ProAir HFA 0.09 MG/ACTUAT Metered Dose Inhaler, 200 ACTUAT

Generic Name: ALBUTEROL SULFATE
Brand Name: PROAIR HFA
  • Substance Name(s):
  • ALBUTEROL SULFATE

DRUG INTERACTIONS

7 Other short-acting sympathomimetic aerosol bronchodilators should not be used concomitantly with PROAIR HFA Inhalation Aerosol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects. Other short-acting sympathomimetic aerosol bronchodilators and adrenergic drugs: May potentiate effect. (7) Beta-blockers: May decrease effectiveness of PROAIR HFA and produce severe bronchospasm. Patients with asthma should not normally be treated with beta-blockers. (7.1) Diuretics, or non-potassium sparing diuretics: May potentiate hypokalemia or ECG changes. Consider monitoring potassium levels. (7.2) Digoxin: May decrease serum digoxin levels. Consider monitoring digoxin levels. (7.3) Monoamine oxidase (MAO) inhibitors and tricyclic antidepressants: May potentiate effect of albuterol on the cardiovascular system. Consider alternative therapy in patients taking MAOs or tricyclic antidepressants. (7.4) 7.1 Beta-Blockers Beta-adrenergic-receptor blocking agents not only block the pulmonary effect of beta-agonists, such as PROAIR HFA Inhalation Aerosol, 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., as 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, consider cardioselective beta-blockers, although they should be administered with caution. 7.2 Diuretics The ECG changes and/or hypokalemia which may result from the administration of non-potassium sparing diuretics (such as loop or 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. 7.3 Digoxin Mean decreases of 16% and 22% in serum digoxin levels were demonstrated after single dose intravenous and oral administration of 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 albuterol 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 PROAIR HFA Inhalation Aerosol. 7.4 Monoamine Oxidase Inhibitors or Tricyclic Antidepressants PROAIR HFA Inhalation Aerosol 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 albuterol on the cardiovascular 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 stimulation and/or occurrence or exaggeration of any of the symptoms listed under ADVERSE REACTIONS, e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats per minute, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Hypokalemia may also occur. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of PROAIR HFA Inhalation Aerosol. Treatment consists of discontinuation of PROAIR HFA Inhalation Aerosol together with appropriate symptomatic therapy. The judicious use of a cardioselective 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 PROAIR HFA Inhalation Aerosol. The oral median lethal dose of albuterol sulfate in mice is greater than 2,000 mg/kg (approximately 6,800 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis and approximately 3,200 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). In mature rats, the subcutaneous median lethal dose of albuterol sulfate is approximately 450 mg/kg (approximately 3,000 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis and approximately 1,400 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). In young rats, the subcutaneous median lethal dose is approximately 2,000 mg/kg (approximately 14,000 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis and approximately 6,400 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). The inhalation median lethal dose has not been determined in animals.

DESCRIPTION

11 The active ingredient of PROAIR HFA (albuterol sulfate) Inhalation Aerosol is albuterol sulfate, a racemic salt, of albuterol. Albuterol sulfate has the chemical name α1-[(tert-butylamino) methyl]-4-hydroxy-m-xylene-α,α’-diol sulfate (2:1) (salt), and has the following chemical structure: The molecular weight of albuterol sulfate is 576.7, and the empirical formula is (C13H21NO3)2•H2SO4. Albuterol sulfate is a white to off-white crystalline powder. It is soluble in water and slightly soluble in ethanol. Albuterol sulfate is the official generic name in the United States, and salbutamol sulfate is the World Health Organization recommended generic name. PROAIR HFA Inhalation Aerosol is a pressurized metered-dose aerosol unit for oral inhalation. It contains a microcrystalline suspension of albuterol sulfate in propellant HFA-134a (1, 1, 1, 2-tetrafluoroethane) and ethanol. Prime the inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks by releasing three sprays into the air, away from the face. After priming, each actuation delivers 108 mcg albuterol sulfate, from the actuator mouthpiece (equivalent to 90 mcg of albuterol base). Each canister provides 200 actuations (inhalations). This product does not contain chlorofluorocarbons (CFCs) as the propellant. proair-hfa

CLINICAL STUDIES

14 14.1 Bronchospasm Associated with Asthma Adult and Adolescent Patients 12 Years of Age and Older: In a 6-week, randomized, double-blind, placebo-controlled trial, PROAIR HFA Inhalation Aerosol (58 patients) was compared to a matched placebo HFA inhalation aerosol (58 patients) in asthmatic patients 12 to 76 years of age at a dose of 180 mcg albuterol four times daily. An evaluator-blind marketed active comparator HFA-134a albuterol inhaler arm (56 patients) was included. Serial FEV1 measurements, shown below as percent change from test-day baseline at Day 1 and at Day 43, demonstrated that two inhalations of PROAIR HFA Inhalation Aerosol produced significantly greater improvement in FEV1 over the pre-treatment value than the matched placebo, as well as a comparable bronchodilator effect to the marketed active comparator HFA-134a albuterol inhaler. FEV1 as Mean Percent Change from Test-Day Pre-Dose in a 6-Week Clinical Trial Day 1 Day 43 In this study, 31 of 58 patients treated with PROAIR HFA Inhalation Aerosol achieved a 15% increase in FEV1 within 30 minutes post-dose on Day 1. In these patients, the median time to onset, median time to peak effect, and median duration of effect were 8.2 minutes, 47 minutes, and approximately 3 hours, respectively. In some patients, the duration of effect was as long as 6 hours. In a placebo-controlled, single-dose, crossover study, PROAIR HFA Inhalation Aerosol, administered at albuterol doses of 90, 180 and 270 mcg, produced bronchodilator responses significantly greater than those observed with a matched placebo HFA inhalation aerosol and comparable to a marketed active comparator HFA-134a albuterol inhaler. Pediatric Patients 4 to 11 Years of Age: In a 3-week, randomized, double-blind, placebo-controlled trial, the same formulation of albuterol as in PROAIR HFA Inhalation Aerosol (50 patients) was compared to a matched placebo HFA inhalation aerosol (45 patients) in asthmatic children 4 to 11 years of age at a dose of 180 mcg albuterol four times daily. Serial FEV1 measurements, expressed as the maximum percent change from test-day baseline in percent predicted FEV1 at Day 1 and at Day 22 observed within two hours post-dose, demonstrated that two inhalations of HFA albuterol sulfate produced significantly greater improvement in FEV1 over the pre-treatment value than the matched placebo. In this study, 21 of 50 pediatric patients treated with the same formulation of albuterol as in PROAIR HFA Inhalation Aerosol achieved a 15% increase in FEV1 within 30 minutes post-dose on Day 1. In these patients, the median time to onset, median time to peak effect and median duration of effect were 10 minutes, 31 minutes, and approximately 4 hours, respectively. In some pediatric patients, the duration of effect was as long as 6 hours. In a placebo-controlled, single-dose, crossover study in 55 pediatric patients 4 to 11 years of age, PROAIR HFA Inhalation Aerosol, administered at albuterol doses of 90 and 180 mcg, was compared with a matched placebo HFA inhalation aerosol. Serial FEV1 measurements, expressed as the baseline-adjusted percent predicted FEV1 observed over 6 hours post-dose, demonstrated that one and two inhalations of PROAIR HFA Inhalation Aerosol produced significantly greater bronchodilator responses than the matched placebo. 14.2 Exercise-Induced Bronchospasm In a randomized, single-dose, crossover study in 24 adults and adolescents with exercise-induced bronchospasm (EIB), two inhalations of PROAIR HFA taken 30 minutes before exercise prevented EIB for the hour following exercise (defined as maintenance of FEV1 within 80% of post-dose, pre-exercise baseline values) in 83% (20 of 24) of patients as compared to 25% (6 of 24) of patients when they received placebo. Some patients who participated in these clinical trials were using concomitant steroid therapy. proair-hfa proair-hfa

HOW SUPPLIED

16 /STORAGE AND HANDLING PROAIR HFA (albuterol sulfate) Inhalation Aerosol is supplied as a pressurized aluminum canister with a red plastic actuator and white dust cap each in boxes of one. Each canister contains 8.5 g of the formulation and provides 200 actuations (NDC 21695-851-85). Each actuation delivers 120 mcg of albuterol sulfate from the canister valve and 108 mcg of albuterol sulfate from the actuator mouthpiece (equivalent to 90 mcg of albuterol base). SHAKE WELL BEFORE USE. Store between 15° and 25°C (59° and 77°F). Contents under pressure. Do not puncture or incinerate. Protect from freezing temperatures and prolonged exposure to direct sunlight. Exposure to temperatures above 120°F may cause bursting. For best results, canister should be at room temperature before use. Avoid spraying in eyes. Keep out of reach of children. See FDA-Approved Patient Labeling (17.8) for priming and cleaning instructions. The red actuator supplied with PROAIR HFA Inhalation Aerosol should not be used with the canister from any other inhalation aerosol products. The PROAIR HFA Inhalation Aerosol canister should not be used with the actuator from any other inhalation aerosol products. The labeled amount of medication in each actuation cannot be assured after 200 actuations, even though the canister may not be completely empty. Discard the inhaler (canister plus actuator) after 200 actuations have been used. Never immerse the canister into water to determine how full the canister is (“float test”). PROAIR HFA Inhalation Aerosol does not contain chlorofluorocarbons (CFCs) as the propellant.

RECENT MAJOR CHANGES

Indications and Usage 9/2008 Dosage and Administration 9/2008

GERIATRIC USE

8.5 Geriatric Use Clinical studies of PROAIR HFA Inhalation Aerosol did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between 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 [see Warnings and Precautions ( 5.4, 5.7 )]. All beta2-adrenergic agonists, including albuterol, are known to be substantially excreted by the kidney, and the risk of toxic reactions 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.

DOSAGE FORMS AND STRENGTHS

3 PROAIR HFA is an inhalation aerosol. PROAIR HFA is supplied as an 8.5 g/200 actuations pressurized aluminum canister with a red plastic actuator and white dust cap each in boxes of one. Each actuation delivers 120 mcg of albuterol sulfate from the canister valve and 108 mcg of albuterol sulfate from the actuator mouthpiece (equivalent to 90 mcg of albuterol base). Inhalation Aerosol: Each actuation delivers 108 mcg of albuterol sulfate from the actuator mouthpiece (equivalent to 90 mcg of albuterol base). Supplied in 8.5-g canister containing 200 actuations. ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Albuterol sulfate is a beta2-adrenergic agonist. The pharmacologic effects of albuterol sulfate are attributable to activation of beta2-adrenergic receptors on airway smooth muscle. Activation of beta2-adrenergic receptors leads to the activation of adenylcyclase and to an increase in the intracellular concentration of cyclic-3′, 5′ adenosine monophosphate (cyclic AMP). This increase of 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. Albuterol relaxes the smooth muscle of all airways, from the trachea to the terminal bronchioles. Albuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway. While it is recognized that beta2-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 cardiac beta2-adrenergic receptors. The precise function of these receptors has not been established [see Warnings and Precautions ( 5.4 )]. Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects. However, inhaled albuterol, like other 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 [see Warnings and Precautions ( 5.4 )].

