Patient Information has been approved by the U.S.

Food and Drug Administration.

Manufactured by: Alkem Laboratories Ltd., INDIA.

Distributed by: Ascend Laboratories, LLC Parsippany, NJ 07054 Revised: November, 2021 PT 2719-05

DOSAGE AND ADMINISTRATION

2 Adults: 5 or 10 mg single dose; separate repeat doses by at least two hours; maximum dose in a 24-hour period: 30 mg ( 2.1 ) Pediatric patients 6 to 17 years: 5 mg single dose in patients less than 40 kg (88 lb); 10 mg single dose in patients 40 kg (88 lb) or more ( 2.2 ) Adjust dose if co-administered with propranolol ( 2.4 ) 2.1 Dosing Information in Adults The recommended starting dose of rizatriptan benzoate tablets are either 5 mg or 10 mg for the acute treatment of migraines in adults.

The 10-mg dose may provide a greater effect than the 5-mg dose, but may have a greater risk of adverse reactions [see Clinical Studies (14.1) ] .

Redosing in Adults Although the effectiveness of a second dose or subsequent doses has not been established in placebo-controlled trials, if the migraine headache returns, a second dose may be administered 2 hours after the first dose.

The maximum daily dose should not exceed 30 mg in any 24-hour period.

The safety of treating, on average, more than four headaches in a 30-day period has not been established.

2.2 Dosing Information in Pediatric Patients (Age 6 to 17 Years) Dosing in pediatric patients is based on the patient’s body weight.

The recommended dose of rizatriptan benzoate tablets is 5 mg in patients weighing less than 40 kg (88 lb), and 10 mg in patients weighing 40 kg (88 lb) or more.

The efficacy and safety of treatment with more than one dose of rizatriptan benzoate tablet within 24 hours in pediatric patients 6 to 17 years of age have not been established.

2.4 Dosage Adjustment for Patients on Propranolol Adult Patients In adult patients taking propranolol, only the 5-mg dose of rizatriptan benzoate tablets are recommended, up to a maximum of 3 doses in any 24-hour period (15 mg) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] .

Pediatric Patients For pediatric patients weighing 40 kg (88 lb) or more, taking propranolol, only a single 5-mg dose of rizatriptan benzoate tablets is recommended (maximum dose of 5 mg in a 24-hour period).

Rizatriptan benzoate tablets should not be prescribed to propranolol-treated pediatric patients who weigh less than 40 kg (88 lb) [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )].

Ketalar (ketamine hydrochloride) 10 MG/ML Injectable Solution

Generic Name: KETAMINE HYDROCHLORIDE
Brand Name: Ketalar
  • Substance Name(s):
  • KETAMINE HYDROCHLORIDE

DRUG INTERACTIONS

7 Theophylline or Aminophylline : Do not co-administer with KETALAR as concomitant use may lower the seizure threshold ( 7.1 ).

Sympathomimetics and Vasopressin : Closely monitor vital signs when co-administered with KETALAR.

Consider dose adjustment individualized to the patient’s clinical situation ( 7.2 ).

Benzodiazepines, Opioid Analgesics, or other CNS Depressants : Concomitant use may result in profound sedation, respiratory depression, coma, or death.

Concomitant use of opioid analgesics may prolong recovery time.

( 7.3 ).

7.1 Theophylline or Aminophylline Concomitant administration of KETALAR and theophylline or aminophylline may lower the seizure threshold.

Consider using an alternative to KETALAR in patients receiving theophylline or aminophylline.

7.2 Sympathomimetics and Vasopressin Sympathomimetics and vasopressin may enhance the sympathomimetic effects of ketamine.

Closely monitor vital signs when KETALAR and sympathomimetics or vasopressin are co-administered and consider dose adjustment individualized to the patient’s clinical situation.

7.3 Benzodiazepines, Opioid Analgesics, Or Other CNS Depressants Concomitant use of ketamine with opioid analgesics, benzodiazepines, or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions ( 5.8 )] .

Opioid analgesics administered concomitantly with KETALAR may prolong time to complete recovery from anesthesia.

OVERDOSAGE

10 Changes in heart rate and blood pressure, respiratory depression, and apnea may occur with overdosage or by a rapid rate of administration of KETALAR.

Monitor patients for clinically relevant changes in heart rate and blood pressure.

Assisted ventilation, including mechanical ventilation, may be required.

In cases of unintentional overdose of KETALAR (up to ten times that usually required), patients had a prolonged but complete recovery.

DESCRIPTION

11 KETALAR (ketamine hydrochloride) injection, for intravenous or intramuscular use, contains ketamine, a nonbarbiturate general anesthetic.

