Drug Intercation

Xopenex Concentrate 1.25 MG in 0.5 ML Inhalant Solution

Generic Name: LEVALBUTEROL HYDROCHLORIDE

Brand Name: Xopenex

Substance Name(s):
LEVALBUTEROL HYDROCHLORIDE

DRUG INTERACTIONS

7 Other short-acting sympathomimetic aerosol bronchodilators and adrenergic drugs: May potentiate effect.

( 7.1 ) Beta-blockers: May block bronchodilatory effects of beta-agonists and produce severe bronchospasm.

Patients with asthma should not normally be treated with beta-blockers.

( 7.2 ) Diuretic: May worsen electrocardiographic changes or hypokalemia associated with diuretic may worsen.

Consider monitoring potassium levels.

( 7.3 ) Digoxin: May decrease serum digoxin levels.

Consider monitoring digoxin levels.

( 7.4 ) Monoamine oxidase inhibitors (MAOs) or tricyclic antidepressants: May potentiate effect of albuterol on the cardiovascular system.

( 7.5 ) 7.1 Short-Acting Bronchodilators Avoid concomitant use of other short-acting sympathomimetic bronchodilators or epinephrine in patients being treated with XOPENEX Inhalation Solution.

If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.

7.2 Beta-blockers Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-adrenergic agonists such as XOPENEX Inhalation Solution, but may produce severe bronchospasm in asthmatic patients.

Therefore, patients with asthma should not normally be treated with beta-blockers.

However, under certain circumstances, e.g., prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma.

In this setting, cardioselective beta-blockers should be considered, although they should be administered with caution.

7.3 Diuretics The ECG changes or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop and thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded.

Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non-potassium-sparing diuretics.

Consider monitoring potassium levels.

7.4 Digoxin Mean decreases of 16% and 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of racemic albuterol, respectively, to normal volunteers who had received digoxin for 10 days.

The clinical significance of these findings for patients with obstructive airway disease who are receiving XOPENEX Inhalation Solution and digoxin on a chronic basis is unclear.

Nevertheless, it would be prudent to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and XOPENEX Inhalation Solution.

7.5 Monoamine Oxidase Inhibitors or Tricyclic Antidepressants XOPENEX Inhalation Solution should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of levalbuterol on the vascular system may be potentiated.

Consider alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants.

OVERDOSAGE

10 The expected symptoms with overdosage are those of excessive beta-adrenergic receptor stimulation and/or occurrence or exaggeration of any of the symptoms listed under Adverse Reactions ( 6 ) , e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min., arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and sleeplessness.

Hypokalemia also may occur.

As with all sympathomimetic medications, cardiac arrest and even death may be associated with the abuse of XOPENEX Inhalation Solution.

Treatment consists of discontinuation of XOPENEX Inhalation Solution together with appropriate symptomatic therapy.

The judicious use of a cardio selective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm.

There is insufficient evidence to determine if dialysis is beneficial for overdosage of XOPENEX Inhalation Solution.

DESCRIPTION

11 XOPENEX Inhalation Solution Concentrate is a sterile, clear, colorless, preservative-free solution of the hydrochloride salt of levalbuterol, the (R)-enantiomer of the drug substance racemic albuterol.

Levalbuterol HCl is a relatively selective beta 2 -adrenergic receptor agonist [see Clinical Pharmacology ( 12 ) ].

The chemical name for levalbuterol HCl is (R)-α 1 -[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol hydrochloride, and its established chemical structure is as follows: The molecular weight of levalbuterol HCl is 275.8, and its empirical formula is C 13 H 21 NO 3 •HCl.

It is a white to off-white, crystalline solid, with a melting point of approximately 187°C and solubility of approximately 180 mg/mL in water.

Levalbuterol HCl is the USAN modified name for (R)-albuterol HCl in the United States.

XOPENEX Inhalation Solution Concentrate is supplied in 0.5 mL unit-dose vials that must be diluted with normal saline before administration by nebulization.

Each 0.5 mL unit-dose vial contains 1.25 mg of levalbuterol (as 1.44 mg of levalbuterol HCl), sodium chloride to adjust tonicity, and hydrochloric acid to adjust the pH to 4.0 (3.3 to 4.5).

Chemical Structure

CLINICAL STUDIES

14 Adults and Adolescents ≥12 Years Old The safety and efficacy of XOPENEX Inhalation Solution were evaluated in a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 362 adult and adolescent patients 12 years of age and older, with mild-to-moderate asthma (mean baseline FEV 1 60% of predicted).

Approximately half of the patients were also receiving inhaled corticosteroids.

Patients were randomized to receive XOPENEX 0.63 mg, XOPENEX 1.25 mg, racemic albuterol sulfate 1.25 mg, racemic albuterol sulfate 2.5 mg, or placebo three times a day administered via a PARI LC Plus™ nebulizer and a Dura-Neb ® portable compressor.

Racemic albuterol delivered by a chlorofluorocarbon (CFC) metered-dose inhaler (MDI) was used on an as-needed basis as the rescue medication.

Efficacy, as measured by the mean percent change from baseline FEV 1 , was demonstrated for all active treatment regimens compared with placebo on day 1 and day 29.

On both day 1 (see Figure 1 ) and day 29 (see Figure 2 ), 1.25 mg of XOPENEX demonstrated the largest mean percent change from baseline FEV 1 compared with the other active treatments.

A dose of 0.63 mg of XOPENEX and 2.5 mg of racemic albuterol sulfate produced a clinically comparable mean percent change from baseline FEV 1 on both day 1 and day 29.

Figure 1: Mean Percent Change from Baseline FEV 1 on Day 1, Adults and Adolescents ≥12 years old Figure 2: Mean Percent Change from Baseline FEV 1 on Day 29, Adults and Adolescents ≥12 years old The mean time to onset of a 15% increase in FEV 1 over baseline for levalbuterol at doses of 0.63 mg and 1.25 mg was approximately 17 minutes and 10 minutes, respectively, and the mean time to peak effect for both doses was approximately 1.5 hours after 4 weeks of treatment.

The mean duration of effect, as measured by a >15% increase from baseline FEV 1 , was approximately 5 hours after administration of 0.63 mg of levalbuterol and approximately 6 hours after administration of 1.25 mg of levalbuterol after 4 weeks of treatment.

In some patients, the duration of effect was as long as 8 hours.

Figure 1 Figure 2 Children 6 to 11 Years Old A multicenter, randomized, double-blind, placebo- and active-controlled study was conducted in children with mild-to-moderate asthma (mean baseline FEV 1 73% of predicted) (n=316).

Following a 1-week placebo run-in, subjects were randomized to XOPENEX (0.31 or 0.63 mg), racemic albuterol (1.25 or 2.5 mg), or placebo, which were delivered three times a day for 3 weeks using a PARI LC Plus™ nebulizer and a Dura-Neb ® 3000 compressor.

Efficacy, as measured by mean peak percent change from baseline FEV 1 , was demonstrated for all active treatment regimens compared with placebo on day 1 and day 21.

Time profile FEV 1 curves for day 1 and day 21 are shown in Figure 3 and Figure 4 , respectively.

The onset of effect (time to a 15% increase in FEV 1 over test-day baseline) and duration of effect (maintenance of a >15% increase in FEV 1 over test-day baseline) of levalbuterol were clinically comparable to those of racemic albuterol.

Figure 3: Mean Percent Change from Baseline FEV 1 on Day 1, Children 6 to 11 Years of Age Figure 4: Mean Percent Change from Baseline FEV 1 on Day 21, Children 6 to 11 Years of Age Figure 3 Figure 4

HOW SUPPLIED

16 /STORAGE AND HANDLING XOPENEX (levalbuterol HCl) Inhalation Solution Concentrate ( foil pouch label color red ) is supplied in 0.5 mL unit-dose, low-density polyethylene (LDPE) vials as a clear, colorless, sterile, preservative-free, aqueous solution.

Each vial contains 1.25 mg of levalbuterol (as 1.44 mg of levalbuterol HCl) and is available in cartons of 30 (NDC 17478-171-30) individually pouched vials.

XOPENEX Inhalation Solution is also available in 3 mL vials in three different strengths of levalbuterol: 0.31 mg (NDC 17478-172-24), 0.63 mg (NDC 17478-173-24), and 1.25 mg (NDC 17478-174-24).

Store XOPENEX Inhalation Solution Concentrate in the protective foil pouch at 20º to 25°C (68º to 77°F) [see USP Controlled Room Temperature].

Protect from light and excessive heat.

Open the foil pouch just prior to administration.

Once the foil pouch is opened, the contents of the vial should be used immediately.

Discard any vial if the solution is not colorless.

Dilute XOPENEX (levalbuterol HCl) Inhalation Solution Concentrate with sterile normal saline before administration by nebulization.

GERIATRIC USE

8.5 Geriatric Use Clinical studies of XOPENEX Inhalation Solution did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.

Only 5 patients 65 years of age and older were treated with XOPENEX Inhalation Solution in a 4-week clinical study [see Clinical Pharmacology ( 12 ) and Clinical Studies ( 14 ) ] (n=2 for 0.63 mg and n=3 for 1.25 mg).

In these patients, bronchodilation was observed after the first dose on day 1 and after 4 weeks of treatment.

In general, patients 65 years of age and older should be started at a dose of 0.63 mg of XOPENEX Inhalation Solution.

If clinically warranted due to insufficient bronchodilator response, the dose of XOPENEX Inhalation Solution may be increased in elderly patients as tolerated, in conjunction with frequent clinical and laboratory monitoring, to the maximum recommended daily dose [see Dosage and Administration ( 2 ) ].

DOSAGE FORMS AND STRENGTHS

3 Inhalation Solution Concentrate: 0.5 mL unit-dose vials containing 1.25 mg of levalbuterol that must be diluted before use.

XOPENEX Inhalation Solution Concentrate is available in cartons of 30 individually pouched vials.

Inhalation Solution Concentrate (unit-dose vial for nebulization): 1.25 mg/0.5 mL Dilute before use.

( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Activation of beta 2 -adrenergic receptors on airway smooth muscle leads to the activation of adenylate cyclase and to an increase in the intracellular concentration of cyclic-3´, 5´-adenosine monophosphate (cyclic AMP).

The increase in cyclic AMP is associated with the activation of protein kinase A, which in turn inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in muscle relaxation.

Levalbuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles.

Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway.

Levalbuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges.

While it is recognized that beta 2 -adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10% to 50% of which are beta 2 -adrenergic receptors.

The precise function of these receptors has not been established [see Warnings and Precautions ( 5.4 ) ].

However, all beta-adrenergic agonist drugs can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.

INDICATIONS AND USAGE

1 XOPENEX (levalbuterol HCl) Inhalation Solution Concentrate is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with reversible obstructive airway disease.

XOPENEX (levalbuterol hydrochloride) Inhalation Solution Concentrate is a beta 2 -adrenergic agonist indicated for: Treatment or prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with reversible obstructive airway disease.

( 1 )

PEDIATRIC USE

8.4 Pediatric Use Pediatric Patients 6 Years of Age and Older The safety and efficacy of XOPENEX Inhalation Solution have been established in pediatric patients 6 years of age and older in an adequate and well-controlled clinical trial [see Adverse Reactions ( 6 ) and Clinical Studies ( 14 ) ].

Pediatric Patients less than 6 Years of Age XOPENEX Inhalation Solution is not indicated for pediatric patients less than 6 years of age.

Clinical trials with XOPENEX Inhalation Solution in this age group failed to meet the primary efficacy endpoint and demonstrated an increased number of asthma-related adverse reactions following chronic XOPENEX treatment.

XOPENEX Inhalation Solution was studied in 379 pediatric patients less than 6 years of age with asthma or reactive airway disease – (291patients 2 to 5 years of age, and 88 patients from birth to less than 2 years of age).

Efficacy and safety data for XOPENEX Inhalation Solution in this age group are primarily available from one 3-week, multicenter, randomized, double-blind, placebo-controlled study (Study 1) in 211 pediatric patients between the ages of 2 and 5 years, of whom 119 received XOPENEX Inhalation Solution.

Over the 3 week treatment period, there were no significant treatment differences in the Pediatric Asthma Questionnaire (PAQ) total score between groups receiving XOPENEX Inhalation Solution 0.31 mg, XOPENEX Inhalation Solution 0.63 mg, racemic albuterol, and placebo.

Additional safety data following chronic dosing is available from a 4-week, multicenter, randomized, modified-blind, placebo-controlled study (Study 2) of 196 patients between the ages of birth and 3 years, of whom 63 received open-label XOPENEX Inhalation Solution.

In these two studies, treatment-emergent asthma exacerbations or asthma-related adverse reactions and treatment discontinuations due to asthma occurred at a higher frequency in XOPENEX Inhalation-treated subjects compared to control ( Table 5 ).

Other adverse reactions were consistent with those observed in the clinical trial population of patients 6 years of age and older [see Adverse Reactions ( 6.1 )].

Table 5.

Asthma-related Adverse Reactions in 3- and 4-Week Clinical Trials in Children Birth to <6 Years of Age *Asthma exacerbation defined as worsening of asthma symptoms or pulmonary function that required any of the following: emergency department visit, hospitalization, therapeutic intervention with oral or parenteral steroids, unscheduled clinic visit to treat acute asthma symptoms **Includes the following Preferred Terms (whether considered by the investigator to be related or unrelated to drug): asthma, cough, hypoxia, status asthmaticus, tachypnea Asthma Exacerbations* n (%) Treatment Discontinuations due to Asthma n (%) Asthma-related Adverse Reactions** n (%) Study 1 XOPENEX 0.31 mg, n=58 6 (10) 4 (7) — XOPENEX 0.63 mg, n=51 7 (14) 6 (12) — Racemic albuterol, n=52 3 (6) 2 (4) — Placebo, n=50 2 (4) 2 (4) — Study 2 XOPENEX 0.31 mg, n=63 — 2 (3) 6 (10) Levalbuterol HFA inhalation aerosol, n=65 — 1 (2) 8 (12) Placebo, n=68 — 0 3 (4)

PREGNANCY

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma medication, including XOPENEX during pregnancy.