INDICATIONS AND USAGE

1 PROAIR HFA inhalation aerosol is a beta2-adrenergic agonist indicated for: Treatment or prevention of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease (1.1) Prevention of exercise-induced bronchospasm in patients 4 years of age and older. (1.2) 1.1 Bronchospasm PROAIR HFA Inhalation Aerosol is indicated for the treatment or prevention of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease. 1.2 Exercise-Induced Bronchospasm PROAIR HFA Inhalation Aerosol is indicated for the prevention of exercise-induced bronchospasm in patients 4 years of age and older.

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of PROAIR HFA Inhalation Aerosol for the treatment or prevention of bronchospasm in children 12 years of age and older with reversible obstructive airway disease is based on one 6-week clinical trial in 116 patients 12 years of age and older with asthma comparing doses of 180 mcg four times daily with placebo, and one single-dose crossover study comparing doses of 90, 180, and 270 mcg with placebo in 58 patients [see Clinical Studies ( 14.1 )]. The safety and effectiveness of PROAIR HFA Inhalation Aerosol for treatment of exercise-induced bronchospasm in children 12 years of age and older is based on one single-dose crossover study in 24 adults and adolescents with exercise-induced bronchospasm comparing doses of 180 mcg with placebo [see Clinical Studies ( 14.2 )]. The safety of PROAIR HFA Inhalation Aerosol in children 4 to 11 years of age is based on one 3-week clinical trial in 50 patients 4 to 11 years of age with asthma using the same formulation of albuterol as in PROAIR HFA Inhalation Aerosol comparing doses of 180 mcg four times daily with placebo. The effectiveness of PROAIR HFA Inhalation Aerosol in children 4 to 11 years of age is extrapolated from clinical trials in patients 12 years of age and older with asthma and exercise-induced bronchospasm, based on data from a single-dose study comparing the bronchodilatory effect of PROAIR HFA 90 mcg and 180 mcg with placebo in 55 patients with asthma and a 3-week clinical trial using the same formulation of albuterol as in PROAIR HFA Inhalation Aerosol in 95 asthmatic children 4 to 11 years of age comparing a dose of 180 mcg albuterol four times daily with placebo [see Clinical Studies ( 14.1 )]. The safety and effectiveness of PROAIR HFA Inhalation Aerosol in pediatric patients below the age of 4 years have not been established.

PREGNANCY

8.1 Pregnancy Teratogenic Effects: Pregnancy Category C: There are no adequate and well-controlled studies of PROAIR HFA Inhalation Aerosol or albuterol sulfate in pregnant women. During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in the offspring of patients treated with albuterol. Some of the mothers were taking multiple medications during their pregnancies. No consistent pattern of defects can be discerned, and a relationship between albuterol use and congenital anomalies has not been established. Animal reproduction studies in mice and rabbits revealed evidence of teratogenicity. PROAIR HFA Inhalation Aerosol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In a mouse reproduction study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at an exposure approximately eight-tenths of the maximum recommended human dose (MRHD) for adults on a mg/m2 basis and in 10 of 108 (9.3%) fetuses at approximately 8 times the MRHD. Similar effects were not observed at approximately one-thirteenth of the MRHD. Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol (positive control). In a rabbit reproduction study, orally administered albuterol sulfate induced cranioschisis in 7 of 19 fetuses (37%) at approximately 630 times the MRHD. In a rat reproduction study, an albuterol sulfate/HFA-134a formulation administered by inhalation did not produce any teratogenic effects at exposures approximately 65 times the MRHD [see Nonclinical Toxicology ( 13.2 )].

NUSRING MOTHERS

8.3 Nursing Mothers Plasma levels of albuterol sulfate and HFA-134a after inhaled therapeutic doses are very low in humans, but it is not known whether the components of PROAIR HFA Inhalation Aerosol are excreted in human milk. Caution should be exercised when PROAIR HFA Inhalation Aerosol is administered to a nursing woman. Because of the potential for tumorigenicity shown for albuterol in animal studies and lack of experience with the use of PROAIR HFA Inhalation Aerosol by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Life-threatening paradoxical bronchospasm may occur. Discontinue PROAIR HFA immediately and treat with alternative therapy. (5.1) Need for more doses of PROAIR HFA than usual may be a sign of deterioration of asthma and requires reevaluation of treatment. (5.2) PROAIR HFA is not a substitute for corticosteroids. (5.3) Cardiovascular effects may occur. Use with caution in patients sensitive to sympathomimetic drugs and patients with cardiovascular or convulsive disorders. (5.4, 5.7) Excessive use may be fatal. Do not exceed recommended dose. (5.5) Immediate hypersensitivity reactions may occur. Discontinue PROAIR HFA immediately. (5.6) Hypokalemia and changes in blood glucose may occur. (5.7, 5.8) 5.1 Paradoxical Bronchospasm PROAIR HFA Inhalation Aerosol can produce paradoxical bronchospasm that may be life threatening. If paradoxical bronchospasm occurs, PROAIR HFA Inhalation Aerosol 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 canister. 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 PROAIR HFA Inhalation Aerosol than usual, this may be a marker of destabilization of asthma and requires re-evaluation 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 The use of beta-adrenergic-agonist bronchodilators 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 PROAIR HFA Inhalation Aerosol, like other beta-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of PROAIR HFA Inhalation Aerosol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce 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, PROAIR HFA Inhalation Aerosol, 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 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 albuterol sulfate, as demonstrated by rare cases of 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 PROAIR HFA Inhalation Aerosol. 5.7 Coexisting Conditions PROAIR HFA Inhalation Aerosol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; 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 use of any beta-adrenergic bronchodilator. Large doses of intravenous albuterol have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis. 5.8 Hypokalemia As with other beta-agonists, PROAIR HFA Inhalation Aerosol 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 (17.8) Patients should be given the following information: 17.1 Frequency of Use The action of PROAIR HFA Inhalation Aerosol should last for 4 to 6 hours. Do not use PROAIR HFA Inhalation Aerosol more frequently than recommended. Instruct patients to not increase the dose or frequency of doses of PROAIR HFA Inhalation Aerosol without consulting the physician. If patients find that treatment with PROAIR HFA Inhalation Aerosol becomes less effective for symptomatic relief, symptoms become worse, and/or they need to use the product more frequently than usual, they should seek medical attention immediately. 17.2 Priming and Cleaning Priming: Priming is essential to ensure appropriate albuterol content in each actuation. Instruct patients to prime the inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks by releasing three sprays into the air, away from the face. Cleaning: To ensure proper dosing and prevent actuator orifice blockage, instruct patients to wash the red plastic actuator mouthpiece and dry thoroughly at least once a week. Detailed cleaning instructions are included in the illustrated Information for the Patient leaflet. 17.3 Paradoxical Bronchospasm Inform patients that PROAIR HFA Inhalation Aerosol can produce paradoxical bronchospasm. Instruct patients to discontinue PROAIR HFA Inhalation Aerosol if paradoxical bronchospasm occurs. 17.4 Concomitant Drug Use While patients are taking PROAIR HFA Inhalation Aerosol, other inhaled drugs and asthma medications should be taken only as directed by a physician. 17.5 Common Adverse Events Common adverse effects of treatment with inhaled albuterol include palpitations, chest pain, rapid heart rate, tremor, or nervousness. 17.6 Pregnancy Patients who are pregnant or nursing should contact their physician about the use of PROAIR HFA Inhalation Aerosol. 17.7 General Information on Use Effective and safe use of PROAIR HFA Inhalation Aerosol includes an understanding of the way that it should be administered. Shake well before each spray. Use PROAIR HFA Inhalation Aerosol only with the actuator supplied with the product. Discard the canister after 200 sprays have been used. Never immerse the canister in water to determine how full the canister is (“float test”). In general, the technique for administering PROAIR HFA Inhalation Aerosol to children is similar to that for adults. Children should use PROAIR HFA Inhalation Aerosol under adult supervision, as instructed by the patient’s physician.

DOSAGE AND ADMINISTRATION

2 For oral inhalation only Treatment or prevention of bronchospasm in adults and children 4 years of age and older: 2 inhalations every 4 to 6 hours. In some patients, one inhalation every 4 hours may be sufficient. (2.1) Prevention of exercise-induced bronchospasm in adults and children 4 years of age and older: 2 inhalations 15 to 30 minutes before exercise. (2.2) Priming information: Prime PROAIR HFA before using for the first time, or when the inhaler has not been used for more than 2 weeks. To prime PROAIR HFA, release 3 sprays into the air away from the face. Shake well before each spray. (2.3) Cleaning information: At least once a week, wash the actuator with warm water, shake off excess, and air dry thoroughly. (2.3) 2.1 Bronchospasm For treatment of acute episodes of bronchospasm or prevention of symptoms associated with bronchospasm, the usual dosage for adults and children 4 years and older is two inhalations repeated every 4 to 6 hours. More frequent administration or a larger number of inhalations is not recommended. In some patients, one inhalation every 4 hours may be sufficient. 2.2 Exercise-Induced Bronchospasm The usual dosage for adults and children 4 years of age or older is two inhalations 15 to 30 minutes before exercise. 2.3 Administration Information Administer PROAIR HFA by oral inhalation only. Shake well before each spray. To maintain proper use of this product and to prevent medication build-up and blockage, it is important to follow the cleaning directions carefully. Priming: Prime the inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks by releasing three sprays into the air, away from the face. Cleaning: As with all HFA-containing albuterol inhalers, to maintain proper use of this product and to prevent medication build-up and blockage, it is important to keep the plastic mouthpiece clean. The inhaler may cease to deliver medication if the plastic actuator mouthpiece is not properly cleaned and dried. To clean: Wash the plastic mouthpiece with warm running water for 30 seconds, shake off excess water, and air dry thoroughly at least once a week. If the mouthpiece becomes blocked, washing the mouthpiece will remove the blockage. If it is necessary to use the inhaler before it is completely dry, shake off excess water, replace canister, spray twice into the air away from face, and take the prescribed dose. After such use, the mouthpiece should be rewashed and allowed to air dry thoroughly [see Patient Counseling Information ( 17.8 )].