Ketamine hydrochloride, USP is a white crystalline powder and has a molecular formula of C 13 H 16 ClNO•HCl and a molecular weight of 274.19.

The chemical name for ketamine hydrochloride is (±)-2-( o -Chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride.

The chemical structure of ketamine hydrochloride is: It is formulated as a slightly acidic (pH 3.5-5.5) sterile solution for intravenous or intramuscular injection.

Each milliliter (mL) of the multiple-dose vials contain either 10 mg ketamine base (equivalent to 11.53 mg ketamine hydrochloride), 50 mg ketamine base (equivalent to 57.67 mg ketamine hydrochloride) or 100 mg ketamine base (equivalent to 115.33 mg ketamine hydrochloride) and not more than 0.10 mg/mL benzethonium chloride added as a preservative in water for injection.

The 10 mg/mL solution has been made isotonic with 6.60 mg sodium chloride.

ketamine hydrochloride

CLINICAL STUDIES

14 KETALAR has been studied in over 12,000 operative and diagnostic procedures, involving over 10,000 patients in 105 separate studies.

During the course of these studies, KETALAR was administered as the sole general anesthetic, as an induction agent prior to administration of other general anesthetics, or to supplement other anesthetic agents.

KETALAR has been evaluated during the following procedures: debridement, dressing changes, and skin grafting in burn patients, as well as other superficial surgical procedures.

neurodiagnostic procedures such as myelograms and lumbar punctures.

diagnostic and operative procedures of the ear, nose, and mouth, including dental extractions.

sigmoidoscopy and minor surgery of the anus and rectum, and circumcision.

extraperitoneal procedures, such as dilatation and curettage.

orthopedic procedures such as closed reductions, manipulations, femoral pinning, amputations, and biopsies.

cardiac catheterization procedures.

HOW SUPPLIED

16 /STORAGE AND HANDLING How Supplied KETALAR injection is a clear, colorless solution supplied as the hydrochloride salt in concentrations equivalent to ketamine base, as follows: Unit of sale Strength NDC 42023-113-10 Unit of 10 200 mg in 20 mL multiple- dose vial (10 mg/mL) 10 mg ketamine base (equivalent to 11.53 mg ketamine hydrochloride) NDC 42023-114-10 Unit of 10 500 mg in 10 mL multiple- dose vial (50 mg/mL) 50 mg ketamine base (equivalent to 57.67 mg ketamine hydrochloride) NDC 42023-115-10 Unit of 10 500 mg in 5 mL multiple- dose vial (100 mg/mL) 100 mg ketamine base (equivalent to 115.33 mg ketamine hydrochloride) Storage and Handling KETALAR injection should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] .

Protect from light.

GERIATRIC USE

8.5 Geriatric Use Clinical studies of ketamine hydrochloride did not include sufficient numbers of subjects aged 65 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.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

DOSAGE FORMS AND STRENGTHS

3 KETALAR injection is a clear, colorless, sterile solution available in multiple-dose vials containing either 10 mg ketamine base (equivalent to 11.53 mg ketamine hydrochloride), 50 mg ketamine base (equivalent to 57.67 mg ketamine hydrochloride) or 100 mg ketamine base (equivalent to 115.33 mg ketamine hydrochloride).

200 mg/20 mL (10 mg/mL) 500 mg/10 mL (50 mg/mL) 500 mg/5 mL (100 mg/mL) Injection: 200 mg/20 mL (10 mg/mL), 500 mg/10 mL (50 mg/mL), and 500 mg/5 mL (100 mg/mL) multiple-dose vials ( 3 ).

MECHANISM OF ACTION

12.1 Mechanism of Action KETALAR, a racemic mixture of ketamine, is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor.

The major circulating metabolite of ketamine (norketamine) demonstrated activity at the same receptor with less affinity.

Norketamine is about 1/3 as active as ketamine in reducing halothane requirements (MAC) of the rat.

INDICATIONS AND USAGE

1 KETALAR (ketamine hydrochloride) injection is indicated: as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation.

for the induction of anesthesia prior to the administration of other general anesthetic agents.

as a supplement to other anesthetic agents.

KETALAR is a general anesthetic indicated: as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation ( 1 ) for the induction of anesthesia prior to the administration of other general anesthetic agents ( 1 ) as a supplement to other anesthetic agents ( 1 ).

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 16 have not been established.

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as KETALAR, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis.

Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss.

Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory.

The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in neonates and young children who require procedures with the potential risks suggested by the nonclinical data [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.1 ), and Nonclinical Toxicology ( 13.2 )] .

PREGNANCY

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of KETALAR in pregnant women.