To enroll in MotherToBaby Pregnancy Studies’ Asthma & Pregnancy Study or for more information about the registry, call 1-877-311-8972 or visit www.mothertobaby.org/ongoing-study/asthma.

Risk Summary There are no adequate and well-controlled studies of XOPENEX Inhalation Solution Concentrate in pregnant women.

There are clinical considerations with the use of XOPENEX Inhalation Solution Concentrate in pregnant women [see Clinical Considerations ].

Following oral administration of levalbuterol HCl to pregnant rabbits, there was no evidence of teratogenicity at doses up to 25 mg/kg/day [approximately 108 times the maximum recommended human daily inhalation dose (MRHDID) of levalbuterol HCl for adults on a mg/m 2 basis]; however, racemic albuterol sulfate was teratogenic in mice (cleft palate) and rabbits (cranioschisis) at doses slightly higher than the human therapeutic range ( see Data ).

The estimated background risk of major birth defects and miscarriage for the indicated populations(s) are 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 Embryo/Fetal Risk In women with poorly or moderately controlled asthma, there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate.

Pregnant women should be closely monitored and medication adjusted as necessary to maintain optimal control.

Labor or Delivery Because of the potential for beta-adrenergic agonists to interfere with uterine contractility, the use of XOPENEX Inhalation Solution for the treatment of bronchospasm during labor should be restricted to those patients for whom the benefits clearly outweigh the risk.

XOPENEX Inhalation Solution has not been approved for the management of preterm labor.

The benefit-risk ratio when XOPENEX is administered for tocolysis has not been established.

Serious adverse reactions, including maternal pulmonary edema, have been reported during or following treatment of premature labor with beta 2 -agonists, including racemic albuterol.

Data Animal Data The oral administration of levalbuterol HCl to pregnant New Zealand White rabbits during the period of organogenesis found no evidence of teratogenicity at doses up to 25 mg/kg/day (approximately 108 times the MRHDID of levalbuterol HCl for adults on a mg/m 2 basis).

In a rat development study, racemic albuterol sulfate administered by inhalation did not produce any teratogenic effects at exposure approximately 63 times the MRHDID (on a mg/m 2 basis at a maternal dose of 10.5 mg/kg).

However, other developmental studies with the racemic albuterol sulfate, did result in teratogenic effects in mice and rabbits at doses slightly higher than the human therapeutic range.

In a rabbit developmental study, orally administered albuterol sulfate induced cranioschisis in 7 of 19 fetuses (37%) at approximately 215 times the MRHDID for adults (on a mg/m 2 basis at a maternal dose of 50 mg/kg).

In a mouse developmental study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at an exposure approximately 0.3 times the MRHDID for adults (on a mg/m 2 basis at a maternal dose of 0.25 mg/kg/day) and in 10 of 108 (9.3%) fetuses at approximately 3 times the MRHDID (on a mg/m 2 basis at a maternal dose of 2.5 mg/kg/day).

Similar effects were not observed at approximately 0.03 times the MRHDID for adults on a mg/m 2 basis at maternal dose of 0.025 mg/kg/day (i.e., less than the therapeutic dose).

Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol (positive control).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Life-threatening paradoxical bronchospasm may occur.

Discontinue XOPENEX Inhalation Solution immediately and treat with alternative therapy.

( 5.1 ) Need for more doses of XOPENEX Inhalation Solution than usual may be a sign of deterioration of asthma and requires reevaluation of treatment.

( 5.2 ) XOPENEX Inhalation Solution is not a substitute for corticosteroids.

( 5.3 ) Cardiovascular effects may occur.

Consider discontinuation of XOPENEX Inhalation Solution if these effects occur.

Use with caution in patients with underlying cardiovascular disorders.

( 5.4 ) Excessive use may be fatal.

Do not exceed recommended dose.

( 5.5 ) Immediate hypersensitivity reactions may occur.

Discontinue XOPENEX Inhalation Solution immediately.

( 5.6 ) Hypokalemia and changes in blood glucose may occur.

( 5.7 , 5.8 ) 5.1 Paradoxical Bronchospasm XOPENEX Inhalation Solution can produce paradoxical bronchospasm, which may be life-threatening.

If paradoxical bronchospasm occurs, XOPENEX Inhalation Solution should be discontinued immediately and alternative therapy instituted.

It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new vial.

5.2 Deterioration of Asthma Asthma may deteriorate acutely over a period of hours or chronically over several days or longer.

If the patient needs more doses of XOPENEX Inhalation Solution than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.

5.3 Use of Anti-Inflammatory Agents XOPENEX Inhalation Solution is not a substitute for corticosteroids.

The use of beta-adrenergic agonist alone may not be adequate to control asthma in many patients.

Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids, to the therapeutic regimen.

5.4 Cardiovascular Effects XOPENEX Inhalation Solution, like other beta-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients, as measured by heart rate, blood pressure, and symptoms.

Although such effects are uncommon after administration of XOPENEX Inhalation Solution at recommended doses, if they occur, the drug may need to be discontinued.

In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the t-wave, prolongation of the QTc interval, and ST segment depression.

The clinical significance of these findings is unknown.

Therefore, XOPENEX Inhalation Solution, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

5.5 Do Not Exceed Recommended Dose Do not exceed the recommended dose.

Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma.

The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected.

5.6 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration of levalbuterol or racemic albuterol.

Reactions have included urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema.

The potential for hypersensitivity must be considered in the clinical evaluation of patients who experience immediate hypersensitivity reactions while receiving XOPENEX Inhalation Solution.

5.7 Coexisting Conditions XOPENEX Inhalation Solution, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, hypertension, and cardiac arrhythmias; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines.

Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after the use of any beta-adrenergic bronchodilator.

Changes in blood glucose may occur.

Large doses of intravenous racemic albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.8 Hypokalemia As with other beta-adrenergic agonist medications, XOPENEX Inhalation Solution may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects.

The decrease is usually transient, not requiring supplementation.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( Patient Information and Instructions for Using XOPENEX Inhalation Solution Concentrate ).

Patients should be given the following information: Hypersensitivity Query patients about previously experienced hypersensitivity to levalbuterol or racemic albuterol and counsel patients to report any hypersensitivity reactions to their physician.

Frequency of Use Inform patients not to increase the dose or use XOPENEX Inhalation Solution more frequently than recommended without consulting their physician.

If patients find that treatment with XOPENEX Inhalation Solution becomes less effective for symptomatic relief, symptoms become worse, or they need to use the product more frequently than usual, they should seek medical attention immediately.

Paradoxical Bronchospasm Inform patients that XOPENEX Inhalation Solution can produce paradoxical bronchospasm.

Instruct patients to discontinue XOPENEX Inhalation Solution if paradoxical bronchospasm occurs.

Concomitant Drug Use Inform patients using XOPENEX Inhalation Solution, that other inhaled drugs and asthma medications should be taken only as directed by their physician.

Common Adverse Reactions Advise patients of the common adverse reactions of treatment with XOPENEX Inhalation Solution include palpitations, chest pain, fast heart rate, headache, dizziness, tremor and nervousness.

Pregnancy Advise patients who are pregnant or nursing to contact their physician about the use of XOPENEX Inhalation Solution.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma medication, including XOPENEX, during pregnancy.

To enroll in the Asthma & Pregnancy Study or for more information about the registry, call 1-877-311-8972 or visit www.mothertobaby.org/ongoing-study/asthma [see Use in Specific Populations ( 8.1 ) ].

General Information on Storage and Use Advise patients to dilute XOPENEX Inhalation Solution Concentrate with sterile normal saline before administration by nebulization.

Advise patients how to store XOPENEX Inhalation Solution Concentrate.

Store in the foil pouch between 20°C to 25°C (68°F to 77°F) protected from light and excessive heat.

Do not use after the expiration date stamped on the container.

Open the foil pouch just prior to administration.

Once the foil pouch is opened, use the contents of the vial immediately.

Discard any vial if the solution is not colorless.

Advise patients not to mix XOPENEX Inhalation Solution with other drugs in a nebulizer.

AKORN Distributed by: Akorn, Inc.

Lake Forest, IL 60045 Manufactured for: Oak Pharmaceuticals, Inc.

For customer service, call 1-800-932-5676.

To report adverse events, call 1-800-932-5676.

For medical information, call 1-800-932-5676.

XOPENEX is a registered trademark of Sunovion Pharmaceuticals Inc.

and is used under license.

XPA0N December 2018 PHARMACIST — DETACH HERE AND GIVE LEAFLET TO PATIENT ————————————————————————————————————

DOSAGE AND ADMINISTRATION

2 XOPENEX Inhalation Solution Concentrate is for oral inhalation only.

Dilute with sterile normal saline before administration.

Administer by nebulization using with a standard jet nebulizer (with a face mask or mouthpiece) connected to an air compressor.

Do not exceed recommended dose.

For dosages less than 1.25 mg, the non-concentrate (i.e., XOPENEX Inhalation Solution, 3 mL) formulation must be used.

FOR ORAL INHALATION ONLY ( 2 ) Dilute XOPENEX (levalbuterol hydrochloride) Inhalation Solution Concentrate with sterile normal saline before administration by nebulization.

Children 6 to 11 years old: 0.31 mg administered three times a day, by nebulization.

Routine dosing should not exceed 0.63 mg three times a day.

( 2 ) Adults and Adolescents ≥ 12 years old: 0.63 mg administered three times a day, every 6 to 8 hours, by nebulization.

The maximum recommended dose is 1.25 mg three times a day.

( 2 ) For use with a standard jet nebulizer (with a face mask or mouthpiece) connected to an air compressor.

( 2 ) Children 6 to 11 years old: The recommended dosage of XOPENEX Inhalation Solution for patients 6 to 11 years old is 0.31 mg administered three times a day, by nebulization.

Routine dosing should not exceed 0.63 mg three times a day.

Adults and Adolescents ≥ 12 years old: The recommended starting dosage of XOPENEX Inhalation Solution for patients 12 years of age and older is 0.63 mg administered three times a day, every 6 to 8 hours, by nebulization.

Patients 12 years of age and older with more severe asthma or patients who do not respond adequately to a dose of 0.63 mg of XOPENEX Inhalation Solution may benefit from a dosage of 1.25 mg three times a day.

Patients receiving the highest dose of XOPENEX Inhalation Solution should be monitored closely for adverse systemic effects, and the risks of such effects should be balanced against the potential for improved efficacy.

The use of XOPENEX Inhalation Solution can be continued as medically indicated to help control recurring bouts of bronchospasm.

During this time, most patients gain optimal benefit from regular use of the inhalation solution.

If a previously effective dosage regimen fails to provide the usual response this may be a marker of destabilization of asthma and requires reevaluation of the patient and the treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.

The drug compatibility (physical and chemical), efficacy, and safety of XOPENEX Inhalation Solution when mixed with other drugs in a nebulizer have not been established.

The safety and efficacy of XOPENEX Inhalation Solution have been established in clinical trials when administered using the PARI LC Jet™ and PARI LC Plus™ nebulizers, and the PARI Master ® Dura-Neb ® 2000 and Dura-Neb ® 3000 compressors.

The safety and efficacy of XOPENEX Inhalation Solution when administered using other nebulizer systems have not been established.

Cephalexin 250 MG Oral Capsule

Generic Name: CEPHALEXIN

Brand Name: Cephalexin

Substance Name(s):
CEPHALEXIN

DRUG INTERACTIONS

7 • Metformin: increased metformin concentrations.

Monitor for hypoglycemia.

(7.1) • Probenecid- The renal excretion of cephalexin capsules is inhibited by probenecid.

Co-administration of probenecid with cephalexin capsules is not recommended.

(7.2) • Administration of cephalexin capsules may result in a false-positive reaction for glucose in the urine (7.3).

7.1 Metformin Administration of cephalexin capsules with metformin results in increased plasma metformin concentrations and decreased renal clearance of metformin.

Careful patient monitoring and dose adjustment of metformin is recommended in patients concomitantly taking cephalexin capsules and metformin [ see Clinical Pharmacology (12.3) ] .

7.2 Probenecid The renal excretion of cephalexin capsules is inhibited by probenecid.

Co-administration of probenecid with cephalexin capsules is not recommended.

7.3 Interaction with Laboratory or Diagnostic Testing A false-positive reaction may occur when testing for the presence of glucose in the urine using Benedict’s solution or Fehling’s solution.

OVERDOSAGE

10 Symptoms of oral overdose may include nausea, vomiting, epigastric distress, diarrhea, and hematuria.

In the event of an overdose, institute general supportive measures.

Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of cephalexin.

DESCRIPTION

11 Cephalexin Capsules, USP are a semisynthetic cephalosporin antibacterial drug intended for oral administration.

It is 7-(D-α-Amino-α-phenylacetamido)-3-methyl-3-cephem-4-carboxylic acid monohydrate.

Cephalexin has the molecular formula C16H17N3O4S∙H2O and the molecular weight is 365.41.

Cephalexin has the following structural formula: Each capsule contains cephalexin monohydrate equivalent to 250 mg or 500 mg of cephalexin.

The capsules also contain colloidal silicon dioxide, D&C Yellow No.

10, FD&C Blue No.

2, gelatin, magnesium stearate, sodium starch glycolate, and titanium dioxide.

Cephalexin Capsules-formula

HOW SUPPLIED

16 /STORAGE AND HANDLING Cephalexin Capsules, USP are supplied as follows: • 250 mg Capsules, bottles of 100 with child-resistant closure NDC 0143-9898-01 • 250 mg Capsules, bottles of 500 NDC 0143-9898-05 • 500 mg Capsules, bottles of 100 with child-resistant closure NDC 0143-9897-01 • 500 mg Capsules, bottles of 500 NDC 0143-9897-05 Cephalexin Capsules, USP should be stored at 20º to 25ºC (68º to 77ºF) [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container using a child resistant closure.

GERIATRIC USE

8.5 Geriatric Use Of the 701 subjects in 3 published clinical studies of cephalexin, 433 (62%) were 65 and over.

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 patients.

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

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection [ see Warnings and Precautions (5.4) ].