Zantac 150 MG (as ranitidine hydrochloride 168 MG) Oral Tablet

Generic Name: RANITIDINE HYDROCHLORIDE
Brand Name: ZANTAC
  • Substance Name(s):
  • RANITIDINE HYDROCHLORIDE

DRUG INTERACTIONS

Drug Interactions: Ranitidine has been reported to affect the bioavailability of other drugs through several different mechanisms such as competition for renal tubular secretion, alteration of gastric pH, and inhibition of cytochrome P450 enzymes. Procainamide: Ranitidine, a substrate of the renal organic cation transport system, may affect the clearance of other drugs eliminated by this route. High doses of ranitidine (e.g., such as those used in the treatment of Zollinger-Ellison syndrome) have been shown to reduce the renal excretion of procainamide and N-acetylprocainamide resulting in increased plasma levels of these drugs. Although this interaction is unlikely to be clinically relevant at usual ranitidine doses, it may be prudent to monitor for procainamide toxicity when administered with oral ranitidine at a dose exceeding 300 mg per day. Warfarin: There have been reports of altered prothrombin time among patients on concomitant warfarin and ranitidine therapy. Due to the narrow therapeutic index, close monitoring of increased or decreased prothrombin time is recommended during concurrent treatment with ranitidine. Ranitidine may alter the absorption of drugs in which gastric pH is an important determinant of bioavailability. This can result in either an increase in absorption (e.g., triazolam, midazolam, glipizide) or a decrease in absorption (e.g., ketoconazole, atazanavir, delavirdine, gefitinib). Appropriate clinical monitoring is recommended. Atazanavir: Atazanavir absorption may be impaired based on known interactions with other agents that increase gastric pH. Use with caution. See atazanavir label for specific recommendations. Delavirdine: Delavirdine absorption may be impaired based on known interactions with other agents that increase gastric pH. Chronic use of H2-receptor antagonists with delavirdine is not recommended. Gefitinib: Gefitinib exposure was reduced by 44% with the coadministration of ranitidine and sodium bicarbonate (dosed to maintain gastric pH above 5.0). Use with caution. Glipizide: In diabetic patients, glipizide exposure was increased by 34% following a single 150-mg dose of oral ranitidine. Use appropriate clinical monitoring when initiating or discontinuing ranitidine. Ketoconazole: Oral ketoconazole exposure was reduced by up to 95% when oral ranitidine was coadministered in a regimen to maintain a gastric pH of 6 or above. The degree of interaction with usual dose of ranitidine (150 mg twice daily) is unknown. Midazolam: Oral midazolam exposure in 5 healthy volunteers was increased by up to 65% when administered with oral ranitidine at a dose of 150 mg twice daily. However, in another interaction trial in 8 volunteers receiving IV midazolam, a 300-mg oral dose of ranitidine increased midazolam exposure by about 9%. Monitor patients for excessive or prolonged sedation when ranitidine is coadministered with oral midazolam. Triazolam: Triazolam exposure in healthy volunteers was increased by approximately 30% when administered with oral ranitidine at a dose of 150 mg twice daily. Monitor patients for excessive or prolonged sedation.

OVERDOSAGE

There has been limited experience with overdosage. Reported acute ingestions of up to 18 g orally have been associated with transient adverse effects similar to those encountered in normal clinical experience (see ADVERSE REACTIONS). In addition, abnormalities of gait and hypotension have been reported. When overdosage occurs, the usual measures to remove unabsorbed material from the gastrointestinal tract, clinical monitoring, and supportive therapy should be employed. Studies in dogs receiving dosages of ZANTAC in excess of 225 mg/kg/day have shown muscular tremors, vomiting, and rapid respiration. Single oral doses of 1,000 mg/kg in mice and rats were not lethal. Intravenous LD50 values in mice and rats were 77 and 83 mg/kg, respectively.

DESCRIPTION

The active ingredient in ZANTAC 150 Tablets and ZANTAC 300 Tablets is ranitidine hydrochloride (HCl), USP, a histamine H2-receptor antagonist. Chemically it is N[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N′-methyl-2-nitro-1,1-ethenediamine, HCl. It has the following structure: The empirical formula is C13H22N4O3S•HCl, representing a molecular weight of 350.87. Ranitidine HCl is a white to pale yellow granular substance that is soluble in water. It has a slightly bitter taste and sulfur-like odor. Each ZANTAC 150 Tablet for oral administration contains 168 mg of ranitidine HCl equivalent to 150 mg of ranitidine. Each tablet also contains the inactive ingredients FD&C Yellow No. 6 Aluminum Lake, hypromellose, magnesium stearate, microcrystalline cellulose, titanium dioxide, triacetin, and yellow iron oxide. Each ZANTAC 300 Tablet for oral administration contains 336 mg of ranitidine HCl equivalent to 300 mg of ranitidine. Each tablet also contains the inactive ingredients croscarmellose sodium, D&C Yellow No. 10 Aluminum Lake, hypromellose, magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin. ranitidine HCl molecular structure

CLINICAL STUDIES

Clinical Trials: Active Duodenal Ulcer: In a multicenter, double-blind, controlled, US trial of endoscopically diagnosed duodenal ulcers, earlier healing was seen in the patients treated with ZANTAC as shown in Table 3. Table 3. Duodenal Ulcer Patient Healing Rates ZANTACa Placeboa Number Entered Healed/ Evaluable Number Entered Healed/ Evaluable Outpatients Week 2 69/182 (38%)b 31/164 (19%) 195 188 Week 4 137/187 (73%)b 76/168 (45%) a All patients were permitted antacids as needed for relief of pain. b P<0.0001. In these trials, patients treated with ZANTAC reported a reduction in both daytime and nocturnal pain, and they also consumed less antacid than the placebo-treated patients. Table 4. Mean Daily Doses of Antacid Ulcer Healed Ulcer Not Healed ZANTAC 0.06 0.71 Placebo 0.71 1.43 Foreign trials have shown that patients heal equally well with 150 mg twice daily and 300 mg at bedtime (85% versus 84%, respectively) during a usual 4-week course of therapy. If patients require extended therapy of 8 weeks, the healing rate may be higher for 150 mg twice daily as compared with 300 mg at bedtime (92% versus 87%, respectively). Trials have been limited to short-term treatment of acute duodenal ulcer. Patients whose ulcers healed during therapy had recurrences of ulcers at the usual rates. Maintenance Therapy in Duodenal Ulcer: Ranitidine has been found to be effective as maintenance therapy for patients following healing of acute duodenal ulcers. In 2 independent, double-blind, multicenter, controlled trials, the number of duodenal ulcers observed was significantly less in patients treated with ZANTAC (150 mg at bedtime) than in patients treated with placebo over a 12-month period. Table 5. Duodenal Ulcer Prevalence Double-Blind, Multicenter, Placebo-Controlled Trials MulticenterTrial Drug Duodenal Ulcer Prevalence No. of Patients 0-4 Months 0-8 Months 0-12 Months USA RAN 20%a 24% 35%a 138 PLC 44% 54% 59% 139 Foreign RAN 12%a 21%a 28%a 174 PLC 56% 64% 68% 165 % = Life table estimate. a = P<0.05 (ZANTAC versus comparator). RAN = ranitidine (ZANTAC). PLC = placebo. As with other H2-antagonists, the factors responsible for the significant reduction in the prevalence of duodenal ulcers include prevention of recurrence of ulcers, more rapid healing of ulcers that may occur during maintenance therapy, or both. Gastric Ulcer: In a multicenter, double-blind, controlled, US trial of endoscopically diagnosed gastric ulcers, earlier healing was seen in the patients treated with ZANTAC as shown in Table 6. Table 6. Gastric Ulcer Patient Healing Rates ZANTACa Placeboa Number Entered Healed/ Evaluable Number Entered Healed/ Evaluable Outpatients Week 2 16/83 (19%) 10/83 (12%) 92 94 Week 6 50/73 (68%)b 35/69 (51%) a All patients were permitted antacids as needed for relief of pain. b P = 0.009. In this multicenter trial, significantly more patients treated with ZANTAC became pain free during therapy. Maintenance of Healing of Gastric Ulcers: In 2 multicenter, double-blind, randomized, placebo-controlled, 12-month trials conducted in patients whose gastric ulcers had been previously healed, ZANTAC 150 mg at bedtime was significantly more effective than placebo in maintaining healing of gastric ulcers. Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome): ZANTAC inhibits gastric acid secretion and reduces occurrence of diarrhea, anorexia, and pain in patients with pathological hypersecretion associated with Zollinger-Ellison syndrome, systemic mastocytosis, and other pathological hypersecretory conditions (e.g., postoperative, “short-gut” syndrome, idiopathic). Use of ZANTAC was followed by healing of ulcers in 8 of 19 (42%) patients who were intractable to previous therapy. Gastroesophageal Reflux Disease (GERD): In 2 multicenter, double-blind, placebo-controlled, 6-week trials performed in the United States and Europe, ZANTAC 150 mg twice daily was more effective than placebo for the relief of heartburn and other symptoms associated with GERD. Ranitidine-treated patients consumed significantly less antacid than did placebo-treated patients. The US trial indicated that ZANTAC 150 mg twice daily significantly reduced the frequency of heartburn attacks and severity of heartburn pain within 1 to 2 weeks after starting therapy. The improvement was maintained throughout the 6-week trial period. Moreover, patient response rates demonstrated that the effect on heartburn extends through both the day and night time periods. In 2 additional US multicenter, double-blind, placebo-controlled, 2-week trials, ZANTAC 150 mg twice daily was shown to provide relief of heartburn pain within 24 hours of initiating therapy and a reduction in the frequency of severity of heartburn. Erosive Esophagitis: In 2 multicenter, double-blind, randomized, placebo-controlled, 12-week trials performed in the United States, ZANTAC 150 mg 4 times daily was significantly more effective than placebo in healing endoscopically diagnosed erosive esophagitis and in relieving associated heartburn. The erosive esophagitis healing rates were as follows: Table 7. Erosive Esophagitis Patient Healing Rates Healed/Evaluable Placeboa n = 229 ZANTAC 150 mg 4 times dailya n = 215 Week 4 43/198 (22%) 96/206 (47%)b Week 8 63/176 (36%) 142/200 (71%)b Week 12 92/159 (58%) 162/192 (84%)b a All patients were permitted antacids as needed for relief of pain. b P<0.001 versus placebo. No additional benefit in healing of esophagitis or in relief of heartburn was seen with a ranitidine dose of 300 mg 4 times daily. Maintenance of Healing of Erosive Esophagitis: In 2 multicenter, double-blind, randomized, placebo-controlled, 48-week trials conducted in patients whose erosive esophagitis had been previously healed, ZANTAC 150 mg twice daily was significantly more effective than placebo in maintaining healing of erosive esophagitis.

HOW SUPPLIED

ZANTAC 150 Tablets (ranitidine HCl equivalent to 150 mg of ranitidine) are peach, film-coated, 5-sided tablets embossed with “ZANTAC 150” on one side and “Glaxo” on the other. They are available in bottles of 60 (NDC 0173-0344-42) tablets. ZANTAC 300 Tablets (ranitidine HCl equivalent to 300 mg of ranitidine) are yellow, film-coated, capsule-shaped tablets embossed with “ZANTAC 300” on one side and “Glaxo” on the other. They are available in bottles of 30 (NDC 0173-0393-40) tablets. Store between 15° and 30°C (59° and 86°F) in a dry place. Protect from light. Replace cap securely after each opening. GlaxoSmithKline Research Triangle Park, NC 27709 ZANTAC is a registered trademark of Boehringer Ingelheim Pharmaceuticals, Inc., used under license. MULTISTIX is a trademark of its respective owner and is not a trademark of the GSK group of companies. The maker of this brand is not affiliated with and does not endorse the GSK group of companies or its products. ©2016 the GSK group of companies. All rights reserved. August 2016 ZNT:9PI

GERIATRIC USE

Geriatric Use: Of the total number of subjects enrolled in US and foreign controlled clinical trials of oral formulations of ZANTAC, for which there were subgroup analyses, 4,197 were aged 65 and older, while 899 were aged 75 and older. 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, but greater sensitivity of some older individuals cannot be ruled out. 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, caution should be exercised in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Geriatrics and DOSAGE AND ADMINISTRATION: Dosage Adjustment for Patients with Impaired Renal Function).