In animal reproduction studies in rats developmental delays (hypoplasia of skeletal tissues) were noted at 0.3 times the human intramuscular dose of 10 mg/kg.

In rabbits, developmental delays and increased fetal resorptions were noted at 0.6 times the human dose.

Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours.

There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans.

The estimated 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 2-4% and 15-20%, respectively.

Clinical Considerations KETALAR use in pregnancy, including obstetrics (either vaginal or abdominal delivery), is not recommended because safe use has not been established [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.4 ) and Nonclinical Toxicology ( 13.2 )] .

Data Animal Data Pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg IM based on body surface area) on either Gestation Days 6 to 10 or Gestation Days 11 to 15.

Ketamine treatment produced an increased incidence of hypoplastic skull, phalanges, and sternebrae in the pups.

Pregnant rabbits were treated intramuscularly with 20 mg/kg ketamine (0.6 times the human dose of 10 mg/kg IM based on body surface area) on either Gestation Days 6 to 10 or Gestation Days 11 to 15.

An increase in resorptions and skeletal hypoplasia of the fetuses were noted.

Additional pregnant rabbits were treated intramuscularly with a single dose 60 mg/kg (1.9 times the human dose of 10 mg/kg IM based on body surface area) on Gestation Day 6 only.

Skeletal hypoplasia was reported in the fetuses.

In a study where pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg IM based on body surface area) from Gestation Day 18 to 21.

There was a slight increase in incidence of delayed parturition by one day in treated dams of this group.

No adverse effects on the litters or pups were noted; however, learning and memory assessments were not completed.

Three (3) pregnant beagle dogs were treated intramuscularly with 25 mg/kg ketamine (1.3 times the human dose of 10 mg/kg IM based on body surface area) twice weekly for the three weeks of the first, second, and third trimesters of pregnancy, respectively, without the development of adverse effects in the pups.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus.

In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring.

With respect to brain development, this time period corresponds to the third trimester of gestation in the human.

The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.4 ), and Nonclinical Toxicology ( 13.2 )] .

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Hemodynamic Instability: Monitor vital signs and cardiac function during KETALAR administration.

( 5.1 ) Emergence Reactions: Postoperative confusional states may occur during the recovery period.

Reduce by minimizing verbal, tactile, and visual stimulation of the patient.

( 5.2 ) Risk of Respiratory Depression: May occur with overdosage or too rapid a rate of administration.

Maintain adequate oxygenation and ventilation.

( 5.3 ) Risks of KETALAR alone for Procedures of the Pharynx, Larynx, or Bronchial Tree : Pharyngeal and laryngeal reflexes are not suppressed with KETALAR when it is used alone.

Avoid use as a sole anesthetic agent in surgery or diagnostic procedures of the pharynx, larynx, or bronchial tree.

Muscle relaxants may be required.

( 5.4 ) Pediatric Neurotoxicity: Long-term cognitive deficits may occur when used for longer than 3 hours in children ≤3 years ( 5.5 ) 5.1 Hemodynamic Instability Transient increases in blood pressure, heart rate, and cardiac index are frequently observed following administration of KETALAR.

Decreases in blood pressure and heart rate, arrhythmias, and cardiac decompensation have also been observed.

Monitor vital signs and cardiac function during KETALAR administration.

KETALAR is contraindicated in patients for whom a significant elevation of blood pressure would constitute a serious hazard [see Contraindications ( 4 )] .

5.2 Emergence Reactions Emergence delirium (postoperative confusional states or agitation) has occurred in approximately 12% of patients during the recovery period, and the duration is generally a few hours.

The neuropsychological manifestations vary in severity between pleasant dream-like states, vivid imagery, hallucinations, and emergence delirium.

In some cases, these states have been accompanied by confusion, excitement, and irrational behavior, which have been recalled as unpleasant experiences.

No residual psychological effects are known to have resulted from use of KETALAR during induction and maintenance of anesthesia.

Intramuscular administration results in a lower incidence of emergence reactions.

The incidence of psychological manifestations during emergence, particularly dream-like observations and emergence delirium, may be reduced by using lower recommended dosages of KETALAR in conjunction with an intravenous benzodiazepine during induction and maintenance of anesthesia [see Dosage and Administration ( 2.3 )] .

Also, these reactions may be reduced if verbal, tactile, and visual stimulation of the patient is minimized during the recovery period.

This does not preclude the monitoring of vital signs.

5.3 Respiratory Depression Respiratory depression may occur with overdosage or a rapid rate of administration of KETALAR.

Maintain adequate oxygenation and ventilation.