DOSAGE FORMS AND STRENGTHS

3 Cephalexin Capsules USP, 250mg: a white to off-white powder filled into size 2 capsules (white opaque and dark green opaque) that are imprinted with identity code “J1” on the dark green opaque cap, and “J1” on the white opaque body in edible black ink.

Cephalexin Capsules USP, 500mg: a white to off-white powder filled into size 0 capsules (light green opaque and dark green opaque) that are imprinted with identity code “J2” on the dark green opaque cap, and “J2” on the light green opaque body in edible black ink.

Capsules: 250 mg, 500 mg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action Cephalexin is a cephalosporin antibacterial drug [see Microbiology (12.4)] .

INDICATIONS AND USAGE

1 Cephalexin capsules are a cephalosporin antibacterial drug indicated for the treatment of the following infections caused by susceptible isolates of designated bacteria: • Respiratory tract infection (1.1) • Otitis media (1.2) • Skin and skin structure infections (1.3) • Bone infections (1.4) • Genitourinary tract infections (1.5) To reduce the development of drug-resistant bacteria and maintain the effectiveness of cephalexin capsules and other antibacterial drugs, cephalexin capsules should be used only to treat infections that are proven or strongly suspected to be caused by bacteria.

(1.6) 1.1 Respiratory Tract Infections Cephalexin capsules are indicated for the treatment of respiratory tract infections caused by susceptible isolates of Streptococcus pneumoniae and Streptococcus pyogenes.

1.2 Otitis Media Cephalexin capsules are indicated for the treatment of otitis media caused by susceptible isolates of Streptococcus pneumoniae , Haemophilus influenzae , Staphylococcus aureus , Streptococcus pyogenes , and Moraxella catarrhalis.

1.3 Skin and Skin Structure Infections Cephalexin capsules are indicated for the treatment of skin and skin structure infections caused by susceptible isolates of the following Gram-positive bacteria: Staphylococcus aureus and Streptococcus pyogenes .

1.4 Bone Infections Cephalexin capsules are indicated for the treatment of bone infections caused by susceptible isolates of Staphylococcus aureus and Proteus mirabilis.

1.5 Genitourinary Tract Infections Cephalexin capsules are indicated for the treatment of genitourinary tract infections, including acute prostatitis, caused by susceptible isolates of Escherichia coli , Proteus mirabilis , and Klebsiella pneumoniae .

1.6 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of cephalexin capsules and other antibacterial drugs, cephalexin capsules should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria.

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

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

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of cephalexin capsules in pediatric patients was established in clinical trials for the dosages described in the dosage and administration section [ see Dosage and Administration (2.2) ] .

PREGNANCY

8.1 Pregnancy Risk Summary Available data from published epidemiologic studies and pharmacovigilance case reports over several decades with cephalosporin use, including cephalexin capsules use in pregnant women have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data).

Animal reproduction studies with mice and rats using oral doses of cephalexin that are 0.6- and 1.2-times the maximum recommended human dose (MRHD) based on body surface area during organogenesis revealed no evidence of harm to the fetus (see Data).

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% to 4% and 15% to 20%, respectively.

Data Human Data While available studies cannot definitively establish the absence of risk, published data from epidemiologic studies and postmarketing case reports over several decades have not identified a consistent association with cephalosporin use, including cephalexin capsules, during pregnancy, and major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups.

Animal Data In animal reproduction studies, pregnant mice and rats administered oral cephalexin doses of 250 or 500 mg/kg/day (approximately 0.6 and 1.2 times the MRHD) based on body surface area, respectively during the period of organogenesis showed no adverse effects on embryofetal development.

In a pre-and post-natal developmental toxicity study, pregnant rats that received oral doses of 250 or 500 mg/kg/day of cephalexin from Day 15 of pregnancy to litter Day 21 showed no adverse effects on parturition, litter size, or growth of offspring.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Serious hypersensitivity (anaphylactic) reactions : Prior to use, inquire regarding history of hypersensitivity to beta-lactam antibacterial drugs.

Discontinue the drug if signs or symptoms of an allergic reaction occur and institute supportive measures.

(5.1) • Clostridium difficile- associated diarrhea (CDAD) : Evaluate if diarrhea occurs.

(5.2) • Direct Coomb’s Test Seroconversion : If anemia develops during or after cephalexin therapy, evaluate for drug-induced hemolytic anemia.(5.3) • Seizure Potential : Use lower dose in patients with renal impairment.

(5.4) 5.1 Hypersensitivity Reactions Allergic reactions in the form of rash, urticaria, angioedema, anaphylaxis, erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis have been reported with the use of cephalexin capsules.

Before therapy with cephalexin capsules is instituted, inquire whether the patient has a history of hypersensitivity reactions to cephalexin, cephalosporins, penicillins, or other drugs.

Cross-hypersensitivity among beta-lactam antibacterial drugs may occur in up to 10% of patients with a history of penicillin allergy.

If an allergic reaction to cephalexin capsules occurs, discontinue the drug and institute appropriate treatment.

5.2 Clostridium difficile -Associated Diarrhea Clostridium difficile – associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cephalexin capsules, 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 .

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.

5.3 Direct Coombs’ Test Seroconversion Positive direct Coombs’ tests have been reported during treatment with the cephalosporin antibacterial drugs including cephalexin.

Acute intravascular hemolysis induced by cephalexin therapy has been reported.

If anemia develops during or after cephalexin therapy, perform a diagnostic work-up for drug-induced hemolytic anemia, discontinue cephalexin and institute appropriate therapy.

5.4 Seizure Potential Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced.

If seizures occur, discontinue cephalexin capsules.

Anticonvulsant therapy can be given if clinically indicated.

5.5 Prolonged Prothrombin Time Cephalosporins may be associated with prolonged prothrombin time.

Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antibacterial therapy, and patients receiving anticoagulant therapy.

Monitor prothrombin time in patients at risk and manage as indicated.

5.6 Development of Drug-Resistant Bacteria Prescribing cephalexin capsules in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Prolonged use of cephalexin capsules may result in the overgrowth of nonsusceptible organisms.

Careful observation of the patient is essential.

If superinfection occurs during therapy, appropriate measures should be taken.

DOSAGE AND ADMINISTRATION

2 Adults and patients at least 15 years of age The usual dose is 250 mg every 6 hours, but a dose of 500 mg every 12 hours may be administered (2.1) Pediatric patients (over 1 year of age) • Otitis media: 75 to 100 mg/kg in equally divided doses every 6 hours (2.2) • All other indications: 25 to 50 mg/kg given in equally divided doses (2.2) • In severe infections: 50 to 100 mg/kg may be administered in equally divided doses (2.2) • Duration of therapy ranges from 7 to14 days depending on the infection type and severity.

(2) • Dosage adjustment is required in patients with severe and end stage renal disease (ESRD) defined as creatinine clearance below 30 mL/min.

(2.3) 2.1 Adults and Pediatric Patients at Least 15 Years of Age The usual dose of oral cephalexin capsules is 250 mg every 6 hours, but a dose of 500 mg every 12 hours may be administered.

Treatment is administered for 7 to 14 days.

For more severe infections larger doses of oral cephalexin capsules may be needed, up to 4 grams daily in two to four equally divided doses.

2.2 Pediatric Patients (over 1 year of age) The recommended total daily dose of oral cephalexin capsules for pediatric patients is 25 to 50 mg/kg given in equally divided doses for 7 to 14 days.

In the treatment of β-hemolytic streptococcal infections, duration of at least 10 days is recommended.

In severe infections, a total daily dose of 50 to 100 mg/kg may be administered in equally divided doses.

For the treatment of otitis media, the recommended daily dose is 75 to 100 mg/kg given in equally divided doses.

2.3 Dosage Adjustments in Adult and Pediatric Patients at Least 15 Years of Age with Renal Impairment Administer the following dosing regimens for cephalexin capsules to patients with renal impairment [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6) ].

Table 1.

Recommended Dose Regimen for Patients with Renal Impairmen t Renal function Dose regimen recommendation Creatinine clearance ≥ 60 mL/min No dose adjustment Creatinine clearance 30 to 59 mL/min No dose adjustment; maximum daily dose should not exceed 1 g Creatinine clearance 15 to 29 mL/min 250 mg, every 8 hours or every 12 hours Creatinine clearance 5 to 14 mL/min not yet on dialysis* 250 mg, every 24 hours Creatinine clearance 1 to 4 mL/min not yet on dialysis* 250 mg, every 48 hours or every 60 hours *There is insufficient information to make dose adjustment recommendations in patients on hemodialysis.

potassium chloride 750 MG Microencapsulated Extended Release Oral

Generic Name: POTASSIUM CHLORIDE

Brand Name: Potassium Chloride

Substance Name(s):
POTASSIUM CHLORIDE

WARNINGS

Hyperkalemia [see OVERDOSAGE ]: In patients with impaired mechanisms for excreting potassium, the administration of potassium salts can produce hyperkalemia and cardiac arrest.

This occurs most commonly in patients given potassium by the intravenous route but may also occur in patients given potassium orally.

Potentially fatal hyperkalemia can develop rapidly and be asymptomatic.

The use of potassium salts in patients with chronic renal disease, or any other condition which impairs potassium excretion, requires particularly careful monitoring of the serum potassium concentration and appropriate dosage adjustment.

Interaction with Potassium–Sparing Diuretics Hypokalemia should not be treated by the concomitant administration of potassium salts and a potassium-sparing diuretic (e.g., spironolactone, triamterene, or amiloride) since the simultaneous administration of these agents can produce severe hyperkalemia.

Interaction with Renin-Angiotensin-Aldosterone System Inhibitors Drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) including angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), spironolactone, eplerenone, or aliskiren produce potassium retention by inhibiting aldosterone production.

Closely monitor potassium in patients receiving concomitant RAAS therapy.

Interaction with Nonsteroidal Anti-Inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAIDs) may produce potassium retention by reducing renal synthesis of prostaglandin E and impairing the renin-angiotensin system.

Closely monitor potassium in patients receiving concomitant NSAID therapy.

Gastrointestinal Lesions Solid oral dosage forms of potassium chloride can produce ulcerative and/or stenotic lesions of the gastrointestinal tract.

Based on spontaneous adverse reaction reports, enteric-coated preparations of potassium chloride are associated with an increased frequency of small bowel lesions (40-50 per 100,000 patient years) compared to sustained-release wax matrix formulations (less than one per 100,000 patient years).

Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric-coated products is not available.

Potassium chloride is a tablet formulated to provide an controlled rate of release of microencapsulated potassium chloride and thus to minimize the possibility of a high local concentration of potassium near the gastrointestinal wall.

Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after one week of solid oral potassium chloride therapy.

The ability of this model to predict events occurring in usual clinical practice is unknown.

Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms.

In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (i.e., 96 mEq per day in divided doses of potassium chloride administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying).

The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (Hemoccult testing).

The relevance of these findings to the usual conditions (i.e., non-fasting, no anticholinergic agent, smaller doses) under which controlled-release potassium chloride products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations.

Potassium chloride extended-release tablets should be discontinued immediately and the possibility of ulceration, obstruction, or perforation should be considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occurs.

Metabolic Acidosis Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing potassium salt such as potassium bicarbonate, potassium citrate, potassium acetate, or potassium gluconate.

DRUG INTERACTIONS

Drug Interactions Potassium-sparing diuretics, angiotensin-converting enzyme inhibitors [see WARNINGS ].

OVERDOSAGE

The administration of oral potassium salts to persons with normal excretory mechanisms for potassium rarely causes serious hyperkalemia.

However, if excretory mechanisms are impaired or if potassium is administered too rapidly intravenously, potentially fatal hyperkalemia can result [see CONTRAINDICATIONS and WARNINGS ].

It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum potassium concentration (6.5 to 8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of S-T segment, and prolongation of the QT-interval).

Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9 to 12 mEq/L).

Treatment measures for hyperkalemia include the following: Patients should be closely monitored for arrythmias and electrolyte changes.

Elimination of foods and medications containing potassium and of any agents with potassium-sparing properties such as potassium-sparing diuretics, ARBs, ACE inhibitors, NSAIDs, certain nutritional supplements and many others.

Intravenous calcium gluconate if the patient is at no risk or low risk of developing digitalis toxicity.

Intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10 to 20 units of crystalline insulin per 1,000 mL.

Correction of acidosis, if present, with intravenous sodium bicarbonate.

Use of exchange resins, hemodialysis or peritoneal dialysis.

In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum potassium concentration can produce digitalis toxicity.

The extended-release feature means that absorption and toxic effects may be delayed for hours.

Consider standard measures to remove any unabsorbed drug.

DESCRIPTION

Potassium chloride extended-release tablets, USP are an immediately dispersing extended-release oral dosage form of potassium chloride containing 750 mg of microencapsulated potassium chloride, USP equivalent to 10 mEq of potassium in a tablet.

Potassium chloride extended-release tablets, USP are an immediately dispersing extended-release oral dosage form of potassium chloride containing 1,550 mg of microencapsulated potassium chloride, USP equivalent to 20 mEq of potassium in a tablet.

These formulations are intended to slow the release of potassium so that the likelihood of a high localized concentration of potassium chloride within the gastrointestinal tract is reduced.

Potassium chloride extended-release tablets, USP are an electrolyte replenisher.

The chemical name of the active ingredient is potassium chloride, and the structural formula is KCl.

Potassium chloride, USP occurs as a white, granular powder or as colorless crystals.

It is odorless and has a saline taste.

Its solutions are neutral to litmus.

It is freely soluble in water and insoluble in alcohol.

Potassium chloride extended-release tablets, USP are a tablet formulation (not enteric-coated or wax matrix) containing individually microencapsulated potassium chloride crystals which disperse upon tablet disintegration.

In simulated gastric fluid at 37°C and in the absence of outside agitation, potassium chloride extended-release tablets, USP begins disintegrating into microencapsulated crystals within seconds and completely disintegrates within one minute.

The microencapsulated crystals are formulated to provide an extended-release of potassium chloride.

Inactive Ingredients: croscarmellose sodium, ethylcellulose and microcrystalline cellulose.