INDICATIONS AND USAGE

ZANTAC is indicated in: 1.Short-term treatment of active duodenal ulcer. Most patients heal within 4 weeks. Trials available to date have not assessed the safety of ranitidine in uncomplicated duodenal ulcer for periods of more than 8 weeks. 2.Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of acute ulcers. No placebo-controlled comparative trials have been carried out for periods of longer than 1 year. 3.The treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome and systemic mastocytosis). 4.Short-term treatment of active, benign gastric ulcer. Most patients heal within 6 weeks and the usefulness of further treatment has not been demonstrated. Trials available to date have not assessed the safety of ranitidine in uncomplicated, benign gastric ulcer for periods of more than 6 weeks. 5.Maintenance therapy for gastric ulcer patients at reduced dosage after healing of acute ulcers. Placebo-controlled trials have been carried out for 1 year. 6.Treatment of GERD. Symptomatic relief commonly occurs within 24 hours after starting therapy with ZANTAC 150 mg twice daily. 7.Treatment of endoscopically diagnosed erosive esophagitis. Symptomatic relief of heartburn commonly occurs within 24 hours of therapy initiation with ZANTAC 150 mg 4 times daily. 8.Maintenance of healing of erosive esophagitis. Placebo-controlled trials have been carried out for 48 weeks. Concomitant antacids should be given as needed for pain relief to patients with active duodenal ulcer; active, benign gastric ulcer; hypersecretory states; GERD; and erosive esophagitis.

PEDIATRIC USE

Pediatric Use: The safety and effectiveness of ZANTAC have been established in the age-group of 1 month to 16 years for the treatment of duodenal and gastric ulcers, gastroesophageal reflux disease and erosive esophagitis, and the maintenance of healed duodenal and gastric ulcer. Use of ZANTAC in this age-group is supported by adequate and well-controlled trials in adults, as well as additional pharmacokinetic data in pediatric patients and an analysis of the published literature (see CLINICAL PHARMACOLOGY: Pediatrics and DOSAGE AND ADMINISTRATION: Pediatric Use). Safety and effectiveness in pediatric patients for the treatment of pathological hypersecretory conditions or the maintenance of healing of erosive esophagitis have not been established. Safety and effectiveness in neonates (aged younger than 1 month) have not been established (see CLINICAL PHARMACOLOGY: Pediatrics).

PREGNANCY

Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses up to 160 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to ZANTAC. 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: Ranitidine is secreted in human milk. Caution should be exercised when ZANTAC is administered to a nursing mother.

DOSAGE AND ADMINISTRATION

Active Duodenal Ulcer: The current recommended adult oral dosage of ZANTAC for duodenal ulcer is 150 mg twice daily. An alternative dosage of 300 mg once daily after the evening meal or at bedtime can be used for patients in whom dosing convenience is important. The advantages of one treatment regimen compared with the other in a particular patient population have yet to be demonstrated (see Clinical Trials: Active Duodenal Ulcer). Smaller doses have been shown to be equally effective in inhibiting gastric acid secretion in US trials, and several foreign trials have shown that 100 mg twice daily is as effective as the 150-mg dose. Antacid should be given as needed for relief of pain (see CLINICAL PHARMACOLOGY: Pharmacokinetics). Maintenance of Healing of Duodenal Ulcers: The current recommended adult oral dosage is 150 mg at bedtime. Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome): The current recommended adult oral dosage is 150 mg twice daily. In some patients it may be necessary to administer ZANTAC 150-mg doses more frequently. Dosages should be adjusted to individual patient needs, and should continue as long as clinically indicated. Dosages up to 6 g/day have been employed in patients with severe disease. Benign Gastric Ulcer: The current recommended adult oral dosage is 150 mg twice daily. Maintenance of Healing of Gastric Ulcers: The current recommended adult oral dosage is 150 mg at bedtime. GERD: The current recommended adult oral dosage is 150 mg twice daily. Erosive Esophagitis: The current recommended adult oral dosage is 150 mg 4 times daily. Maintenance of Healing of Erosive Esophagitis: The current recommended adult oral dosage is 150 mg twice daily. Pediatric Use: The safety and effectiveness of ZANTAC have been established in the age-group of 1 month to 16 years. There is insufficient information about the pharmacokinetics of ZANTAC in neonatal patients (aged younger than 1 month) to make dosing recommendations. The following 3 subsections provide dosing information for each of the pediatric indications. Treatment of Duodenal and Gastric Ulcers: The recommended oral dose for the treatment of active duodenal and gastric ulcers is 2 to 4 mg/kg twice daily to a maximum of 300 mg/day. This recommendation is derived from adult clinical trials and pharmacokinetic data in pediatric patients. Maintenance of Healing of Duodenal and Gastric Ulcers: The recommended oral dose for the maintenance of healing of duodenal and gastric ulcers is 2 to 4 mg/kg once daily to a maximum of 150 mg/day. This recommendation is derived from adult clinical trials and pharmacokinetic data in pediatric patients. Treatment of GERD and Erosive Esophagitis: Although limited data exist for these conditions in pediatric patients, published literature supports a dosage of 5 to 10 mg/kg/day, usually given as 2 divided doses. Dosage Adjustment for Patients with Impaired Renal Function: On the basis of experience with a group of subjects with severely impaired renal function treated with ZANTAC, the recommended dosage in patients with a creatinine clearance <50 mL/min is 150 mg every 24 hours. Should the patient's condition require, the frequency of dosing may be increased to every 12 hours or even further with caution. Hemodialysis reduces the level of circulating ranitidine. Ideally, the dosing schedule should be adjusted so that the timing of a scheduled dose coincides with the end of hemodialysis. Elderly patients are more likely to have decreased renal function, therefore caution should be exercised in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Geriatrics and PRECAUTIONS: Geriatric Use).

gabapentin 300 MG Oral Capsule

Generic Name: GABAPENTIN
Brand Name: Gabapentin
  • Substance Name(s):
  • GABAPENTIN

DRUG INTERACTIONS

7 •Morphine increases gabapentin concentrations; dose adjustment may be needed (5.4, 7.2) 7.1 Other Antiepileptic Drugs Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly co-administered antiepileptic drugs [see Clinical Pharmacology (12.3)]. 7.2 Opioids Hydrocodone Co-administration of gabapentin with hydrocodone decreases hydrocodone exposure [see Clinical Pharmacology (12.3)].The potential for alteration in hydrocodone exposure and effect should be considered when gabapentin is started or discontinued in a patient taking hydrocodone. Morphine When gabapentin is administered with morphine, patients should be observed for signs of central nervous system (CNS) depression, such as somnolence, sedation and respiratory depression [see Clinical Pharmacology (12.3)]. 7.3 MAALOX® (aluminum hydroxide, magnesium hydroxide) The mean bioavailability of gabapentin was reduced by about 20% with concomitant use of an antacid (Maalox®) containing magnesium and aluminum hydroxides. It is recommended that gabapentin be taken at least 2 hours following Maalox administration [see Clinical Pharmacology (12.3)]. 7.4 Drug/Laboratory Test Interactions Because false positive readings were reported with the Ames N-Multistix SG® dipstick test for urinary protein when gabapentin was added to other antiepileptic drugs, the more specific sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine protein.

OVERDOSAGE

10 A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation. Acute oral overdoses of gabapentin up to 49 grams have been reported. In these cases, double vision, slurred speech, drowsiness, lethargy, and diarrhea were observed. All patients recovered with supportive care. Coma, resolving with dialysis, has been reported in patients with chronic renal failure who were treated with gabapentin. Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients with significant renal impairment. If overexposure occurs, call your poison control center at 1-800-222-1222.

DESCRIPTION

11 The active ingredient in gabapentin capsules, USP is gabapentin, USP which has the chemical name 1-(aminomethyl)cyclohexaneacetic acid. The molecular formula of gabapentin is C9H17NO2 and the molecular weight is 171.24. The structural formula of gabapentin is: Gabapentin, USP is a white to off-white crystalline solid with a pKa1 of 3.7 and a pKa2 of 10.7. It is freely soluble in water and both basic and acidic aqueous solutions. The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is –1.25. Each gabapentin, USP capsule contains 100 mg, 300 mg, or 400 mg of gabapentin and the following inactive ingredients: magnesium stearate, pregelatinized starch (corn), starch (corn) and talc. The 100 mg capsule shell contains gelatin, sodium lauryl sulfate and titanium dioxide. The 300 mg capsule shell contains gelatin, sodium lauryl sulfate, titanium dioxide, and iron oxide yellow. The 400 mg capsule shell contains gelatin, sodium lauryl sulfate, titanium dioxide, FD&C Yellow No.6 and FD&C Blue No.1. chem structure