5.4 Risks of Ketalar Alone for Procedures of the Pharynx, Larynx, or Bronchial Tree KETALAR does not suppress pharyngeal and laryngeal reflexes.

Avoid KETALAR administration as a sole anesthetic agent during procedures of the pharynx, larynx, or bronchial tree, including mechanical stimulation of the pharynx.

Muscle relaxants may be required for successful completion of procedures of the pharynx, larynx, or bronchial tree.

5.5 Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours.

The clinical significance of these findings is not clear.

However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see Use in Specific Populations ( 8.1 , 8.4 ), Nonclinical Toxicology ( 13.2 )].

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects.

These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other.

Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

5.6 Drug-Induced Liver Injury Ketamine administration is associated with hepatobiliary dysfunction (most often a cholestatic pattern), with recurrent use (e.g., misuse/abuse or medically supervised unapproved indications).

Biliary duct dilatation with or without evidence of biliary obstruction has also been reported with recurrent use.

Obtain baseline LFTs, including alkaline phosphatase and gamma glutamyl transferase, in patients receiving ketamine as part of a treatment plan that utilizes recurrent dosing.

Monitor those receiving recurrent ketamine at periodic intervals during treatment.

5.7 Increase in Cerebrospinal Fluid Pressure An increase in intracranial pressure has been reported following administration of ketamine hydrochloride.

Patients with elevated intracranial pressure should be in a monitored setting with frequent neurologic assessments.

5.8 Drug Interactions Theophylline or Aminophylline : Concomitant administration of KETALAR and theophylline or aminophylline may lower the seizure threshold [see Drug Interactions ( 7.1 )] .

Consider using an alternative to KETALAR in patients receiving theophylline or aminophylline.

Sympathomimetics and Vasopressin : Sympathomimetics and vasopressin may enhance the sympathomimetic effects of ketamine [see Drug Interactions ( 7.2 )] .

Closely monitor vital signs when KETALAR and sympathomimetics or vasopressin are co-administered and consider dose adjustment individualized to the patient’s clinical situation.

Benzodiazepines, Opioid Analgesics, or Other CNS Depressants Concomitant use of ketamine with opioid analgesics, benzodiazepines, or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Drug Interactions ( 7.3 )] .

Closely monitor neurological status and respiratory parameters, including respiratory rate and pulse oximetry, when KETALR and opioid analgesics, benzodiazepines, or other CNS depressants are co-administered.

Consider dose adjustment individualized to the patient’s clinical situation.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains.

Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs [see Warnings and Precautions ( 5.5 )] .

Due to the residual anesthetic effects and the potential for drowsiness, advise patients not to drive an automobile, operate hazardous machinery, or engage in hazardous activities within 24 hours of receiving KETALAR.

DOSAGE AND ADMINISTRATION

2 See Full Prescribing Information for important dosage and administration instructions.

( 2 ) Induction of anesthesia: — Intravenous route : Initially, 1 to 4.5 mg/kg administered slowly (over a period of 60 seconds).

Alternatively, administer a dose of 1 to 2 mg/kg at a rate of 0.5 mg/kg/min.

( 2.2 ) — Intramuscular route : Initially, 6.5 to 13 mg/kg.

( 2.2 ) Maintenance of anesthesia: Increments of one-half to the full induction dose may be repeated as needed ( 2.2 ).

Adjust the dose according to the patient’s anesthetic needs and whether an additional anesthetic agent is employed.

( 2.2 ) Supplement to other anesthetic agents : The regimen of a reduced dose of KETALAR supplemented with diazepam can be used to produce balanced anesthesia by combination with other agents.

( 2.2 ) 2.1 Important Dosage and Administration Information KETALAR should be administered by or under the direction of physicians experienced in the administration of general anesthetics, maintenance of a patent airway, and oxygenation and ventilation.

Continuously monitor vital signs in patients receiving KETALAR.

Emergency airway equipment must be immediately available.

Do not administer the 100 mg/mL concentration of KETALAR intravenously without proper dilution [see Dosage and Administration ( 2.3 )] .

Must be used immediately after dilution.

While some degree of airway protection may be afforded due to active laryngeal-pharyngeal reflexes, vomiting and aspiration may occur with KETALAR.

KETALAR is not recommended for use in patients who have not followed nil per os guidelines.

Due to the potential for salivation during KETALAR administration, administer an antisialagogue prior to induction of anesthesia.

In individuals with a history of chronic ketamine use for off-label indications, there have been case reports of genitourinary pain that may be related to the ketamine treatment, not the underlying condition [see Adverse Reactions ( 6 )] .

Consider cessation of ketamine if genitourinary pain continues in the setting of other genitourinary symptoms.