HOW SUPPLIED

Product: 50090-2257 NDC: 50090-2257-0 30 TABLET, EXTENDED RELEASE in a BOTTLE NDC: 50090-2257-1 100 TABLET, EXTENDED RELEASE in a BOTTLE NDC: 50090-2257-2 90 TABLET, EXTENDED RELEASE in a BOTTLE NDC: 50090-2257-3 60 TABLET, EXTENDED RELEASE in a BOTTLE

GERIATRIC USE

Geriatric Use Clinical studies of potassium chloride 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.

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

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection; and it may be useful to monitor renal function.

INDICATIONS AND USAGE

BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE POTASSIUM CHLORIDE PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT POTASSIUM PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.

For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxication and in patients with hypokalemic familial periodic paralysis.

If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia.

For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop, e.g., digitalized patients or patients with significant cardiac arrhythmias.

The use of potassium salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used.

Serum potassium should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases.

In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with potassium salts may be indicated.

PEDIATRIC USE

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

PREGNANCY

Pregnancy Animal reproduction studies have not been conducted with potassium chloride.

It is unlikely that potassium supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.

NUSRING MOTHERS

Nursing Mothers The normal potassium ion content of human milk is about 13 mEq per liter.

Since oral potassium becomes part of the body potassium pool, so long as body potassium is not excessive, the contribution of potassium chloride supplementation should have little or no effect on the level in human milk.

INFORMATION FOR PATIENTS

Information for Patients Physicians should consider reminding the patient of the following: To take each dose with meals and with a full glass of water or other liquid.

To take each dose without crushing, chewing or sucking the tablets.

If those patients are having difficulty swallowing whole tablets, they may try one of the following alternate methods of administration: a.

Break the tablet in half and take each half separately with a glass of water.

Prepare an aqueous (water) suspension as follows: Place the whole tablet(s) in approximately ½ glass of water (4 fluid ounces).

Allow approximately 2 minutes for the tablet(s) to disintegrate.

Stir for about half a minute after the tablet(s) has disintegrated.

Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.

Add another 1 fluid ounce of water, swirl, and consume immediately.

Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of potassium chloride that is not taken immediately should be discarded.

The use of other liquids for suspending potassium chloride is not recommended.

To take this medicine following the frequency and amount prescribed by the physician.

This is especially important if the patient is also taking diuretics and/or digitalis preparations.

To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding is noticed.

DOSAGE AND ADMINISTRATION

The usual dietary intake of potassium by the average adult is 50 to 100 mEq per day.

Potassium depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of potassium from the total body store.

Dosage must be adjusted to the individual needs of each patient.

The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day.

Doses of 40 to 100 mEq per day or more are used for the treatment of potassium depletion.

Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose.

Each potassium chloride extended-release tablet, USP 10 mEq provides 10 mEq of potassium.

Each potassium chloride extended-release tablet, USP 20 mEq provides 20 mEq of potassium.

Potassium chloride extended-release tablets, USP should be taken with meals and with a glass of water or other liquid.

This product should not be taken on an empty stomach because of its potential for gastric irritation [see WARNINGS ].

Patients having difficulty swallowing whole tablets may try one of the following alternate methods of administration: a.

Break the tablet in half and take each half separately with a glass of water.

Prepare an aqueous (water) suspension as follows: Place the whole tablet(s) in approximately ½ glass of water (4 fluid ounces).

Allow approximately 2 minutes for the tablet(s) to disintegrate.

Stir for about half a minute after the tablet(s) has disintegrated.

Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.

Add another 1 fluid ounce of water, swirl, and consume immediately.

Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of potassium chloride is not taken immediately should be discarded.

The use of other liquids for suspending potassium chloride is not recommended.

Chloramphenicol 100 MG/ML Injectable Solution

DESCRIPTION

Description IMPORTANT CONSIDERATIONS IN PRESCRIBING INJECTABLE CHLORAMPHENICOL SODIUM SUCCINATE.

CHLORAMPHENICOL SODIUM SUCCINATE IS INTENDED FOR INTRAVENOUS USE ONLY.

IT HAS BEEN DEMONSTRATED TO BE INEFFECTIVE WHEN GIVEN INTRAMUSCULARLY.

Chloramphenicol sodium succinate for injection must be hydrolyzed to its microbiologically active form, and there is a lag in achieving adequate blood levels compared with the base given intravenously.

The oral form of chloramphenicol is readily absorbed and adequate blood levels are achieved and maintained on the recommended dosage.

Patients started on intravenous chloramphenicol sodium succinate for injection should be changed to the oral form as soon as practicable.

Chloramphenicol is an antibiotic that is clinically useful for, and should be reserved for, serious infections caused by organisms susceptible to its antimicrobial effects when less potentially hazardous therapeutic agents are ineffective or contraindicated.

Sensitivity testing is essential to determine its indicated use, but may be performed concurrently with therapy initiated on clinical impression that one of the indicated conditions exists (see INDICATIONS AND USAGE section).

When reconstituted as directed, each vial contains a sterile solution equivalent to 100 mg of chloramphenicol per mL (1g/10mL).

Each gram (10 mL of a 10% solution) of chloramphenicol sodium succinate contains approximately 52 mg (2.25 mEq) of sodium.

The chemical name for chloramphenicol sodium succinate is D-threo-(-)-2, 2-Dichloro-N-[b- hydroxy-a-(hydroxymethyl)-pnitrophenethyl] acetamide a-(sodium succinate).

The empirical and structural formulas are: Formula1.jpg

HOW SUPPLIED

How Supplied Chloromycetin Sodium Succinate for Injection, USP is freeze-dried in the vial.

When reconstituted as directed, each vial contains a sterile solution equivalent to 100 mg of chloramphenicol per mL (1 g/10 mL).

Product No.

NDC No.

1115 63323-011-15 Available in packages of 10 vials.

Store between 20° and 25°C (68° and 77°F).

[See USP Controlled room Temperature].

Preservative Free.

APP Pharmaceuticals, LLC Schaumburg, IL 60173

INDICATIONS AND USAGE

Indications and Usage In accord with the concepts in the Warning Box and this section, chloramphenicolmust be used only in those serious infections for which less potentially dangerous drugs are ineffective or contraindicated.

However, chloramphenicol may be chosen to initiate antibiotic therapy on the clinical impression that one of the conditions below is believed to be present; in vitro sensitivity tests should be performed concurrently so that the drug may be discontinued as soon as possible if less potentially dangerous agents are indicated by such tests.

The decision to continue use of chloramphenicol rather than another antibiotic when both are suggested by in vitro studies to be effective against a specific pathogen should be based upon severity of the infection, susceptibility of the pathogen to the various antimicrobial drugs, efficacy of the various drugs in the infection, and the important additional concepts contained in the Warning Box above.

Acute infections caused by Salmonella typhi* It is not recommended for the routine treatment of the typhoid carrier state.

Serious infections caused by susceptible strains in accordance with the concepts expressed above: a) Salmonella species b) H.

influenzae, specially meningeal infections c) Rickettsia d) Lymphogranuloma-psittacosis group e) Various gram-negative bacteria causing bacteremia, meningitis, or other serious gram-negative infections f) Other susceptible organisms which have been demonstrated to be resistant to all other appropriate antimicrobial agents.

Cystic fibrosis regimens *In treatment of typhoid fever some authorities recommend that chloramphenicol be administered at therapeutic levels for 8 to 10 days after the patient has become afebrile to lessen the possibility of relapse.

BOXED WARNING

Boxed Warning WARNING Serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, and granulocytopenia) are known to occur after the administration of chloramphenicol.

In addition, there have been reports of aplastic anemia attributed to chloramphenicol which later terminated in leukemia.

Blood dyscrasias have occurred after both short-term and prolonged therapy with this drug.

Chloramphenicol must not be used when less potentially dangerous agents will be effective, as described in the INDICATIONS AND USAGE section.

It must not be used in the treatment of trivial infections or where it is not indicated, as in colds, influenza, infections of the throat; or as a prophylactic agent to prevent bacterial infections.

Precautions: It is essential that adequate blood studies be made during treatment with the drug.

While blood studies may detect early peripheral blood changes, such as leukopenia, reticulocytopenia, or granulocytopenia, before they become irreversible, such studies cannot be relied on to detect bone marrow depression prior to development of aplastic anemia.

To facilitate appropriate studies and observation during therapy, it is desirable that patients be hospitalized.

DOSAGE AND ADMINISTRATION

Dosage and Administration Chloramphenicol, like other potent drugs, should be prescribed at recommended doses known to have therapeutic activity.

Administration of 50 mg/kg/day in divided doses will produce blood levels of the magnitude to which the majority of susceptible microorganisms will respond.

As soon as feasible an oral dosage form of another appropriate antibiotic should be substituted for intravenous chloramphenicol sodium succinate.

The following method of administration is recommended: Intravenously as a 10% (100 mg/mL) solution to be injected over at least a one-minute interval.

This is prepared by the addition of 10 mL of an aqueous diluent such as water for injection or 5% dextrose injection.

Adults Adults should receive 50 mg/kg/day in divided doses at 6-hour intervals.

In exceptional cases patients with infections due to moderately resistant organisms may require increased dosage up to 100 mg/kg/day to achieve blood levels inhibiting the pathogen, but these high doses should be decreased as soon as possible.

Adults with impairment of hepatic or renal function or both may have reduced ability to metabolize and excrete the drug.

In instances of impaired metabolic processes, dosages should be adjusted accordingly.

(See discussion under Newborn Infants.) Precise control of concentration of the drug in the blood should be carefully followed in patients with impaired metabolic processes by the available microtechniques (information available on request).

Children Dosage of 50 mg/kg/day divided into 4 doses at 6-hour intervals yields blood levels in the range effective against most susceptible organisms.

Severe infections (eg, bacteremia or meningitis), especially when adequate cerebrospinal fluid concentrations are desired, may require dosage up to 100 mg/kg/day; however, it is recommended that dosage be reduced to 50 mg/kg/day as soon as possible.

Children with impaired liver or kidney function may retain excessive amounts of the drug.

Newborn Infants (See section titled “Gray Syndrome” under ADVERSE REACTIONS.) A total of 25 mg/kg/day in 4 equal doses at 6-hour intervals usually produces and maintains concentrations in blood and tissues adequate to control most infections for which the drug is indicated.

Increased dosage in these individuals, demanded by severe infections, should be given only to maintain the blood concentration within a therapeutically effective range.

After the first two weeks of life, full-term neonates ordinarily may receive up to a total of 50 mg/kg/day equally divided into 4 doses at 6-hour intervals.

These dosage recommendations are extremely important because blood concentration in all premature and full-term neonates under two weeks of age differs from that of other infants neonates.

This difference is due to variations in the maturity of the metabolic functions of the liver and the kidneys.

When these functions are immature (or seriously impaired in adults), high concentrations of the drug are found which tend to increase with succeeding doses.

Infants and Children with Immature Metabolic Processes In young infants and other pediatric patients in whom immature metabolic functions are suspected, a dose of 25 mg/kg/day will usually produce therapeutic concentrations of the drug in the blood.

In this group particularly, the concentration of the drug in the blood should be carefully followed by microtechniques.

(Information available on request.)

caffeine citrate 20 MG/ML Oral Solution

WARNINGS

During the double-blind, placebo-controlled clinical trial, 6 cases of necrotizing enterocolitis developed among the 85 infants studied (caffeine=46, placebo=39), with 3 cases resulting in death.

Five of the six patients with necrotizing enterocolitis were randomized to or had been exposed to caffeine citrate.

Reports in the published literature have raised a question regarding the possible association between the use of methylxanthines and development of necrotizing enterocolitis, although a causal relationship between methylxanthine use and necrotizing enterocolitis has not been established.

Therefore, as with all preterm infants, patients being treated with caffeine citrate should be carefully monitored for the development of necrotizing enterocolitis.

OVERDOSAGE

Following overdose, serum caffeine levels have ranged from approximately 24 mg/L (a post marketing spontaneous case report in which an infant exhibited irritability, poor feeding and insomnia) to 350 mg/L.

Serious toxicity has been associated with serum levels greater than 50 mg/L (see PRECAUTIONS-Laboratory Tests and DOSAGE AND ADMINISTRATION ).

Signs and symptoms reported in the literature after caffeine overdose in preterm infants include fever, tachypnea, jitteriness, insomnia, fine tremor of the extremities, hypertonia, opisthotonos, tonic-clonic movements, nonpurposeful jaw and lip movements, vomiting, hyperglycemia, elevated blood urea nitrogen, and elevated total leukocyte concentration.

Seizures have also been reported in cases of overdose.

One case of caffeine overdose complicated by development of intraventricular hemorrhage and long-term neurological sequelae has been reported.

Another case of caffeine citrate overdose (from New Zealand) of an estimated 600 mg caffeine citrate (approximately 322 mg/kg) administered over 40 minutes was complicated by tachycardia, ST depression, respiratory distress, heart failure, gastric distention, acidosis and a severe extravasation burn with tissue necrosis at the peripheral intravenous injection site.

No deaths associated with caffeine overdose have been reported in preterm infants.

Treatment of caffeine overdose is primarily symptomatic and supportive.

Caffeine levels have been shown to decrease after exchange transfusions.

Convulsions may be treated with intravenous administration of diazepam or a barbiturate such as pentobarbital sodium.

DESCRIPTION

Both caffeine citrate injection for intravenous administration and caffeine citrate oral solution are clear, colorless, sterile, non-pyrogenic, preservative-free, aqueous solutions adjusted to pH 4.7.

Each mL contains 20 mg caffeine citrate (equivalent to 10 mg of caffeine base) prepared in solution by the addition of 10 mg caffeine anhydrous, USP to 5 mg citric acid monohydrate, USP, 8.3 mg sodium citrate dihydrate, USP and Water for Injection, USP.

Caffeine, a central nervous system stimulant, is an odorless white crystalline powder or granule, with a bitter taste.

It is sparingly soluble in water and ethanol at room temperature.

The chemical name of caffeine is 3,7-dihydro-1,3,7-trimethyl-1 H -purine-2,6-dione.

In the presence of citric acid it forms caffeine citrate salt in solution.

The structural formula and molecular weight of caffeine citrate follows.

Caffeine citrate C 14 H 18 N 4 O 9 Mol.

Wt.