CLINICAL STUDIES

14 14.1 Postherpetic Neuralgia Gabapentin was evaluated for the management of postherpetic neuralgia (PHN) in two randomized, double-blind, placebo-controlled, multicenter studies. The intent-to-treat (ITT) population consisted of a total of 563 patients with pain for more than 3 months after healing of the herpes zoster skin rash (Table 6). TABLE 6. Controlled PHN Studies: Duration, Dosages, and Number of Patients Study Study Duration Gabapentin (mg/day)a Target Dose Patients Receiving Gabapentin Patients Receiving Placebo 1 8 weeks 3600 113 116 2 7 weeks 1800, 2400 223 111 Total 336 227 a Given in 3 divided doses (TID) Each study included a 7 -or 8-week double-blind phase (3 or 4 weeks of titration and 4 weeks of fixed dose). Patients initiated treatment with titration to a maximum of 900 mg/day gabapentin over 3 days. Dosages were then to be titrated in 600 to 1200 mg/day increments at 3-to 7-day intervals to the target dose over 3 to 4 weeks. Patients recorded their pain in a daily diary using an 11-point numeric pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). A mean pain score during baseline of at least 4 was required for randomization. Analyses were conducted using the ITT population (all randomized patients who received at least one dose of study medication). Both studies demonstrated efficacy compared to placebo at all doses tested. The reduction in weekly mean pain scores was seen by Week 1 in both studies, and were maintained to the end of treatment. Comparable treatment effects were observed in all active treatment arms.Pharmacokinetic/pharmacodynamic modeling provided confirmatory evidence of efficacy across all doses. Figures 1 and 2 show pain intensity scores over time for Studies 1 and 2. Figure 1. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 1 Figure 2. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 2 The proportion of responders (those patients reporting at least 50% improvement in endpoint pain score compared with baseline) was calculated for each study (Figure 3). Figure 3. Proportion of Responders (patients with ≥50% reduction in pain score) at Endpoint: Controlled PHN Studies figure 1 figure 2 figure 3 14.2 Epilepsy for Partial Onset Seizures (Adjunctive Therapy) The effectiveness of gabapentin as adjunctive therapy (added to other antiepileptic drugs) was established in multicenter placebo-controlled, double-blind, parallel-group clinical trials in adult and pediatric patients (3 years and older) with refractory partial seizures. Evidence of effectiveness was obtained in three trials conducted in 705 patients (age 12 years and above) and one trial conducted in 247 pediatric patients (3 to 12 years of age). The patients enrolled had a history of at least 4 partial seizures per month in spite of receiving one or more antiepileptic drugs at therapeutic levels and were observed on their established antiepileptic drug regimen during a 12-week baseline period (6 weeks in the study of pediatric patients). In patients continuing to have at least 2 (or 4 in some studies) seizures per month, gabapentin or placebo was then added on to the existing therapy during a 12-week treatment period. Effectiveness was assessed primarily on the basis of the percent of patients with a 50% or greater reduction in seizure frequency from baseline to treatment (the “responder rate”) and a derived measure called response ratio, a measure of change defined as (T -B)/(T + B), in which B is the patient’s baseline seizure frequency and T is the patient’s seizure frequency during treatment. Response ratio is distributed within the range -1 to +1. A zero value indicates no change while complete elimination of seizures would give a value of -1; increased seizure rates would give positive values. A response ratio of -0.33 corresponds to a 50% reduction in seizure frequency. The results given below are for all partial seizures in the intent-to-treat (all patients who received any doses of treatment) population in each study, unless otherwise indicated. One study compared gabapentin 1200 mg/day, in three divided doses, with placebo. Responder rate was 23% (14/61) in the gabapentin group and 9% (6/66) in the placebo group; the difference between groups was statistically significant. Response ratio was also better in the gabapentin group (-0.199) than in the placebo group (-0.044), a difference that also achieved statistical significance. A second study compared primarily gabapentin 1200 mg/day, in three divided doses (N=101), with placebo (N=98). Additional smaller gabapentin dosage groups (600 mg/day, N=53; 1800 mg/day, N=54) were also studied for information regarding dose response. Responder rate was higher in the gabapentin 1200 mg/day group (16%) than in the placebo group (8%), but the difference was not statistically significant. The responder rate at 600 mg (17%) was also not significantly higher than in the placebo, but the responder rate in the 1800 mg group (26%) was statistically significantly superior to the placebo rate. Response ratio was better in the gabapentin 1200 mg/day group (-0.103) than in the placebo group (-0.022); but this difference was also not statistically significant (p = 0.224). A better response was seen in the gabapentin 600 mg/day group (-0.105) and 1800 mg/day group (-0.222) than in the 1200 mg/day group, with the 1800 mg/day group achieving statistical significance compared to the placebo group. A third study compared gabapentin 900 mg/day, in three divided doses (N=111), and placebo (N=109). An additional gabapentin 1200 mg/day dosage group (N=52) provided dose-response data. A statistically significant difference in responder rate was seen in the gabapentin 900 mg/day group (22%) compared to that in the placebo group (10%). Response ratio was also statistically significantly superior in the gabapentin 900 mg/day group (-0.119) compared to that in the placebo group (-0.027), as was response ratio in 1200 mg/day gabapentin (-0.184) compared to placebo. Analyses were also performed in each study to examine the effect of gabapentin on preventing secondarily generalized tonic-clonic seizures. Patients who experienced a secondarily generalized tonic-clonic seizure in either the baseline or in the treatment period in all three placebo-controlled studies were included in these analyses. There were several response ratio comparisons that showed a statistically significant advantage for gabapentin compared to placebo and favorable trends for almost all comparisons. Analysis of responder rate using combined data from all three studies and all doses (N=162, gabapentin; N=89, placebo) also showed a significant advantage for gabapentin over placebo in reducing the frequency of secondarily generalized tonic-clonic seizures. In two of the three controlled studies, more than one dose of gabapentin was used. Within each study, the results did not show a consistently increased response to dose. However, looking across studies, a trend toward increasing efficacy with increasing dose is evident (see Figure 4). Figure 4. Responder Rate in Patients Receiving Gabapentin Expressed as a Difference from Placebo by Dose and Study: Adjunctive Therapy Studies in Patients ≥12 Years of Age with Partial Seizures In the figure, treatment effect magnitude, measured on the Y axis in terms of the difference in the proportion of gabapentin and placebo-assigned patients attaining a 50% or greater reduction in seizure frequency from baseline, is plotted against the daily dose of gabapentin administered (X axis). Although no formal analysis by gender has been performed, estimates of response (Response Ratio) derived from clinical trials (398 men, 307 women) indicate no important gender differences exist. There was no consistent pattern indicating that age had any effect on the response to gabapentin. There were insufficient numbers of patients of races other than Caucasian to permit a comparison of efficacy among racial groups. A fourth study in pediatric patients age 3 to 12 years compared 25 to 35 mg/kg/day gabapentin (N=118) with placebo (N=127). For all partial seizures in the intent-to-treat population, the response ratio was statistically significantly better for the gabapentin group (-0.146) than for the placebo group (-0.079). For the same population, the responder rate for gabapentin (21%) was not significantly different from placebo (18%). A study in pediatric patients age 1 month to 3 years compared 40 mg/kg/day gabapentin (N=38) with placebo (N=38) in patients who were receiving at least one marketed antiepileptic drug and had at least one partial seizure during the screening period (within 2 weeks prior to baseline). Patients had up to 48 hours of baseline and up to 72 hours of double-blind video EEG monitoring to record and count the occurrence of seizures. There were no statistically significant differences between treatments in either the response ratio or responder rate. figure 4

HOW SUPPLIED

16 /STORAGE AND HANDLING Gabapentin capsules, USP are supplied as follows: 100 mg capsules: White-White, opaque hard gelatin capsules printed with “IP 101” on both cap and body. They are available as follows: Boxes of 10×10 UD 100 NDC 63739-591-10 300 mg capsules: Buff-Buff, opaque hard gelatin capsules printed with “IP 102” on both cap and body. They are available as follows: Boxes of 10×10 UD 100 NDC 63739-236-10 400 mg capsules: Light caramel-Light caramel, opaque hard gelatin capsules printed with “IP 103” on both cap and body. They are available as follows: Boxes of 10×10 UD 100 NDC 63739-984-10 Store gabapentin capsules at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Dispense in tight (USP), child-resistant containers.

RECENT MAJOR CHANGES

•Warnings and Precautions: Anaphylaxis and Angioedema: discontinue gabapentin and evaluate patient immediately (5.2) 9/2015

GERIATRIC USE

8.5 Geriatric Use The total number of patients treated with gabapentin in controlled clinical trials in patients with postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%) were 75 years of age and older. There was a larger treatment effect in patients 75 years of age and older compared with younger patients who received the same dosage. Since gabapentin is almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients ≥75 years may be a consequence of increased gabapentin exposure for a given dose that results from an age-related decrease in renal function. However, other factors cannot be excluded. The types and incidence of adverse reactions were similar across age groups except for peripheral edema and ataxia, which tended to increase in incidence with age. Clinical studies of gabapentin in epilepsy did not include sufficient numbers of subjects aged 65 and over to determine whether they responded 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 dose should be adjusted based on creatinine clearance values in these patients [see Dosage and Administration (2.4), Adverse Reactions (6), and Clinical Pharmacology (12.3)].

DOSAGE FORMS AND STRENGTHS

3 Capsules: •100 mg: white-white, opaque hard gelatin capsules printed with “IP 101” on both cap and body. •300 mg: buff-buff, opaque hard gelatin capsules printed with “IP 102” on both cap and body. •400 mg: light caramel-light caramel, opaque hard gelatin capsules printed with “IP 103” on both cap and body. •Capsules: 100 mg, 300 mg, and 400 mg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action The precise mechanisms by which gabapentin produces its analgesic and antiepileptic actions are unknown. Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA) but has no effect on GABA binding, uptake, or degradation. In vitro studies have shown that gabapentin binds with high-affinity to the α2δ subunit of voltage-activated calcium channels; however, the relationship of this binding to the therapeutic effects of gabapentin is unknown.

INDICATIONS AND USAGE

1 Gabapentin capsules, USP are indicated for: •Management of postherpetic neuralgia in adults •Adjunctive therapy in the treatment of partial onset seizures, with and without secondary generalization, in adults and pediatric patients 3 years and older with epilepsy Gabapentin capsules are indicated for: •Postherpetic neuralgia in adults (1) •Adjunctive therapy in the treatment of partial onset seizures, with and without secondary generalization, in adults and pediatric patients 3 years and older with epilepsy (1)

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness of gabapentin in the management of postherpetic neuralgia in pediatric patients have not been established. Effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below the age of 3 years has not been established [see Clinical Studies (14.2)].

PREGNANCY

8.1 Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. In nonclinical studies in mice, rats, and rabbits, gabapentin was developmentally toxic when administered to pregnant animals at doses similar to or lower than those used clinically. Gabapentin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When pregnant mice received oral doses of gabapentin (500, 1000, or 3000 mg/kg/day) during the period of organogenesis, embryo-fetal toxicity (increased incidences of skeletal variations) was observed at the two highest doses. The no-effect dose for embryo-fetal developmental toxicity in mice was 500 mg/kg/day or approximately ½ of the maximum recommended human dose (MRHD) of 3600 mg/kg on a body surface area (mg/m2) basis. In studies in which rats received oral doses of gabapentin (500 to 2000 mg/kg/day), during pregnancy, adverse effect on offspring development (increased incidences of hydroureter and/or hydronephrosis) were observed at all doses. The lowest effect dose for developmental toxicity in rats is approximately equal to the MRHD on a mg/m2 basis. When pregnant rabbits were treated with gabapentin during the period of organogenesis, an increase in embryo-fetal mortality was observed at all doses tested (60, 300, or 1500 mg/kg). The lowest effect dose for embryo-fetal developmental toxicity in rabbits is less than the MRHD on a mg/m2 basis. In a published study, gabapentin (400 mg/kg/day) was administered by intraperitoneal injection to neonatal mice during the first postnatal week, a period of synaptogenesis in rodents (corresponding to the last trimester of pregnancy in humans). Gabapentin caused a marked decrease in neuronal synapse formation in brains of intact mice and abnormal neuronal synapse formation in a mouse model of synaptic repair. Gabapentin has been shown in vitro to interfere with activity of the α2δ subunit of voltage-activated calcium channels, a receptor involved in neuronal synaptogenesis. The clinical significance of these findings is unknown. To provide information regarding the effects of in utero exposure to gabapentin, physicians are advised to recommend that pregnant patients taking gabapentin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