2.2 Recommended Dosage and Administration The KETALAR dosage must be individualized and titrated to the desired clinical effect.

If a longer duration of effect is desired, additional increments can be administered intravenously or intramuscularly to maintain anesthesia.

However, a higher total dose will result in a longer time to complete recovery.

Induction of Anesthesia Intravenous Route: The initial dose of KETALAR administered intravenously may range from 1 mg/kg to 4.5 mg/kg.

The average amount required to produce 5 to 10 minutes of surgical anesthesia within 30 seconds following injection is 2 mg/kg.

Administer KETALAR slowly (i.e., over a period of 60 seconds).

Rapid administration may result in respiratory depression and enhanced vasopressor response.

The induction dose may be administered as an intravenous infusion at a rate of 0.5 mg/kg/min.

Intramuscular Route : The initial dose of KETALAR administered intramuscularly may range from 6.5 to 13 mg/kg.

A dose of 9 to 13 mg/kg usually produces surgical anesthesia within 3 to 4 minutes following injection, with the anesthetic effect usually lasting 12 to 25 minutes.

Administer a benzodiazepine, if clinically indicated, for the prevention of neuropsychological manifestations during emergence from anesthesia.

Maintenance of Anesthesia Adjust the maintenance dose according to the patient’s anesthetic needs and whether an additional anesthetic agent is administered.

Repeat increments of one-half to the full induction dose as needed for maintenance of anesthesia.

Purposeless and tonic-clonic movements of extremities may occur during the course of ketamine anesthesia.

These movements do not imply a light plane and are not indicative of the need for additional doses of the anesthetic.

KETALAR given by slow microdrip infusion technique at a dose of 0.1 to 0.5 mg/minute will maintain general anesthesia in adult patients induced with KETALAR.

Augment KETALAR with an intravenous benzodiazepine for the prevention of neuropsychological manifestations during emergence.

Supplement to Other Anesthetic Agents KETALAR can be administered to supplement other general and local anesthetic agents.

Continuously monitor patients for changes in respiratory and hemodynamic parameters.

A reduced dose of KETALAR can be used to produce balanced anesthesia when used in combination with other anesthetic agents.

2.3 Preparation of Dilution KETALAR is a clear, colorless sterile solution.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Discard if product is discolored or contains particulate matter.

Induction of Anesthesia : Do not intravenously inject the 100 mg/mL concentration of KETALAR without proper dilution.

Dilute KETALAR with an equal volume of either Sterile Water for injection, USP, 0.9% Sodium Chloride Injection, USP (Normal Saline), or 5% Dextrose in Water.

Use immediately after dilution.

Maintenance of Anesthesia : To prepare a dilute solution containing 1 mg of ketamine per mL, aseptically transfer 10 mL from a 50 mg per mL vial or 5 mL from a 100 mg per mL vial to 500 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (Normal Saline) and mix well.

The resultant solution will contain 1 mg of ketamine per mL.

Use immediately after dilution.

When fluid restriction is required, KETALAR can be added to a 250 mL infusion as described above to provide a KETALAR concentration of 2 mg/mL.

KETALAR 10 mg/mL vials are not recommended for dilution.

Cholecalciferol 3775 UNT / folate 1 MG Oral Capsule

DESCRIPTION

Zolate is an orally-administered (capsule) prescription folate product specifically formulated for the dietary management of patients with unique nutritional needs due to medical conditions and disease states requiring increased folate levels and specific Vitamin D supplementation levels.

HOW SUPPLIED

Zolate are clear gelatin capsules, and are supplied in bottles of 30 capsules.

INDICATIONS AND USAGE

Zolate is indicated for the distinct nutritional requirements of patients in need of folate and Vitamin D supplementation as determined by a licensed medical practitioner.

Zolate should be administered under the supervision of a licensed medical practitioner.

WARNING AND CAUTIONS

WARNINGS AND PRECAUTIONS Caution is recommended in patients with a history of bipolar illness, as mood elevation is possible in this population.

Patients taking anticonvulsant medications should also exercise caution before taking this product, as folate may (i) interfere with anticonvulsant medication, and/or (ii) lower seizure threshold.

Conversely, anticonvulsant medications may interfere with folate metabolism, although the exact mechanism of action is not clear or well understood.

Patients undergoing cancer treatment should consult their licensed medical practitioner for advice.

Folate alone is improper therapy in the treatment of pernicious anemia and other megaloblastic anemias where vitamin B12 is deficient.

Folate in doses above 0.1 mg daily may obscure pernicious anemia in that hematologic remission may occur while neurological manifestations progress.

DOSAGE AND ADMINISTRATION

One (1) capsule daily or as directed by a licensed medical practitioner.