386.31 MM1

HOW SUPPLIED

Both caffeine citrate injection and caffeine citrate oral solution are available as clear, colorless, sterile, non-pyrogenic, preservative-free, aqueous solutions in 5 mL colorless glass vials.

The vials of caffeine citrate injection are sealed with gray rubber stopper and white flip off aluminum seal printed with “FOR INTRAVENOUS USE ONLY” in red.

The vials of caffeine citrate oral solution are sealed with gray rubber stopper and a dark blue matte finish, flip off tear off aluminum seal printed with “FOR ORAL USE ONLY – FLIP UP & TEAR” in white.

Both the injection and oral solution vials contain 3 mL solution at a concentration of 20 mg/mL caffeine citrate (60 mg/vial) equivalent to 10 mg/mL caffeine base (30 mg/vial).

Caffeine citrate injection, USP NDC 47335-289-40: 3 mL vial, individually packaged in a carton.

Caffeine citrate oral solution, USP NDC 47335-290-44: 3 mL vial (NOT CHILD-RESISTANT), 10 vials per white polypropylene child-resistant container.

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature].

Preservative free.

For single use only.

Discard unused portion.

ATTENTION PHARMACIST: Detach “Instructions for Use” from the package insert and dispense with caffeine citrate oral solution prescription.

INDICATIONS AND USAGE

INDICATIONS & USAGE Caffeine citrate injection and caffeine citrate oral solution are indicated for the short term treatment of apnea of prematurity in infants between 28 and <33 weeks gestational age.

DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION Prior to initiation of caffeine citrate, baseline serum levels of caffeine should be measured in infants previously treated with theophylline, since preterm infants metabolize theophylline to caffeine.

Likewise, baseline serum levels of caffeine should be measured in infants born to mothers who consumed caffeine prior to delivery, since caffeine readily crosses the placenta.

The recommended loading dose and maintenance doses of caffeine citrate follow.

Dose of Caffeine Citrate Volume Dose of Caffeine Citrate mg/kg Route Frequency Loading Dose 1 mL/kg 20 mg/kg Intravenous* (over 30 minutes) One Time Maintenance Dose 0.25 mL/kg 5 mg/kg Intravenous* (over 10 minutes) or Orally Every 24 hours** * using a syringe infusion pump ** beginning 24 hours after the loading dose NOTE THAT THE DOSE OF CAFFEINE BASE IS ONE-HALF THE DOSE WHEN EXPRESSED AS CAFFEINE CITRATE (e.g., 20 mg of caffeine citrate is equivalent to 10 mg of caffeine base).

Serum concentrations of caffeine may need to be monitored periodically throughout treatment to avoid toxicity.

Serious toxicity has been associated with serum levels greater than 50 mg/L.

Caffeine citrate injection and caffeine citrate oral solution should be inspected visually for particulate matter and discoloration prior to administration.

Vials containing discolored solution or visible particulate matter should be discarded.

To test for drug compatibility with common intravenous solutions or medications, 20 mL of caffeine citrate injection were combined with 20 mL of a solution or medication, with the exception of an Intralipid ® admixture, which was combined as 80 mL/80 mL.

The physical appearance of the combined solutions was evaluated for precipitation.

The admixtures were mixed for 10 minutes and then assayed for caffeine.

The admixtures were then continually mixed for 24 hours, with further sampling for caffeine assays at 2, 4, 8, and 24 hours.

Based on this testing, caffeine citrate injection, 60 mg/3 mL is chemically stable for 24 hours at room temperature when combined with the following test products.

Dextrose Injection, USP 5% 50% Dextrose Injection USP Intralipid ® 20% IV Fat Emulsion Aminosyn ® 8.5% Crystalline Amino Acid Solution Dopamine HCI Injection, USP 40 mg/mL diluted to 0.6 mg/mL with Dextrose Injection, USP 5% Calcium Gluconate Injection, USP 10% (0.465 mEq/Ca+2/mL) Heparin Sodium Injection, USP 1000 units/mL diluted to 1 unit/mL with Dextrose Injection, USP 5% Fentanyl Citrate Injection, USP 50 µg/mL diluted to 10 µg/mL with Dextrose Injection, USP 5%

Ketoprofen 50 MG Oral Capsule

WARNINGS

Cardiovascular Effects Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal.

Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs.

The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease.

However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate.

Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment.

The increase in CV thrombotic risk has been observed most consistently at higher doses.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible.

Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms.

Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.

The concurrent use of aspirin and an NSAID, such as ketoprofen, increases the risk of serious gastrointestinal (GI) events (see ).

Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.

NSAIDs are contraindicated in the setting of CABG (see CONTRAINDICATIONS ).

Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment.

In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients.

Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

Avoid the use of ketoprofen capsules in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events.

If ketoprofen capsules are used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

Hypertension NSAIDs, including ketoprofen capsules, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events.

Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs.

NSAIDs, including ketoprofen capsules, should be used with caution in patients with hypertension.

Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients.

In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs.

Use of ketoprofen may blunt the CV effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs)] (see DRUG INTERACTIONS ).

Avoid the use of ketoprofen capsules in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure.

If ketoprofen capsules are used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation NSAIDs, including ketoprofen capsules, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation, of the stomach, small intestine, or large intestine, which can be fatal.

These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs.

Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic.

Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year.

These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy.

However, even short-term therapy is not without risk.

NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding.

Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10 fold increased risk for developing a GI bleed compared to patients with neither of these risk factors.

Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status.

Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration.

Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected.

This should include discontinuation of the NSAID until a serious GI adverse event is ruled out.

For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.

Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion.

In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation.

Patients at greater risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors, and the elderly.

Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Advanced Renal Disease No information is available from controlled clinical studies regarding the use of ketoprofen capsules in patients with advanced renal disease.

Therefore, treatment with ketoprofen capsules is not recommended in these patients with advanced renal disease.

If ketoprofen capsule therapy must be initiated, close monitoring of the patient’s renal function is advisable.

Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to ketoprofen capsules.

Ketoprofen capsules should not be given to patients with the aspirin triad.

This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS , Preexisting Asthma ).

Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Skin Reactions NSAIDs, including ketoprofen capsules, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.

These serious events may occur without warning.

Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Pregnancy In late pregnancy, as with other NSAIDs, ketoprofen capsules should be avoided because they may cause premature closure of the ductus arteriosus.

DRUG INTERACTIONS

Drug Interactions The following drug interactions were studied with ketoprofen doses of 200 mg/day.

The possibility of increased interaction should be kept in mind when ketoprofen capsule doses greater than 50 mg as a single dose or 200 mg of ketoprofen per day are used concomitantly with highly bound drugs.

ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors.

This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.

Antacids Concomitant administration of magnesium hydroxide and aluminum hydroxide does not interfere with the rate or extent of the absorption of ketoprofen administered as ketoprofen capsules.

Aspirin Ketoprofen does not alter aspirin absorption; however, in a study of 12 normal subjects, concurrent administration of aspirin decreased ketoprofen protein binding and increased ketoprofen plasma clearance from 0.07 L/kg/h without aspirin to 0.11 L/kg/h with aspirin.

The clinical significance of these changes is not known; however, as with other NSAIDs, concomitant administration of ketoprofen and aspirin is not generally recommended because of the potential of increased adverse effects.

Diuretics NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients.

Hydrochlorothiazide, given concomitantly with ketoprofen, produces a reduction in urinary potassium and chloride excretion compared to hydrochlorothiazide alone.

Patients taking diuretics are at a greater risk of developing renal failure secondary to a decrease in renal blood flow caused by prostaglandin inhibition (see PRECAUTIONS ).

During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS , Renal Effects ), as well as to assure diuretic efficacy.

Digoxin In a study in 12 patients with congestive heart failure where ketoprofen and digoxin were concomitantly administered, ketoprofen did not alter the serum levels of digoxin.

Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance.

The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%.

These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID.

Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Methotrexate Ketoprofen, like other NSAIDs, may cause changes in the elimination of methotrexate leading to elevated serum levels of the drug and increased toxicity.

NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices.

This may indicate that they could enhance the toxicity of methotrexate.

Caution should be used when NSAIDs are administered concomitantly with methotrexate.

Probenecid Probenecid increases both free and bound ketoprofen by reducing the plasma clearance of ketoprofen to about one-third, as well as decreasing its protein binding.

Therefore, the combination of ketoprofen and probenecid is not recommended.

Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.

In a short-term controlled study in 14 normal volunteers, ketoprofen did not significantly interfere with the effect of warfarin on prothrombin time.

Bleeding from a number of sites may be a complication of warfarin treatment and GI bleeding a complication of ketoprofen treatment.

Because prostaglandins play an important role in hemostasis and ketoprofen has an effect on platelet function as well (see Drug/Laboratory Test Interactions , Effect on Blood Coagulation ), concurrent therapy with ketoprofen and warfarin requires close monitoring of patients on both drugs.

OVERDOSAGE

Signs and symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care.

Respiratory depression, coma, or convulsions have occurred following large ketoprofen overdoses.

Gastrointestinal bleeding, hypotension, hypertension, or acute renal failure may occur, but are rare.

Patients should be managed by symptomatic and supportive care following an NSAID overdose.

There are no specific antidotes.

Gut decontamination may be indicated in patients with symptoms seen within 4 hours or following a large overdose (5 to 10 times the usual dose).

This should be accomplished via emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) with a saline cathartic or sorbitol added to the first dose.

Forced diuresis, alkalinization of the urine, hemodialysis or hemoperfusion would probably not be useful due to ketoprofen’s high protein binding.

Case reports include twenty-six overdoses: 6 were in children, 16 in adolescents, and 4 in adults.

Five of these patients had minor symptoms (vomiting in 4, drowsiness in 1 child).

A 12-year-old girl had tonic-clonic convulsions 1 to 2 hours after ingesting an unknown quantity of ketoprofen and 1 or 2 tablets of acetaminophen with hydrocodone.

Her ketoprofen level was 1128 mg/L (56 times the upper therapeutic level of 20 mg/L) 3 to 4 hours post ingestion.

Full recovery ensued 18 hours after ingestion following management with intubation, diazepam, and activated charcoal.

A 45-year-old woman ingested twelve 200 mg extended-release ketoprofen capsules and 375 mL vodka, was treated with emesis and supportive measures 2 hours after ingestion, and recovered completely with her only complaint being mild epigastric pain.

DESCRIPTION

Ketoprofen capsules USP are a non-steroidal anti-inflammatory drug.

The chemical name for ketoprofen, USP is 2-(3-benzoylphenyl)-propionic acid with the following structural formula: C 16 H 14 O 3 M.W.

254.29 It has a pKa of 5.94 in methanol: water (3:1) and an n-octanol: water partition coefficient of 0.97 (buffer pH 7.4).

Ketoprofen, USP is a white or practically white, crystalline powder, melting at about 95°C.

It is freely soluble in ethanol, chloroform, acetone, ether and soluble in benzene and strong alkali, but practically insoluble in water at 20°C.

Ketoprofen capsules USP contain 50 mg or 75 mg of ketoprofen, USP for oral administration.

Inactive Ingredients Drug Product Lactose, magnesium stearate, and sodium starch glycolate.

Capsule Shell Constituents Gelatin, printing ink, sodium lauryl sulfate, titanium dioxide, D&C Red #28, and FD&C Blue #1.

ketoprofen structural formula

CLINICAL STUDIES

Clinical Trials Rheumatoid Arthritis and Osteoarthritis The efficacy of ketoprofen has been demonstrated in patients with rheumatoid arthritis and osteoarthritis.

In other trials, ketoprofen demonstrated effectiveness comparable to aspirin, ibuprofen, naproxen, piroxicam, diclofenac, and indomethacin.

In some of these studies there were more dropouts due to gastrointestinal side effects among patients on ketoprofen than among patients on other NSAIDs.

In studies with patients with rheumatoid arthritis, ketoprofen was administered in combination with gold salts, antimalarials, low-dose methotrexate, d-penicillamine, and/or corticosteroids with results comparable to those seen with control non-steroidal drugs.

Management of Pain The effectiveness of immediate-release ketoprofen capsules as a general-purpose analgesic has been studied in standard pain models which have shown the effectiveness of doses of 25 to 150 mg.

Doses of 25 mg were superior to placebo.

Doses larger than 25 mg generally could not be shown to be significantly more effective, but there was a tendency toward faster onset and greater duration of action with 50 mg, and, in the case of dysmenorrhea, a significantly greater effect overall with 75 mg.

Doses greater than 50 to 75 mg did not have increased analgesic effect.

Studies in postoperative pain have shown that ketoprofen in doses of 25 to 100 mg was comparable to 650 mg of acetaminophen with 60 mg of codeine, or 650 mg of acetaminophen with 10 mg of oxycodone.

Ketoprofen tended to be somewhat slower in onset; peak pain relief was about the same and the duration of the effect tended to be 1 to 2 hours longer, particularly with the higher doses of ketoprofen.

HOW SUPPLIED

Ketoprofen capsules USP are available as follows: 50 mg: Blue cap and light blue body, imprinted “93” over “3193” on the cap and on the body, in bottles of, 20 Capsules NDC# 68788-6400-2 30 Capsules NDC# 68788-6400-3 60 Capsules NDC# 68788-6400-6 90 Capsules NDC# 68788-6400-9 100 Capsules NDC# 68788-6400-1 120 Capsules NDC# 68788-6400-8 Keep tightly closed.

Store 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, with a child-resistant closure (as required).

Distributed By: TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454 Rev.

L 7/2015 Repackaged By: Preferred Pharmaceuticals Inc

GERIATRIC USE

Geriatric Use As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).

In pharmacokinetic studies, ketoprofen clearance was reduced in older patients receiving ketoprofen capsules, compared with younger patients.

Peak ketoprofen concentrations and free drug AUC were increased in older patients (see Special Populations ).

The glucuronide conjugate of ketoprofen, which can serve as a potential reservoir for the parent drug, is known to be substantially excreted by the kidney.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection.

It is recommended that the initial dosage of ketoprofen capsules should be reduced for patients over 75 years of age and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION ).

In addition, the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Elderly patients may be more sensitive to the antiprostaglandin effects of NSAIDs (on the gastrointestinal tract and kidneys) than younger patients (see WARNINGS and PRECAUTIONS ).