NUSRING MOTHERS

8.3 Nursing Mothers Gabapentin is secreted into human milk following oral administration. A nursed infant could be exposed to a maximum dose of approximately 1 mg/kg/day of gabapentin. Because the effect on the nursing infant is unknown, gabapentin should be used in women who are nursing only if the benefits clearly outweigh the risks.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Drug Reaction with Eosinophilia and Systemic Symptoms (Multiorgan hypersensitivity): discontinue gabapentin if an alternative etiology cannot be established (5.1) •Anaphylaxis and Angioedema: discontinue gabapentin and evaluate patient immediately (5.2) • Driving impairment: warn patients not to drive until they have gained sufficient experience with gabapentin to assess whether it will impair their ability to drive (5.3) • Somnolence/Sedation and Dizziness: gabapentin may impair the patient’s ability to operate complex machinery (5.4) •Increased seizure frequency may occur in patients with seizure disorders if gabapentin is abruptly discontinued (5.5) • Suicidal Behavior and Ideation: monitor for suicidal thoughts and behavior (5.6) • Neuropsychiatric Adverse Reactions in Children 3 to 12 Years of Age: monitor for such events (5.7) 5.1 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with gabapentin. Some of these reactions have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Gabapentin should be discontinued if an alternative etiology for the signs or symptoms cannot be established. 5.2 Anaphylaxis and Angioedema Gabapentin can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms in reported cases have included difficulty breathing, swelling of the lips, throat, and tongue, and hypotension requiring emergency treatment. Patients should be instructed to discontinue gabapentin and seek immediate medical care should they experience signs or symptoms of anaphylaxis or angioedema. 5.3 Effects on Driving and Operating Heavy Machinery Patients taking gabapentin should not drive until they have gained sufficient experience to assess whether gabapentin impairs their ability to drive. Driving performance studies conducted with a prodrug of gabapentin (gabapentin enacarbil tablet, extended release) indicate that gabapentin may cause significant driving impairment. Prescribers and patients should be aware that patients’ ability to assess their own driving competence, as well as their ability to assess the degree of somnolence caused by gabapentin, can be imperfect. The duration of driving impairment after starting therapy with gabapentin is unknown. Whether the impairment is related to somnolence [see Warnings and Precautions (5.4)] or other effects of gabapentin is unknown. Moreover, because gabapentin causes somnolence and dizziness [see Warnings and Precautions (5.4)], patients should be advised not to operate complex machinery until they have gained sufficient experience on gabapentin to assess whether gabapentin impairs their ability to perform such tasks. 5.4 Somnolence/Sedation and Dizziness During the controlled epilepsy trials in patients older than 12 years of age receiving doses of gabapentin up to 1800 mg daily, somnolence, dizziness, and ataxia were reported at a greater rate in patients receiving gabapentin compared to placebo: i.e., 19% in drug versus 9% in placebo for somnolence, 17% in drug versus 7% in placebo for dizziness, and 13% in drug versus 6% in placebo for ataxia. In these trials somnolence, ataxia and fatigue were common adverse reactions leading to discontinuation of gabapentin in patients older than 12 years of age, with 1.2%, 0.8% and 0.6% discontinuing for these events, respectively. During the controlled trials in patients with post-herpetic neuralgia, somnolence and dizziness were reported at a greater rate compared to placebo in patients receiving gabapentin, in dosages up to 3600 mg per day: i.e., 21% in gabapentin-treated patients versus 5% in placebo-treated patients for somnolence and 28% in gabapentin-treated patients versus 8% in placebo-treated patients for dizziness. Dizziness and somnolence were among the most common adverse reactions leading to discontinuation of gabapentin. Patients should be carefully observed for signs of central nervous system (CNS) depression, such as somnolence and sedation, when gabapentin is used with other drugs with sedative properties because of potential synergy. In addition, patients who require concomitant treatment with morphine may experience increases in gabapentin concentrations and may require dose adjustment [see Drug Interactions (7.2) ]. 5.5 Withdrawal Precipitated Seizure, Status Epilepticus Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency. In the placebo-controlled epilepsy studies in patients >12 years of age, the incidence of status epilepticus in patients receiving gabapentin was 0.6% (3 of 543) vs. 0.5% in patients receiving placebo (2 of 378). Among the 2074 patients >12 years of age treated with gabapentin across all epilepsy studies (controlled and uncontrolled), 31 (1.5%) had status epilepticus. Of these, 14 patients had no prior history of status epilepticus either before treatment or while on other medications. Because adequate historical data are not available, it is impossible to say whether or not treatment with gabapentin is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with gabapentin. 5.6 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including gabapentin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono-and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. TABLE 2. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing gabapentin or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. 5.7 Neuropsychiatric Adverse Reactions (Pediatric Patients 3 to 12 Years of Age) Gabapentin use in pediatric patients with epilepsy 3 to 12 years of age is associated with the occurrence of central nervous system related adverse reactions. The most significant of these can be classified into the following categories: 1) emotional lability (primarily behavioral problems), 2) hostility, including aggressive behaviors, 3) thought disorder, including concentration problems and change in school performance, and 4) hyperkinesia (primarily restlessness and hyperactivity). Among the gabapentin-treated patients, most of the reactions were mild to moderate in intensity. In controlled clinical epilepsy trials in pediatric patients 3 to 12 years of age, the incidence of these adverse reactions was: emotional lability 6% (gabapentin-treated patients) vs. 1.3% (placebo-treated patients); hostility 5.2% vs. 1.3%; hyperkinesia 4.7% vs. 2.9%; and thought disorder 1.7% vs. 0%. One of these reactions, a report of hostility, was considered serious. Discontinuation of gabapentin treatment occurred in 1.3% of patients reporting emotional lability and hyperkinesia and 0.9% of gabapentin-treated patients reporting hostility and thought disorder. One placebo-treated patient (0.4%) withdrew due to emotional lability. 5.8 Tumorigenic Potential In an oral carcinogenicity study, gabapentin increased the incidence of pancreatic acinar cell tumors in rats [see Nonclinical Toxicology (13.1)]. The clinical significance of this finding is unknown. Clinical experience during gabapentin’s premarketing development provides no direct means to assess its potential for inducing tumors in humans. In clinical studies in adjunctive therapy in epilepsy comprising 2085 patient-years of exposure in patients >12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ), and preexisting tumors worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following discontinuation of gabapentin. Without knowledge of the background incidence and recurrence in a similar population not treated with gabapentin, it is impossible to know whether the incidence seen in this cohort is or is not affected by treatment. 5.9 Sudden and Unexplained Death in Patients with Epilepsy During the course of premarketing development of gabapentin, 8 sudden and unexplained deaths were recorded among a cohort of 2203 epilepsy patients treated (2103 patient-years of exposure) with gabapentin. Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0038 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving gabapentin (ranging from 0.0005 for the general population of epileptics to 0.003 for a clinical trial population similar to that in the gabapentin program, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or raise further concern depends on comparability of the populations reported upon to the gabapentin cohort and the accuracy of the estimates provided.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Administration Information Inform patients that gabapentin is taken orally with or without food. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Prior to initiation of treatment with gabapentin, instruct patients that a rash or other signs or symptoms of hypersensitivity (such as fever or lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately [see Warnings and Precautions (5.1)]. Anaphylaxis and Angioedema Advise patients to discontinue gabapentin and seek medical care if they develop signs or symptoms of anaphylaxis or angioedema [see Warnings and Precautions (5.2)]. Dizziness and Somnolence and Effects on Driving and Operating Heavy Machinery Advise patients that gabapentin may cause dizziness, somnolence, and other symptoms and signs of CNS depression. Other drugs with sedative properties may increase these symptoms. Accordingly, although patients’ ability to determine their level of impairment can be unreliable, advise them neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on gabapentin to gauge whether or not it affects their mental and/or motor performance adversely. Inform patients that it is not known how long this effect lasts [see Warnings and Precautions (5.3) and Warnings and Precautions (5.4)]. Suicidal Thinking and Behavior Counsel the patient, their caregivers, and families that AEDs, including gabapentin, may increase the risk of suicidal thoughts and behavior. Advise patients of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients to report behaviors of concern immediately to healthcare providers [see Warnings and Precautions (5.6)]. Use in Pregnancy Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breast feeding or intend to breast feed during therapy [see Use in Specific Populations (8.1) and (8.3)]. Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations (8.1)]. This product’s label may have been updated. For full prescribing information, please visit www.amneal.com. *Trademarks are the property of their respective owners. Manufactured by: Amneal Pharmaceuticals 400 Crossing Boulevard, 3rd Floor Bridgewater, NJ 08807 Distributed by: McKesson Packaging Services a business unit of McKesson Corporation 7101 Weddington Rd., Concord, NC 28027 IS-4015283 November 2015