In particular, elderly or debilitated patients who receive NSAID therapy seem to tolerate gastrointestinal ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this population.

Therefore, caution should be exercised in treating the elderly, and when individualizing their dosage, extra care should be taken when increasing the dose (see DOSAGE AND ADMINISTRATION ).

In ketoprofen capsule clinical studies involving a total of 1540 osteoarthritis or rheumatoid arthritis patients, 369 (24%) were ≥ 65 years of age, and 92 (6%) were ≥ 75 years of age.

For ketoprofen capsule acute pain studies, 23 (5%) of 484 patients were ≥ 60 years of age.

No overall differences in effectiveness were observed between these patients and younger patients.

INDICATIONS AND USAGE

Carefully consider the potential benefits and risks of ketoprofen capsules USP and other treatment options before deciding to use ketoprofen capsules USP.

Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ).

Ketoprofen capsules USP are indicated for the management of the signs and symptoms of rheumatoid arthritis and osteoarthritis.

Ketoprofen capsules USP are indicated for the management of pain.

Ketoprofen capsules USP are also indicated for treatment of primary dysmenorrhea.

PEDIATRIC USE

Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 have not been established.

PREGNANCY

Pregnancy Teratogenic Effects Pregnancy category C In teratology studies ketoprofen administered to mice at doses up to 12 mg/kg/day (36 mg/m 2 /day) and rats at doses up to 9 mg/kg/day (54 mg/m 2 /day), the approximate equivalent of 0.2 times the maximum recommended therapeutic dose of 185 mg/m 2 /day, showed no teratogenic or embryotoxic effects.

In separate studies in rabbits, maternally toxic doses were associated with embryotoxicity but not teratogenicity.

However, animal reproduction studies are not always predictive of human response.

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

Ketoprofen capsules should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.

NUSRING MOTHERS

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

Data on secretion in human milk after ingestion of ketoprofen do not exist.

In rats, ketoprofen at doses of 9 mg/kg (54 mg/m 2 /day; approximately 0.3 times the maximum human therapeutic dose) did not affect perinatal development.

Upon administration to lactating dogs, the milk concentration of ketoprofen was found to be 4 to 5% of the plasma drug level.

As with other drugs that are excreted in milk, ketoprofen is not recommended for use in nursing mothers.

BOXED WARNING

Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal.

This risk may occur early in treatment and may increase with duration of use (see WARNINGS and PRECAUTIONS ).

• Ketoprofen capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS and WARNINGS ).

Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal.

These events can occur at any time during use and without warning symptoms.

Elderly patients are at greater risk for serious gastrointestinal (GI) events (see WARNINGS ).

INFORMATION FOR PATIENTS

Information for Patients Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy.

Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately (see WARNINGS ).

Ketoprofen capsules, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death.

Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis.

Patients should be apprised of the importance of this follow-up (see WARNINGS , Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation ).

Ketoprofen capsules, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death.

Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms.

Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.

Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see WARNINGS ).

Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms).

If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.

Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat).

If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS ).

In late pregnancy, as with other NSAIDs, ketoprofen capsules should be avoided because they may cause premature closure of the ductus arteriosus.

NSAIDs are often essential agents in the management of arthritis and have a major role in the treatment of pain, but they also may be commonly employed for conditions which are less serious.

Physicians may wish to discuss with their patients the potential risks (see WARNINGS , PRECAUTIONS , and ADVERSE REACTIONS ) and likely benefits of NSAID treatment, particularly when the drugs are used for less serious conditions where treatment without NSAIDs may represent an acceptable alternative to both the patient and physician.

Because aspirin causes an increase in the level of unbound ketoprofen, patients should be advised not to take aspirin while taking ketoprofen (see Drug Interactions ).

It is possible that minor adverse symptoms of gastric intolerance may be prevented by administering ketoprofen capsules with antacids, food, or milk.

Because food and milk do affect the rate but not the extent of absorption (see CLINICAL PHARMACOLOGY ), physicians may want to make specific recommendations to patients about when they should take ketoprofen in relation to food and/or what patients should do if they experience minor GI symptoms associated with ketoprofen therapy.

DOSAGE AND ADMINISTRATION

Carefully consider the potential benefits and risks of ketoprofen capsules and other treatment options before deciding to use ketoprofen capsules.

Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ).

After observing the response to initial therapy with ketoprofen capsules, the dose and frequency should be adjusted to suit an individual patient’s needs.

Concomitant use of ketoprofen capsules and ketoprofen extended-release capsules is not recommended.

If minor side effects appear, they may disappear at a lower dose which may still have an adequate therapeutic effect.

If well tolerated but not optimally effective, the dosage may be increased.

Individual patients may show a better response to 300 mg of ketoprofen capsules daily as compared to 200 mg, although in well-controlled clinical trials patients on 300 mg did not show greater mean effectiveness.

They did, however, show an increased frequency of upper- and lower-GI distress and headaches.

It is of interest that women also had an increased frequency of these adverse effects compared to men.

When treating patients with 300 mg/day, the physician should observe sufficient increased clinical benefit to offset potential increased risk.

In patients with mildly impaired renal function, the maximum recommended total daily dose of ketoprofen capsules is 150 mg.

In patients with a more severe renal impairment (GFR less than 25 mL/min/1.73 m 2 or end-stage renal impairment), the maximum total daily dose of ketoprofen capsules should not exceed 100 mg.

In elderly patients, renal function may be reduced with apparently normal serum creatinine and/or BUN levels.

Therefore, it is recommended that the initial dosage of ketoprofen capsules should be reduced for patients over 75 years of age (see Geriatric Use ).

It is recommended that for patients with impaired liver function and serum albumin concentration less than 3.5 g/dL, the maximum initial total daily dose of ketoprofen capsules should be 100 mg.

All patients with metabolic impairment, particularly those with both hypoalbuminemia and reduced renal function, may have increased levels of free (biologically active) ketoprofen and should be closely monitored.

The dosage may be increased to the range recommended for the general population, if necessary, only after good individual tolerance has been ascertained.

Because hypoalbuminemia and reduced renal function both increase the fraction of free drug (biologically active form), patients who have both conditions may be at greater risk of adverse effects.

Therefore, it is recommended that such patients also be started on lower doses of ketoprofen capsules and closely monitored.

Rheumatoid Arthritis and Osteoarthritis The recommended starting dose of ketoprofen capsules in otherwise healthy patients is 75 mg three times or 50 mg four times a day.

Smaller doses of ketoprofen capsules should be utilized initially in small individuals or in debilitated or elderly patients.

The recommended maximum daily dose of ketoprofen capsules is 300 mg/day.

Dosages higher than 300 mg/day of ketoprofen capsules are not recommended because they have not been studied.

Concomitant use of ketoprofen capsules and ketoprofen extended-release capsules is not recommended.

Relatively smaller people may need smaller doses.

As with other non-steroidal anti-inflammatory drugs, the predominant adverse effects of ketoprofen are gastrointestinal.

To attempt to minimize these effects, physicians may wish to prescribe that ketoprofen capsules be taken with antacids, food, or milk.

Although food delays the absorption of ketoprofen capsules (see CLINICAL PHARMACOLOGY ), in most of the clinical trials ketoprofen was taken with food or milk.

Physicians may want to make specific recommendations to patients about when they should take ketoprofen capsules in relation to food and/or what patients should do if they experience minor GI symptoms associated with ketoprofen capsules.

Management of Pain and Dysmenorrhea The usual dose of ketoprofen capsules recommended for mild-to-moderate pain and dysmenorrhea is 25 to 50 mg every 6 to 8 hours as necessary.

A smaller dose should be utilized initially in small individuals, in debilitated or elderly patients, or in patients with renal or liver disease (see PRECAUTIONS ).

A larger dose may be tried if the patient’s response to a previous dose was less than satisfactory, but doses above 75 mg have not been shown to give added analgesia.

Daily doses above 300 mg are not recommended because they have not been adequately studied.

Because of its typical non-steroidal anti-inflammatory drug-side-effect profile, including as its principal adverse effect GI side effects (see WARNINGS and ADVERSE REACTIONS ), higher doses of ketoprofen capsules should be used with caution and patients receiving them observed carefully.

ascorbic acid 100 MG / biotin 0.3 MG / calcium carbonate 100 MG / calcium pantothenate 7 MG / folic acid 1 MG / niacin 25 MG / pyridoxine HCl 30 MG / riboflavin 5 MG / succinic acid 150 MG / thiamine HCl 5 MG / vitamin b 12 0.01 MG Oral Tablet

Generic Name: IRON, FOLIC ACID, VITAMIN/MINERAL SUPPLEMENT

Brand Name: IROSPAN 24/6

DESCRIPTION

IROSPAN TABLET : Each light blue capsule-shaped film coated tablet has a pleasant sweet flavor with WC002 imprinted on one side.

SUCCINIC ACID TABLET : Each white round film coated tablet has a pleasant sweet flavor with WC imprinted on one side.

HOW SUPPLIED

How Supplied IROSPAN® 24/6 tablets for oral administration are available in four child resistant blister cards containing 30 tablets (24 light blue tablets and 6 white tablets) (NDC 50967-126-30)

RECENT MAJOR CHANGES

INDICATIONS AND USAGE

INDICATION AND USAGE: IROSPAN 24/6 is indicated for the treatment of all anemias that are responsive to oral iron therapy.

These include: hypochromic anemia associated with pregnancy, chronic and/or acute blood loss, metabolic disease, post-surgical convalescence, and dietary needs.

BOXED WARNING

WARNING: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6.

KEEP THIS PRODUCT OUT OF THE REACH OF CHILDREN.

In case of accidental overdose, call a doctor or poison control center immediately.

DOSAGE AND ADMINISTRATION

Dosage and Administration Usual adult dosage is 1 tablet daily or as directed by a physician.

The IROSPAN® carton contains a 30 day course of iron therapy that consists of 24 light blue tablets and 6 white tablets.

Take 1 light blue tablet daily for 24 days, followed by 1 white tablet daily for 6 days.

After the 30 tablets have been taken, a new course may be started if prescribed.

Cefixime 40 MG/ML Oral Suspension

Generic Name: CEFIXIME

Brand Name: Cefixime

Substance Name(s):
CEFIXIME

DRUG INTERACTIONS

7 Elevated carbamazepine levels have been reported in postmarketing experience when cefixime is administered concomitantly.

(7.1) Increased prothrombin time, with or without clinical bleeding, has been reported when cefixime is administered concomitantly with warfarin and anticoagulants.

(7.2) 7.1 Carbamazepine Elevated carbamazepine levels have been reported in postmarketing experience when cefixime is administered concomitantly.

Drug monitoring may be of assistance in detecting alterations in carbamazepine plasma concentrations.

7.2 Warfarin and Anticoagulants Increased prothrombin time, with or without clinical bleeding, has been reported when cefixime is administered concomitantly.

7.3 Drug/Laboratory Test Interactions A false-positive reaction for ketones in the urine may occur with tests using nitroprusside but not with those using nitroferricyanide.

The administration of cefixime may result in a false-positive reaction for glucose in the urine using Clinitest ®** , Benedict’s solution, or Fehling’s solution.

It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix ®** or TesTape ®** ) be used.

A false-positive direct Coombs test has been reported during treatment with other cephalosporins; therefore, it should be recognized that a positive Coombs test may be due to the drug.

** Clinitest ® and Clinistix ® are registered trademarks of Ames Division, Miles Laboratories, Inc.

Tes-Tape ® is a registered trademark of Eli Lilly and Company.

OVERDOSAGE

10 Gastric lavage may be indicated; otherwise, no specific antidote exists.

Cefixime is not removed in significant quantities from the circulation by hemodialysis or peritoneal dialysis.

Adverse reactions in small numbers of healthy adult volunteers receiving single doses up to 2 g of cefixime did not differ from the profile seen in patients treated at the recommended doses.

DESCRIPTION

11 Cefixime is a semisynthetic, cephalosporin antibacterial for oral administration.

Chemically, it is ( 6R,7R )-7-[2-(2-Amino-4-thiazolyl)glyoxylamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, 7 2 -( Z )-[ O -(carboxy methyl) oxime] trihydrate.

Molecular weight = 507.50 as the trihydrate.

Chemical Formula is C 16 H 15 N 5 O 7 S 2 .3H 2 O.

The structural formula for cefixime is: Inactive ingredients contained in cefixime powder for oral suspension USP are: colloidal silicon dioxide, strawberry guarana flavor, sucrose, and xanthan gum.

Chemical Structure

CLINICAL STUDIES

14 Comparative clinical trials of otitis media were conducted in nearly 400 children between the ages of 6 months to 10 years.

Streptococcus pneumoniae was isolated from 47% of the patients, Haemophilus influenzae from 34%, Moraxella catarrhalis from 15% and S.

pyogenes from 4%.

The overall response rate of Streptococcus pneumoniae to cefixime was approximately 10% lower and that of Haemophilus influenzae or Moraxella catarrhalis approximately 7% higher (12% when beta-lactamase positive isolates of H.

influenzae are included) than the response rates of these organisms to the active control drugs.

In these studies, patients were randomized and treated with either cefixime at dose regimens of 4 mg/kg twice a day or 8 mg/kg once a day, or with a comparator.

Sixty-nine to 70% of the patients in each group had resolution of signs and symptoms of otitis media when evaluated 2 to 4 weeks post-treatment, but persistent effusion was found in 15% of the patients.

When evaluated at the completion of therapy, 17% of patients receiving cefixime and 14% of patients receiving effective comparative drugs (18% including those patients who had Haemophilus influenzae resistant to the control drug and who received the control antibacterial drug) were considered to be treatment failures.

By the 2 to 4 week follow-up, a total of 30% to 31% of patients had evidence of either treatment failure or recurrent disease.

(a) Number eradicated/number isolated.

(b) An additional 20 beta-lactamase positive isolates of Haemophilus influenzae were isolated, but were excluded from this analysis because they were resistant to the control antibacterial drug.

In nineteen of these, the clinical course could be assessed and a favorable outcome occurred in 10.

When these cases are included in the overall bacteriological evaluation of therapy with the control drugs, 140/185 (76%) of pathogens were considered to be eradicated.