DOSAGE AND ADMINISTRATION

2 •Postherpetic Neuralgia (2.1) •Dose can be titrated up as needed to a dose of 1800 mg/day •Day 1: Single 300 mg dose •Day 2: 600 mg/day (i.e., 300 mg two times a day) •Day 3: 900 mg/day (i.e., 300 mg three times a day) •Epilepsy with Partial Onset Seizures (2.2) •Patients 12 years of age and older: starting dose is 300 mg three times daily; may be titrated up to 600 mg three times daily •Patients 3 to 11 years of age: starting dose range is 10 to 15 mg/kg/day, given in three divided doses; recommended dose in patients 3 to 4 years of age is 40 mg/kg/day, given in three divided doses; the recommended dose in patients 5 to 11 years of age is 25 to 35 mg/kg/day, given in three divided doses. The recommended dose is reached by upward titration over a period of approximately 3 days • Dose should be adjusted in patients with reduced renal function (2.3, 2.4) 2.1 Dosage for Postherpetic Neuralgia In adults with postherpetic neuralgia, gabapentin capsules, USP may be initiated on Day 1 as a single 300 mg dose, on Day 2 as 600 mg/day (300 mg two times a day), and on Day 3 as 900 mg/day (300 mg three times a day). The dose can subsequently be titrated up as needed for pain relief to a dose of 1800 mg/day (600 mg three times a day). In clinical studies, efficacy was demonstrated over a range of doses from 1800 mg/day to 3600 mg/day with comparable effects across the dose range; however, in these clinical studies, the additional benefit of using doses greater than 1800 mg/day was not demonstrated. 2.2 Dosage for Epilepsy with Partial Onset Seizures Patients 12 years of age and above The starting dose is 300 mg three times a day. The recommended maintenance dose of gabapentin capsules, USP is 300 mg to 600 mg three times a day. Dosages up to 2400 mg/day have been well tolerated in long-term clinical studies. Doses of 3600 mg/day have also been administered to a small number of patients for a relatively short duration, and have been well tolerated. Administer gabapentin capsules, USP three times a day using 300 mg or 400 mg capsules. The maximum time between doses should not exceed 12 hours. Pediatric Patients Age 3 to 11 years The starting dose range is 10 mg/kg/day to 15 mg/kg/day, given in three divided doses, and the recommended maintenance dose reached by upward titration over a period of approximately 3 days. The recommended maintenance dose of gabapentin capsules, USP in patients 3 to 4 years of age is 40 mg/kg/day, given in three divided doses. The recommended maintenance dose of gabapentin capsules, USP in patients 5 to 11 years of age is 25 mg/kg/day to 35 mg/kg/day, given in three divided doses. Gabapentin capsules, USP may be administered as the oral solution, capsule, or tablet, or using combinations of these formulations. Dosages up to 50 mg/kg/day have been well tolerated in a long-term clinical study. The maximum time interval between doses should not exceed 12 hours. 2.3 Dosage Adjustment in Patients with Renal Impairment Dosage adjustment in patients 12 years of age and older with renal impairment or undergoing hemodialysis is recommended, as follows (see dosing recommendations above for effective doses in each indication): TABLE 1. Gabapentin Capsules, USP Dosage Based on Renal Function Renal Function Creatinine Clearance (mL/min) Total Daily Dose Range (mg/day) Dose Regimen (mg) ≥ 60 900 to 3600 300 TID 400 TID 600 TID 800 TID 1200 TID >30 to 59 400 to 1400 200 BID 300 BID 400 BID 500 BID 700 BID >15 to 29 200 to 700 200 QD 300 QD 400 QD 500 QD 700 QD 15a 100 to 300 100 QD 125 QD 150 QD 200 QD 300 QD Post-Hemodialysis Supplemental Dose (mg)b Hemodialysis 125b 150 b 200 b 250 b 350 b TID = Three times a day; BID = Two times a day; QD = Single daily dose a For patients with creatinine clearance <15 mL/min, reduce daily dose in proportion to creatinine clearance (e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients with a creatinine clearance of 15 mL/min receive). b Patients on hemodialysis should receive maintenance doses based on estimates of creatinine clearance as indicated in the upper portion of the table and a supplemental post-hemodialysis dose administered after each 4 hours of hemodialysis as indicated in the lower portion of the table. Creatinine clearance (CLCr) is difficult to measure in outpatients. In patients with stable renal function, creatinine clearance can be reasonably well estimated using the equation of Cockcroft and Gault: The use of gabapentin capsules, USP in patients less than 12 years of age with compromised renal function has not been studied. formula 2.4 Dosage in Elderly Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and dose should be adjusted based on creatinine clearance values in these patients. 2.5 Administration Information Administer gabapentin capsules, USP orally with or without food. Gabapentin capsules, USP should be swallowed whole with water. If the gabapentin capsules, USP dose is reduced, discontinued, or substituted with an alternative medication, this should be done gradually over a minimum of 1 week (a longer period may be needed at the discretion of the prescriber).

tramadol hydrochloride 200 MG 24 HR Extended Release Oral Tablet

Generic Name: TRAMADOL HYDROCHLORIDE
Brand Name: TRAMADOL HYDROCHLORIDE
  • Substance Name(s):
  • TRAMADOL HYDROCHLORIDE

DRUG INTERACTIONS

7 Table 2 includes clinically significant drug interactions with tramadol hydrochloride extended-release tablets. Table 2: Clinically Significant Drug Interactions with Tramadol Hydrochloride Extended-Release Tablets Inhibitors of CYP2D6 Clinical Impact: The concomitant use of tramadol hydrochloride extended-release tablets and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)]. Intervention: If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation. Examples Quinidine, fluoxetine, paroxetine and bupropion Inhibitors of CYP3A4 Clinical Impact: The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Intervention: If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride extended-release tablets until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal. Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol, [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures and serotonin syndrome, and potentially fatal respiratory depression. Intervention: If concomitant use is necessary, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride extended-release tablets dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride extended-release tablets and carbamazepine is not recommended. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.6)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]. Intervention: Do not use tramadol hydrochloride extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of tramadol hydrochloride extended-release tablets and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride extended-release tablets and/or the muscle relaxant as necessary. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride extended-release tablets are used concomitantly with anticholinergic drugs. Digoxin Clinical Impact: Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity. Intervention: Follow patients for signs of digoxin toxicity and adjust the dosage of digoxin as needed. Warfarin Clinical Impact: Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times. Intervention: Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with tramadol hydrochloride extended-release tablets because they may reduce analgesic effect of tramadol hydrochloride extended-release tablets or precipitate withdrawal symptoms. (5.15, 7)

OVERDOSAGE

10 Clinical Presentation Acute overdosage with tramadol hydrochloride extended-release tablets can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)]. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques. The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to tramadol overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to tramadol overdose. While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. In animals, convulsions following the administration of toxic doses of tramadol hydrochloride extended-release tablets could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice. Hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period. Because the duration of opioid reversal is expected to be less than the duration of action of tramadol in tramadol hydrochloride extended-release tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. Tramadol hydrochloride extended-release tablets will continue to release tramadol and add to the tramadol load for 24 to 48 hours or longer following ingestion, necessitating prolonged monitoring. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

DESCRIPTION

11 Tramadol hydrochloride is an opioid agonist in an extended-release tablet formulation for oral use. The chemical name is (±)cis-2-[(dimethylamino) methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is: The molecular weight of tramadol hydrochloride is 299.84. It is a white, crystalline powder that is freely soluble in water and methanol, very slightly soluble in acetone and has a pKa of 9.41. The n-octanol/water log partition coefficient (logP) is 1.35 at pH 7. Tramadol hydrochloride extended-release tablets contain 100 mg, 200 mg or 300 mg of tramadol hydrochloride, USP in an extended-release formulation. The tablets are white in color and contain the inactive ingredients pregelatinized maize starch, hypromellose, mannitol, magnesium stearate, cellulose acetate and polyethylene glycol. Imprinting ink contains, shellac glaze, iron oxide black, N-butyl alcohol, ammonium hydroxide and propylene glycol. tramadol-structure

CLINICAL STUDIES

14 Clinical Trial Experience Tramadol hydrochloride extended-release tablets were studied in patients with chronic, moderate to moderately severe pain due to osteoarthritis and/or low back pain in four 12-week, randomized, double-blind, placebocontrolled trials. To qualify for inclusion into these studies, patients were required to have moderate to moderately severe pain as defined by a pain intensity score of ≥40 mm, off previous medications, on a 0 to 100 mm visual analog scale (VAS). Adequate evidence of efficacy was demonstrated in the following two studies: Study 1 : Osteoarthritis of the Knee and/or Hip In one 12-week randomized, double-blind, placebo-controlled study, patients with moderate to moderately severe pain due to osteoarthritis of the knee and/or hip were administered doses from 100 mg to 400 mg daily. Treatment was initiated at 100 mg QD for four days then increased by 100 mg per day increments every five days to the randomized fixed dose. Between 51% and 59% of patients in the tramadol hydrochloride extended-release tablets treatment groups completed the study and 56% of patients in the placebo group completed the study. Discontinuations due to adverse events were more common in the tramadol hydrochloride extended-release tablets 200 mg, 300 mg and 400 mg treatment groups (20%, 27%, and 30% of discontinuations, respectively) compared to 14% of the patients treated with tramadol hydrochloride extended-release tablets 100 mg and 10% of patients treated with placebo. Pain, as assessed by the WOMAC Pain subscale, was measured at 1, 2, 3, 6, 9, and 12 weeks and change from baseline assessed. A responder analysis based on the percent change in WOMAC Pain subscale demonstrated a statistically significant improvement in pain for the 100 mg and 200 mg treatment groups compared to placebo (see Figure 3). Study 2: Osteoarthritis of the Knee In one 12-week randomized, double-blind, placebo-controlled flexible-dosing trial of tramadol hydrochloride extended-release tablets in patients with osteoarthritis of the knee, patients titrated to an average daily tramadol hydrochloride extended-release tablets dose of approximately 270 mg/day. Forty-nine percent of patients randomized to tramadol hydrochloride extended-release tablets completed the study, while 52% of patients randomized to placebo completed the study. Most of the early discontinuations in the tramadol hydrochloride extended-release tablets treatment group were due to adverse events, accounting for 27% of the early discontinuations in contrast to 7% of the discontinuations from the placebo group. Thirty-seven percent of the placebo-treated patients discontinued the study due to lack of efficacy compared to 15% of tramadol hydrochloride extended-release tablets-treated patients. The tramadol hydrochloride extended-release tablets group demonstrated a statistically significant decrease in the mean VAS score, and a statistically significant difference in the responder rate, based on the percent change from baseline in the VAS score, measured at 1, 2, 4, 8, and 12 weeks, between patients receiving tramadol hydrochloride extended-release tablets and placebo (see Figure 4). tramadol-figure3 tramadol-figure4

HOW SUPPLIED

16 /STORAGE AND HANDLING Tramadol hydrochloride extended-release tablets are supplied in the following package and dose strength forms: 100 mg: White, round shape, biconvex, beveled edge, coated tablet with release portal on the center of the tablet on any one side, imprinted “531” with black ink on one side and plain on other side. Bottles of 30’s with Child Resistant Cap ……………… NDC 47335-859-83 Bottles of 100’s with Child Resistant Cap ……………. NDC 47335-859-88 Bottles of 100’s with Non Child Resistant Cap ……… NDC 47335-859-08 Bottles of 1000’s with Non Child Resistant Cap …….. NDC 47335-859-18 200 mg: White, round shape, biconvex, beveled edge, coated tablet with release portal on the center of the tablet on any one side, imprinted “533” with black ink on one side and plain on other side. Bottles of 30’s with Child Resistant Cap ……………… NDC 47335-860-83 Bottles of 100’s with Child Resistant Cap ……………. NDC 47335-860-88 Bottles of 100’s with Non Child Resistant Cap ……… NDC 47335-860-08 Bottles of 1000’s with Non Child Resistant Cap …….. NDC 47335-860-18 300 mg: White, round shape, biconvex, beveled edge, coated tablet with release portal on the center of the tablet on any one side, imprinted “537” with black ink on one side and plain on other side. Bottles of 30’s with Child Resistant Cap ……………… NDC 47335-861-83 Bottles of 100’s with Child Resistant Cap ……………. NDC 47335-861-88 Bottles of 100’s with Non Child Resistant Cap ……… NDC 47335-861-08 Bottles of 1000’s with Non Child Resistant Cap …….. NDC 47335-861-18 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]. Dispense in a tight, light resistant container. Warning: keep out of reach of children.