Bacteriological Outcome of Otitis Media at Two to Four Weeks Post-Therapy Based on Repeat Middle Ear Fluid Culture or Extrapolation from Clinical Outcome Organism Cefixime(a) 4 mg/kg BID Cefixime(a) 8 mg/kg QD Control(a) drugs Streptococcus pneumoniae 48/70 (69%) 18/22 (82%) 82/100 (82%) Haemophilus influenzae beta-lactamase negative 24/34 (71%) 13/17 (76%) 23/34 (68%) Haemophilus influenzae beta-lactamase positive 17/22 (77%) 9/12 (75%) 1/1 (b) Moraxella catarrhalis 26/31 (84%) 5/5 18/24 (75%) S.

pyogenes 5/5 3/3 6/7 All Isolates 120/162 (74%) 48/59 (81%) 130/166 (78%)

HOW SUPPLIED

16 /STORAGE AND HANDLING Cefixime for oral suspension USP 100 mg/5 mL is off-white to pale yellow colored powder – Each 5 mL of reconstituted off-white to pale yellow, strawberry flavored suspension contains cefixime trihydrate equivalent to 100 mg cefixime.

50 mL Bottles NDC 65862-751-50 100 mL Bottles NDC 65862-751-01 Cefixime for oral suspension USP 200 mg/5 mL is off-white to pale yellow colored powder – Each 5 mL of reconstituted off-white to pale yellow, strawberry flavored suspension contains cefixime trihydrate equivalent to 200 mg cefixime.

50 mL Bottles NDC 65862-752-50 75 mL Bottles NDC 65862-752-75 Storage Prior to Reconstitution : Store drug powder at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

After Reconstitution : Store at room temperature or under refrigeration.

Shake well before using.

Discard unused portion after 14 days.

Keep tightly closed.

GERIATRIC USE

8.5 Geriatric Use Clinical studies did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently than younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

A pharmacokinetic study in the elderly detected differences in pharmacokinetic parameters [see Clinical Pharmacology (12.3) ] .

These differences were small and do not indicate a need for dosage adjustment of the drug in the elderly.

DOSAGE FORMS AND STRENGTHS

3 Cefixime is available for oral administration in the following strengths: Powder for oral suspension, when reconstituted, provides either 100 mg/5 mL or 200 mg/5 mL of cefixime as trihydrate.

The powder has an off-white to pale yellow color and is strawberry flavored.

Oral Suspension: 100 mg/5 mL and 200 mg/5 mL (3)

MECHANISM OF ACTION

12.1 Mechanism of Action Cefixime is a semisynthetic cephalosporin antibacterial drug [see Microbiology (12.4) ].

INDICATIONS AND USAGE

1 Cefixime for oral suspension is a cephalosporin antibacterial drug indicated in the treatment of adults and pediatric patients six months and older with the following infections: Uncomplicated Urinary Tract Infections (1.1) Otitis Media (1.2) Pharyngitis and Tonsillitis (1.3) Acute Exacerbations of Chronic Bronchitis (1.4) Uncomplicated Gonorrhea (cervical/urethral) (1.5) To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefixime for oral suspension and other antibacterial drugs, cefixime for oral suspension should be used only to treat infections that are proven or strongly suspected to be caused by bacteria.

(1.6) 1.1 Uncomplicated Urinary Tract Infections Cefixime for oral suspension is indicated in the treatment of adults and pediatric patients six months of age or older with uncomplicated urinary tract infections caused by susceptible isolates of Escherichia coli and Proteus mirabilis .

1.2 Otitis Media Cefixime for oral suspension is indicated in the treatment of adults and pediatric patients six months of age or older with otitis media caused by susceptible isolates of Haemophilus influenzae , Moraxella catarrhalis , and Streptococcus pyogenes.

(Efficacy for Streptococcus pyogenes in this organ system was studied in fewer than 10 infections.) Note: For patients with otitis media caused by Streptococcus pneumoniae , overall response was approximately 10% lower for cefixime than for the comparator [see Clinical Studies (14) ].

1.3 Pharyngitis and Tonsillitis Cefixime for oral suspension is indicated in the treatment of adults and pediatric patients six months of age or older with pharyngitis and tonsillitis caused by susceptible isolates of Streptococcus pyogenes.

(Note: Penicillin is the usual drug of choice in the treatment of Streptococcus pyogenes infections.

Cefixime for oral suspension is generally effective in the eradication of Streptococcus pyogenes from the nasopharynx; however, data establishing the efficacy of cefixime for oral suspension in the subsequent prevention of rheumatic fever is not available.) 1.4 Acute Exacerbations of Chronic Bronchitis Cefixime for oral suspension is indicated in the treatment of adults and pediatric patients six months of age or older with acute exacerbations of chronic bronchitis caused by susceptible isolates of Streptococcus pneumoniae and Haemophilus influenzae.

1.5 Uncomplicated Gonorrhea (cervical/urethral) Cefixime for oral suspension is indicated in the treatment of adults and pediatric patients six months of age or older with uncomplicated gonorrhea (cervical/urethral) caused by susceptible isolates of Neisseria gonorrhoeae (penicillinase-and non-penicillinase-producing isolates).

1.6 Usage To reduce the development of drug resistant bacteria and maintain the effectiveness of cefixime for oral suspension and other antibacterial drugs, cefixime for oral suspension should be used only to treat 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 antimicrobial therapy.

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

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness of cefixime in pediatric patients younger than 6 months of age have not been established.

The incidence of gastrointestinal adverse reactions, including diarrhea and loose stools, in the pediatric patients receiving the suspension, was comparable to the incidence seen in adult patients receiving tablets.

PREGNANCY

8.1 Pregnancy Risk Summary Available data from published observational studies, case series, and case reports over several decades with cephalosporin use, including cefixime, in pregnant women have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) .

Reproduction studies have been performed in mice and rats at doses equivalent to 40 and 80 times, respectively, the adult human recommended dose and have revealed no evidence of harm to the fetus due to cefixime (see Data ).

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 risks 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 Embryo/Fetal Risk Maternal gonorrhea may be associated with preterm birth, low neonatal birth weight, chorioamnionitis, intrauterine growth restriction, small for gestational age and premature rupture of membranes.

Perinatal transmission of gonorrhea to the offspring can result in infant blindness, joint infections, and bloodstream infections.

Data Human Data While available studies cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified a consistent association with cephalosporin use, including cefixime, during pregnancy, and major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Available studies have methodological limitations, including small sample size, retrospective data collection, and inconsistent comparator groups.

Animal data The results of embryo-fetal development studies in mice and rats show that cefixime, at doses up to 3200 mg/kg/day administered during the period of organogenesis did not adversely affect development.

In these studies, in mice and rats, cefixime did not affect postnatal development or reproductive capacity of the F 1 generation or fetal development of the F 2 generation.

In an embryo-fetal development study in rabbits, cefixime at doses of 3.2, 10 or 32 mg/kg given daily during the period of organogenesis (gestation days 6 through 18) resulted in abortions and/or maternal deaths at doses > 10 mg/kg (typically associated with the administration of antibiotics in this species), but no malformations were reported at lower doses.

A pre- and post-natal development study of cefixime at oral doses up to 3200 mg/kg/day in rats demonstrated no effect on the duration of pregnancy, process of parturition, development and viability of offspring, or reproductive capacity of the F 1 generation and development of their fetuses (F 2 ).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Hypersensitivity reactions including shock and fatalities have been reported with cefixime.

Discontinue use if a reaction occurs.

(5.1) Clostridium difficile associated diarrhea: Evaluate if diarrhea occurs.

(5.2) 5.1 Hypersensitivity Reactions Anaphylactic/anaphylactoid reactions (including shock and fatalities) have been reported with the use of cefixime.

Before therapy with cefixime is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins, or other drugs.

If this product is to be given to penicillin-sensitive patients, caution should be exercised because cross hypersensitivity among beta-lactam antibacterial drugs has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy.

If an allergic reaction to cefixime occurs, discontinue the drug.

5.2 Clostridium difficile -Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefixime, 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.

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

Hypertoxin producing isolates of C.

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

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

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

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

difficile may need to be discontinued.

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

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

5.3 Dose Adjustment in Renal Impairment The dose of cefixime should be adjusted in patients with renal impairment as well as those undergoing continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD).

Patients on dialysis should be monitored carefully [see Dosage and Administration (2) ] .

5.4 Coagulation Effects Cephalosporins, including cefixime, may be associated with a fall in prothrombin activity.

Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy.

Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated.

5.5 Development of Drug-Resistant Bacteria Prescribing cefixime in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Drug Resistance Patients should be counseled that antibacterial drugs, including cefixime, should only be used to treat bacterial infections.

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

When cefixime 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 cefixime for oral suspension or other antibacterial drugs in the future.

Diarrhea Advise patients that diarrhea is a common problem caused by antibacterial drugs which usually ends when the antibacterial drug is discontinued.

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

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

Distributed by: Aurobindo Pharma USA, Inc .

279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 032, India Revised: 10/2021

DOSAGE AND ADMINISTRATION

2 Adults: 400 mg daily (2.1) Pediatric patients (6 months and older): 8 mg/kg/day (2.2) 2.1 Adults The recommended dose of cefixime is 400 mg daily.

This may be given as a 400 mg tablet or capsule daily or the 400 mg tablet may be split and given as one half tablet every 12 hours.

For the treatment of uncomplicated cervical/urethral gonococcal infections, a single oral dose of 400 mg is recommended.

The capsule and tablet may be administered without regard to food.

In the treatment of infections due to Streptococcus pyogenes , a therapeutic dosage of cefixime should be administered for at least 10 days.

2.2 Pediatric Patients (6 months or older) The recommended dose is 8 mg/kg/day of the suspension.

This may be administered as a single daily dose or may be given in two divided doses, as 4 mg/kg every 12 hours.

Note: A suggested dose has been determined for each pediatric weight range.

Refer to Table 1.

Ensure all orders that specify a dose in milliliters include a concentration, because cefixime for oral suspension is available in three different concentrations (100 mg/5 mL, 200 mg/5 mL, and 500 mg/5 mL).

Table 1.

Suggested doses for pediatric patients * The preferred concentrations of oral suspension to use are 100 mg/5 mL or 200 mg/5 mL for pediatric patients in these weight ranges.

PEDIATRIC DOSAGE CHART Doses are suggested for each weight range and rounded for ease of administration Cefixime for oral suspension Cefixime chewable tablet 100 mg/5 mL 200 mg/5 mL 500 mg/5 mL Patient Weight (kg) Dose/Day (mg) Dose/Day (mL) Dose/Day (mL) Dose/Day (mL) Dose 5 to 7.5* 50 2.5 — — — 7.6 to 10* 80 4 2 — — 10.1 to 12.5 100 5 2.5 1 1 tablet of 100 mg 12.6 to 20.5 150 7.5 4 1.5 1 tablet of 150 mg 20.6 to 28 200 10 5 2 1 tablet of 200 mg 28.1 to 33 250 12.5 6 2.5 1 tablet of 100 mg and 1 tablet of 150 mg 33.1 to 40 300 15 7.5 3 2 tablets of 150 mg 40.1 to 45 350 17.5 9 3.5 1 tablet of 150 mg and 1 tablet of 200 mg 45.1 or greater 400 20 10 4 2 tablets of 200 mg Children weighing more than 45 kg or older than 12 years should be treated with the recommended adult dose.

Cefixime chewable tablets must be chewed or crushed before swallowing.

Otitis media should be treated with the chewable tablets or suspension.

Clinical trials of otitis media were conducted with the chewable tablets or suspension, and the chewable tablets or suspension results in higher peak blood levels than the tablet when administered at the same dose.

Therefore, the tablet or capsule should not be substituted for the chewable tablets or suspension in the treatment of otitis media [see Clinical Pharmacology (12.3) ].

In the treatment of infections due to Streptococcus pyogenes , a therapeutic dosage of cefixime should be administered for at least 10 days.

2.3 Renal Impairment Cefixime for oral suspension may be administered in the presence of impaired renal function.

Normal dose and schedule may be employed in patients with creatinine clearances of 60 mL/min or greater.

Refer to Table 2 for dose adjustments for adults with renal impairment.

Neither hemodialysis nor peritoneal dialysis removes significant amounts of drug from the body.

Table 2.

Doses for Adults with Renal Impairment * The preferred concentrations of oral suspension to use are 200 mg/5 mL or 500 mg/5 mL for patients with this renal dysfunction Renal Dysfunction Cefixime for oral suspension Tablet Chewable Tablet Creatinine Clearance (mL/min) 100 mg/5 mL 200 mg/5 mL 500 mg/5 mL 400 mg 200 mg Dose/Day (mL) Dose/Day (mL) Dose/Day (mL) Dose/Day Dose/Day 60 or greater Normal dose Normal dose Normal dose Normal dose Normal dose 21 to 59* OR renal hemodialysis* 13 6.5 2.6 Not Appropriate Not Appropriate 20 or less OR continuous peritoneal dialysis 8.6 4.4 1.8 0.5 tablet 1 tablet 2.4 Reconstitution Directions for Oral Suspension Strength Bottle Size Reconstitution Directions 100 mg/5 mL 100 mL To reconstitute, suspend with 70 mL water .

Method: Tap the bottle several times to loosen powder contents prior to reconstitution.

Add approximately half the total amount of water for reconstitution and shake well.

Add the remainder of water and shake well.

200 mg/5 mL 75 mL To reconstitute, suspend with 52.5 mL water .

Method: Tap the bottle several times to loosen powder contents prior to reconstitution.

Add approximately half the total amount of water for reconstitution and shake well.

Add the remainder of water and shake well.

100 mg/5 mL and 200 mg/5 mL 50 mL To reconstitute, suspend with 35 mL water .

Method: Tap the bottle several times to loosen powder contents prior to reconstitution.

Add approximately half the total amount of water for reconstitution and shake well.

Add the remainder of water and shake well.

After reconstitution, the suspension may be kept for 14 days either at room temperature, or under refrigeration, without significant loss of potency.

Keep tightly closed.

Shake well before using.

Discard unused portion after 14 days.

Cefadroxil 100 MG/ML Oral Suspension

Generic Name: CEFADROXIL

Brand Name: Cefadroxil

Substance Name(s):
CEFADROXIL

WARNINGS

BEFORE THERAPY WITH CEFADROXIL MONOHYDRATE IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFADROXIL, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS.

IF THIS PRODUCT IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-SENSITIVITY AMONG BETA-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY.

IF AN ALLERGIC REACTION TO CEFADROXIL MONOHYDRATE OCCURS, DISCONTINUE THE DRUG.

SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, INTRAVENOUS FLUIDS, INTRAVENOUS ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.

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

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.

OVERDOSAGE

A study of children under six years of age suggested that ingestion of less than 250 mg/ kg of cephalosporins is not associated with significant outcomes.

No action is required other than general support and observation.

For amounts greater than 250 mg/kg, induce gastric emptying.

In five anuric patients, it was demonstrated that an average of 63% of a 1 g oral dose is extracted from the body during a 6 to 8 hour hemodialysis session.

DESCRIPTION

Cefadroxil monohydrate is a semisynthetic cephalosporin antibiotic intended for oral administration.

It is a white to yellowish-white crystalline powder.

It is soluble in water and it is acid-stable.

It is chemically designated as 5-Thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid, 7-[[amino (4-hydroxyphenyl)acetyl]amino]-3-methyl-8-oxo-, monohydrate, [6R-[6 α (,7β (R*)]]-.

It has the formula C 16 H 17 N 3 O 5 S•H 2 O and the molecular weight of 381.40.

It has the following structural formula: Cefadroxil for oral suspension, USP contains cefadroxil monohydrate, USP.

After reconstitution, each 5 mL contains Cefadroxil monohydrate, USP equivalent to 250 mg or 500 mg of cefadroxil.

In addition, cefadroxil for oral suspension, USP contains the following inactive ingredients: FD&C Yellow No.

6, orange powder flavor, pineapple powder flavor, polysorbate 80, sodium benzoate, sugar (sucrose), and xanthan gum.

Cefadroxil for oral suspension, USP is off-white yellow powder, forming an orange colored suspension on constitution.

Chemical Structure

HOW SUPPLIED

Cefadroxil for oral suspension, USP is an off-white to yellow powder with orange and pineapple flavor, and is supplied as follows: 250 mg/5 mL 50 mL Bottle with child-resistant closure 100 mL Bottle with child-resistant closure 500 mg/5 mL 75 mL Bottle with child-resistant closure 100 mL Bottle with child-resistant closure Prior to reconstitution: Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

After reconstitution: Store in refrigerator.

Shake well before using.

Keep container tightly closed.

Discard unused portion after 14 days.

Distributed By: West-Ward Pharmaceuticals Corp.

Eatontown, NJ 07724 USA.

Manufactured By: Jazeera Pharmaceutical Industries (JPI) AL-Kharj Road P.O Box 106229 Riyadh 11666 Saudi Arabia.

An Affiliate of: Hikma Pharmaceuticals P.O Box 182400 Amman 11118-Jordan Revised: October 2020

GERIATRIC USE

Geriatric Use Of approximately 650 patients who received cefadroxil for the treatment of urinary tract infections in three clinical trials, 28% were 60 years and older, while 16% were 70 years and older.

Of approximately 1000 patients who received cefadroxil for the treatment of skin and skin structure infection in 14 clinical trials, 12% were 60 years and older while 4% were 70 years and over.

No overall differences in safety were observed between the elderly patients in these studies and younger patients.

Clinical studies of cefadroxil for the treatment of pharyngitis or tonsillitis did not include sufficient numbers of patients 65 years and older to determine whether they respond differently from younger patients.

Other reported clinical experience with cefadroxil has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Cefadroxil is substantially excreted by the kidney, and dosage adjustment is indicated for patients with renal impairment (see DOSAGE AND ADMINISTRATION: Renal Impairment ).

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

INDICATIONS AND USAGE

Cefadroxil for oral suspension is indicated for the treatment of patients with infection caused by susceptible strains of the designated organisms in the following diseases: Urinary tract infections caused by E.

coli , P.

mirabilis , and Klebsiella species.

Skin and skin structure infections caused by staphylococci and/or streptococci.

Pharyngitis and/or tonsillitis caused by Streptococcus pyogenes (Group A beta-hemolytic streptococci).

Note: Only penicillin by the intramuscular route of administration has been shown to be effective in the prophylaxis of rheumatic fever.

Cefadroxil monohydrate is generally effective in the eradication of streptococci from the oropharynx.

However, data establishing the efficacy of cefadroxil monohydrate for the prophylaxis of subsequent rheumatic fever are not available.

Note: Culture and susceptibility tests should be initiated prior to and during therapy.

Renal function studies should be performed when indicated.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefadroxil for oral suspension and other antibacterial drugs, cefadroxil for oral suspension 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 (See DOSAGE AND ADMINISTRATION ).

PREGNANCY

Pregnancy Teratogenic Effects: Pregnancy Category B Reproduction studies have been performed in mice and rats at doses up to 11 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to cefadroxil monohydrate.

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

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

NUSRING MOTHERS

Nursing Mothers Caution should be exercised when cefadroxil monohydrate is administered to a nursing mother.

INFORMATION FOR PATIENTS

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

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

When cefadroxil for oral suspension 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 cefadroxil for oral suspension 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

Cefadroxil for oral suspension is acid-stable and may be administered orally without regard to meals.

Administration with food may be helpful in diminishing potential gastrointestinal complaints occasionally associated with oral cephalosporin therapy.

Adults Urinary Tract Infections For uncomplicated lower urinary tract infections (i.e., cystitis) the usual dosage is 1 or 2 g per day in a single (q.d.) or divided doses (b.i.d.).

For all other urinary tract infections the usual dosage is 2 g per day in divided doses (b.i.d.).

Skin and Skin Structure Infections For skin and skin structure infections the usual dosage is 1 g per day in single (q.d.) or divided doses (b.i.d.).

Pharyngitis and Tonsillitis Treatment of group A beta-hemolytic streptococcal pharyngitis and tonsillitis— 1 g per day in single (q.d.) or divided doses (b.i.d.) for 10 days.

Children For urinary tract infections, the recommended daily dosage for children is 30 mg/kg/day in divided doses every 12 hours.

For pharyngitis, tonsillitis, and impetigo, the recommended daily dosage for children is 30 mg/kg/day in a single dose or in equally divided doses every 12 hours.

For other skin and skin structure infections, the recommended daily dosage is 30 mg/kg/day in equally divided doses every 12 hours.

In the treatment of beta-hemolytic streptococcal infections, a therapeutic dosage of cefadroxil for oral suspension should be administered for at least 10 days.

See chart for total daily dosage for children.

DAILY DOSAGE OF CEFADROXIL FOR ORAL SUSPENSION Child’s Weight 250 mg/5 mL 500 mg/5 mL lbs kg 10 4.5 ½ tsp – 20 9.1 1 tsp – 30 13.6 1½ tsp – 40 18.2 2 tsp 1 tsp 50 22.7 2½ tsp 1¼ tsp 60 27.3 3 tsp 1½ tsp 70 & Above 31.8+ — 2 tsp Renal Impairment In patients with renal impairment, the dosage of cefadroxil monohydrate should be adjusted according to creatinine clearance rates to prevent drug accumulation.

The following schedule is suggested.

In adults, the initial dose is 1000 mg of cefadroxil monohydrate and the maintenance dose (based on the creatinine clearance rate [mL/min/1.73 m 2 ]) is 500 mg at the time intervals listed below.

Creatinine Clearances Dosage Interval 0 to 10 mL/min 36 hours 10 to 25 mL/min 24 hours 25 to 50 mL/min 12 hours Patients with creatinine clearance rates over 50 mL/min may be treated as if they were patients having normal renal function.

Reconstitution Directions for Oral Suspension Bottle Size Reconstitution Directions 100 mL Suspend in a total of 67 mL water.

Method: Tap bottle lightly to loosen powder.

Add 67 mL of water in two portions.

Shake well after each addition.

75 mL Suspend in a total of 51 mL water Method: Tap bottle lightly to loosen powder.

Add 51 mL of water in two portions.

Shake well after each addition.

50 mL Suspend in a total of 34 mL water Method: Tap bottle lightly to loosen powder.

Add 34 mL of water in two portions.

Shake well after each addition.

After reconstitution, store in refrigerator.

Shake well before using.

Keep container tightly closed.

Discard unused portion after 14 days.

Fluphenazine Hydrochloride 5 MG Oral Tablet

WARNINGS

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

Fluphenazine hydrochloride is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING ).

Tardive Dyskinesia: Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with neuroleptic (antipsychotic) drugs.

Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of neuroleptic treatment, which patients are likely to develop the syndrome.

Whether neuroleptic drug products differ in their potential to cause tardive dyskinesia is unknown.

Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of neuroleptic drugs administered to the patient increase.

However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if neuroleptic treatment is withdrawn.

Neuroleptic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process.

The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, neuroleptics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.

Chronic neuroleptic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to neuroleptic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.

In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought.

The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on neuroleptics, drug discontinuation should be considered.

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

(For further information about the description of tardive dyskinesia and its clinical detection, please refer to the sections on PRECAUTIONS, Information for Patients and ADVERSE REACTIONS, Tardive Dyskinesia .) Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs.

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

The diagnostic evaluation of patients with this syndrome is complicated.

In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).

Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and, 3) treatment of any concomitant serious medical problems for which specific treatments are available.

There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

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

The patient should be carefully monitored, since recurrences of NMS have been reported.

The use of this drug may impair the mental and physical abilities required for driving a car or operating heavy machinery.

Potentiation of the effects of alcohol may occur with the use of this drug.

Since there is no adequate experience in children who have received this drug, safety and efficacy in children have not been established.

Falls Fluphenazine hydrochloride tablets, USP may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.

For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Usage in Pregnancy: The safety for the use of this drug during pregnancy has not been established; therefore, the possible hazards should be weighed against the potential benefits when administering this drug to pregnant patients.

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

There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates.

These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

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

DESCRIPTION

Fluphenazine hydrochloride is a trifluoromethyl phenothiazine derivative intended for the management of schizophrenia.

The chemical designation is 4-[3-[2-(Trifluoromethyl) phenothiazin-10-yl] propyl]-1-piperazineethanol dihydrochloride.

The structural formula is represented below: Fluphenazine Hydrochloride Tablets, USP, for oral administration, contain 1 mg, 2.5 mg, 5 mg, or 10 mg fluphenazine hydrochloride, USP per tablet.

Each tablet also contains corn starch, D&C Red No.

27 (2.5 mg and 5 mg tablet), D&C Red No.

30 (5 mg tablet), D&C Yellow No.

10 (5 mg tablet), dibasic calcium phosphate dihydrate, FD&C Blue No.

1 (5 mg tablet), FD&C Blue No.

2 (2.5 mg tablet), FD&C Red No.

40 (10 mg tablet), FD&C Yellow No.

6 (10 mg tablet), hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80, pregelatinized starch, purified water, and titanium dioxide.

fluphenazine-molec-structure

HOW SUPPLIED

Fluphenazine Hydrochloride Tablets, USP are available as follows: 1 mg tablets are white, round, film-coated tablets debossed “LCI” on one side and “1788” on the other side.

They are supplied in bottles of 100 (NDC 0527-1788-01) and 500 (NDC 0527-1788-05).

2.5 mg tablets are blue, round, film-coated tablets debossed “LCI” on one side and “1789” on the other side.

They are supplied in bottles of 100 (NDC 0527-1789-01) and 500 (NDC 0527-1789-05).

5 mg tablets are dark pink, round, film-coated tablets debossed “LCI” on one side and “1790” on the other side.

They are supplied in bottles of 100 (NDC 0527-1790-01) and 500 (NDC 0527-1790-05).

10 mg tablets are orange, round, film-coated tablets debossed “LCI” on one side and “1791” on the other side.

They are supplied in bottles of 100 (NDC 0527-1791-01) and 500 (NDC 0527-1791-05).

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Avoid excessive heat.

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure.

Distributed by: Lannett Company, Inc.

Philadelphia, PA 19154 CIB70359C Rev.

08/17

INDICATIONS AND USAGE

Fluphenazine hydrochloride tablets are indicated in the management of manifestations of psychotic disorders.

Fluphenazine hydrochloride has not been shown effective in the management of behavioral complications in patients with mental retardation.

PREGNANCY

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

There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates.

These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

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

BOXED WARNING

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

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

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

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

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

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

Fluphenazine hydrochloride is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS ).

INFORMATION FOR PATIENTS

Information for Patients: Given the likelihood that some patients exposed chronically to neuroleptics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk.

The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided.

DOSAGE AND ADMINISTRATION

Depending on severity and duration of symptoms, total daily dosage for adult psychotic patients may range initially from 2.5 mg to 10 mg and should be divided and given at 6 to 8 hour intervals.

The smallest amount that will produce the desired results must be carefully determined for each individual, since optimal dosage levels of this potent drug vary from patient to patient.

In general, the oral dose has been found to be approximately 2 to 3 times the parenteral dose of fluphenazine.

Treatment is best instituted with a low initial dosage, which may be increased, if necessary, until the desired clinical effects are achieved.

Therapeutic effect is often achieved with doses under 20 mg daily.

Patients remaining severely disturbed or inadequately controlled may require upward titration of dosage.

Daily doses up to 40 mg may be necessary; controlled clinical studies have not been performed to demonstrate safety of prolonged administration of such doses.

When symptoms are controlled, dosage can generally be reduced gradually to daily maintenance doses of 1 mg to 5 mg, often given as a single daily dose.

Continued treatment is needed to achieve maximum therapeutic benefits; further adjustments in dosage may be necessary during the course of therapy to meet the patient’s requirements.

For psychotic patients who have been stabilized on a fixed daily dosage of orally administered fluphenazine hydrochloride dosage forms, conversion to the long-acting fluphenazine decanoate may be indicated (see package insert for fluphenazine decanoate for conversion information).

For geriatric patients, the suggested starting dose is 1 mg to 2.5 mg daily, adjusted according to the response of the patient.