RECENT MAJOR CHANGES

Boxed Warning 12/2016 Indication and Usage (1) 12/2016 Dosage and Administration (2) 12/2016 Contraindications (4) 12/2016 Warnings and Precautions (5) 12/2016

GERIATRIC USE

8.5 Geriatric Use Nine-hundred-one elderly (65 years of age or older) subjects were exposed to tramadol hydrochloride extended-release tablets in clinical trials. Of those subjects, 156 were 75 years of age and older. In general, higher incidence rates of adverse events were observed for patients older than 65 years of age compared with patients 65 years and younger, particularly for the following adverse events: constipation, fatigue, weakness, postural hypotension and dyspepsia. For this reason, tramadol hydrochloride extended-release tablets should be used with caution in patients over 65 years of age, and with even greater caution in patients older than 75 years of age [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioidtolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of tramadol hydrochloride extended-release tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.10)]. Tramadol is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

DOSAGE FORMS AND STRENGTHS

3 DOSAGE FORMS & STRENGTHS Extended-release tablets are available as: 100 mg tablets: White, round shape, biconvex, beveled edge, coated tablet with release portal on the center of the tablet on any one side, imprinted “531” with black ink on one side and plain on other side. 200 mg tablets: White, round shape, biconvex, beveled edge, coated tablet with release portal on the center of the tablet on any one side, imprinted “533” with black ink on one side and plain on other side. 300 mg tablets: White, round shape, biconvex, beveled edge, coated tablet with release portal on the center of the tablet on any one side, imprinted “537” with black ink on one side and plain on other side. Extended-release tablets 100 mg, 200 mg, and 300 mg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action Tramadol hydrochloride extended-release tablets contain tramadol, an opioid agonist and an inhibitor of reuptake of norepinephrine and serotonin. Although the mode of action of tramadol is not completely understood, the analgesic effect of tramadol is believed to be due to both binding to μ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. Opioid activity of tramadol is due to both low affinity binding of the parent compound and higher affinity binding of the O-desmethyl metabolite M1 to μ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opioid antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound. Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol. Apart from analgesia, tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function, or cardiac index. Orthostatic hypotension has been observed.

INDICATIONS AND USAGE

1 INDICATIONS & USAGE Tramadol hydrochloride extended-release tablets are indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations [see Warnings and Precautions (5.1)], reserve tramadol hydrochloride extended-release tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Tramadol hydrochloride extended-release tablets are not indicated as an as-needed (prn) analgesic. Tramadol hydrochloride is an opioid agonist indicated for the management of pain severe enough to require daily around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. (1) Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve tramadol hydrochloride extended-release tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. (1) Tramadol hydrochloride extended-release tablets are not indicated as an as-needed (prn) analgesic. (1)

PEDIATRIC USE

8.4 Pediatric Use The safety and efficacy of tramadol hydrochloride extended-release tablets in patients under 18 years of age have not been established. The use of tramadol hydrochloride extended-release tablets in the pediatric population is not recommended.

PREGNANCY

8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.3)]. Available data with tramadol hydrochloride extended-release tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, tramadol administration during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (MRHD). Tramadol decreased pup body weight and increased pup mortality at 1.2 and 1.9 times the MRHD [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms and signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.3)]. Neonatal seizures, neonatal withdrawal syndrome, fetal death and stillbirth have been reported with tramadol during post-approval use of tramadol immediate-release products. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Tramadol hydrochloride extended-release tablets are not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including tramadol hydrochloride extended-release tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor. The effect of tramadol hydrochloride extended-release tablets, if any, on the later growth, development, and functional maturation of the child is unknown. Data Animal Data Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg), rats (25 mg/kg) and rabbits (75 mg/kg) at maternally toxic dosages, but was not teratogenic at these dose levels. These doses on a mg/m2 basis are 1.9, 0.8, and 4.9 times the maximum recommended human daily dosage (MRHD) for mouse, rat and rabbit, respectively. No drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg), rats (up to 80 mg/kg) or rabbits (up to 300 mg/kg) treated with tramadol by various routes. Embryo and fetal toxicity consisted primarily of decreased fetal weights, decreased skeletal ossification, and increased supernumerary ribs at maternally toxic dose levels. Transient delays in developmental or behavioral parameters were also seen in pups from rat dams allowed to deliver. Embryo and fetal lethality were reported only in one rabbit study at 300 mg/kg, a dose that would cause extreme maternal toxicity in the rabbit. The dosages listed for mouse, rat, and rabbit are 2.3, 2.6, and 19 times the MRHD, respectively. Tramadol was evaluated in pre- and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (1.6 times the MRHD) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (2.6 times the MRHD).

NUSRING MOTHERS

8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)].

BOXED WARNING

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENTING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES AND OTHER CNS DEPRESSANTS Addi ction, Abus e, a nd Misuse Tramadol hydrochloride extended-release tablets expos e pa ti en ts and o th er us ers to the risks of opio id addi ction, abus e, and misus e, w hi ch can l ead to ov erdose and d ea th. Ass ess ea ch pa ti en t’s risk p rior to p res c ribing tramadol hydrochloride extended-release tablets, and moni t or all pa ti en ts regula rly for the d ev elop ment of th ese b ehavio rs and con di tions [s ee Warnings and Pr ecautions (5.1 ) ]. Li f e-Th rea tening Resp i ra to ry D ep ression S erious, li f e-th rea tening, or fa tal respi ra to ry d ep ression may o ccur wi th use of tramadol hydrochloride extended-release tablets. Moni t or for respi ra to ry d ep r e ssion, esp ecially du r ing ini tia tion of tramadol hydrochloride extended-release tablets or follo wing a dose in creas e. Ins tru ct pa ti en ts to s wallow tramadol hydrochloride extended-release tablets in ta ct, and not to cu t, b reak, ch e w, c rush, or dissolve the tabl ets to avoid exposu re to a po ten tially fa tal dose of tra madol [s ee Warnings and Pr e cautions (5.2 ) ]. Accid en tal Ing es tion Accid en tal ing es tion of ev en one dose of tramadol hydrochloride extended-release tablet, esp ecially by child ren, can result in a fa tal ov erdose of tr a madol [s ee War nings and Pr ecautio ns (5.2 ) ]. Neonatal Opioid Withdrawal Syndrome Prolonged use of tramadol hydrochloride extended-release tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available[ see Warnings and Precautions (5.3)]. Interactions with Drugs Affecting Cytochrome P450 Isoenzymes The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol hydrochloride extended-release tablets requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1 [see Warnings and Precautions (5.4), Drug Interactions (7) ]. Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.5), Drug Interactions (7) ]. • Reserve concomitant prescribing of tramadol hydrochloride extended-release injection and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. • Limit dosages and durations to the minimum required. • Follow patients for signs and symptoms of respiratory depression and sedation. WARNING: ADDICTION, ABUSE, AND MISUSE; LIFETHREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES AND OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning . Tramadol hydrochloride extended-release tablets expose users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and monitor regularly for these behaviors and conditions. (5.1) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow tramadol hydrochloride extended-release tablets intact, and not to cut, break, chew, crush, or dissolve the tablets to avoid exposure to a potentially fatal dose of tramadol. (5.2) Accidental ingestion of tramadol hydrochloride extended-release tablets, especially by children, can result in a fatal overdose of tramadol. (5.2) Prolonged use of tramadol hydrochloride extended-release tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.3) The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol hydrochloride extended-release tablets requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1 (5.4, 7) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. (5.5, 7)

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Serotonin Syndrome: Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected. (5.6) Risk of Seizure: Present within recommended dosage range. Risk is increased with higher than recommended doses and concomitant use of SSRIs, SNRIs, anorectics, tricyclic antidepressants and other tricyclic compounds, other opioids, MAOIs, neuroleptics, other drugs that reduce seizure threshold, in patients with epilepsy or at risk for seizures. (5.7, 7) Risk of Suicide: Do not use tramadol hydrochloride extended-release tablets in suicidal or addiction-prone patients. Use with caution in those taking tranquilizers, antidepressants or abuse alcohol. (5.8) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.9) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. (5.10) Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of tramadol hydrochloride extended-release tablets in patients with circulatory shock. (5.11) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of tramadol hydrochloride extended-release tablets in patients with impaired consciousness or coma. (5.12) 5.1 Addiction, Abuse, and Misuse Tramadol hydrochloride extended-release tablet contains tramadol, a Schedule IV controlled substance. As an opioid, tramadol hydrochloride extended-release tablet exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as tramadol hydrochloride extended-release tablets deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of tramadol present [see Drug Abuse and Dependence (9)]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed tramadol hydrochloride extended-release tablets. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing tramadol hydrochloride extended-release tablets, and monitor all patients receiving tramadol hydrochloride extended-release tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as tramadol hydrochloride extended-release tablets, but use in such patients necessitates intensive counseling about the risks and proper use of tramadol hydrochloride extended-release tablets along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of tramadol hydrochloride extended-release tablets by cutting, breaking, chewing, crushing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tramadol and can result in overdose and death [see Overdosage (10)]. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing tramadol hydrochloride extended-release tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [ see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid- induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of tramadol hydrochloride extended-release tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of tramadol hydrochloride extended-release tablets. To reduce the risk of respiratory depression, proper dosing and titration of tramadol hydrochloride extended-release tablets are essential [see Dosage and Administration (2)]. Overestimating the tramadol hydrochloride extended-release tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of tramadol hydrochloride extended-release tablet, especially by children, can result in respiratory depression and death due to an overdose of tramadol. 5.3 Neonatal Opioid Withdrawal Syndrome Prolonged use of tramadol hydrochloride extended-release tablets during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life- threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)]. 5.4 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors on levels of tramadol and M1 from tramadol hydrochloride extended-release tablets are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol hydrochloride extended-release tablets requires careful consideration of the effects on the parent drug, tramadol which is a weak serotonin and norepinephrine reuptake inhibitor and µ-opioid agonist, and the active metabolite, M1, which is more potent than tramadol in µ-opioid receptor binding [see Drug Interactions (7)]. Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors The concomitant use of tramadol hydrochloride extended-release tablets with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in tramadol plasma levels and a decrease in the levels of the active metabolite, M1. A decrease in M1 exposure in patients who have developed physical dependence to tramadol, may result in signs and symptoms of opioid withdrawal and reduced efficacy. The effect of increased tramadol levels may be an increased risk for serious adverse events including seizures and serotonin syndrome. Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in tramadol plasma levels and an increase in active metabolite M1 levels, which could increase or prolong adverse reactions related to opioid toxicity and may cause potentially fatal respiratory depression. Follow patients receiving tramadol hydrochloride extended-release tablets and any CYP2D6 inhibitor for the risk of serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity, and opioid withdrawal when tramadol hydrochloride extended-release tablets are used in conjunction with inhibitors of CYP2D6 [see Drug Interactions (7)]. Cytochrome P450 3A4 Interaction The concomitant use of tramadol hydrochloride extended-release tablets with cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in tramadol plasma concentrations, which could increase or prolong adverse reactions, increase the risk for serious adverse events including seizures and serotonin syndrome, and may cause potentially fatal respiratory depression. The concomitant use of tramadol hydrochloride extended-release tablets with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower tramadol levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal. Follow patients receiving tramadol hydrochloride extended-release tablets and any CYP3A4 inhibitor or inducer for the risk for serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity and opioid withdrawal when tramadol hydrochloride extended-release tablets are used in conjunction with inhibitors and inducers of CYP3A4 [see Drug Interactions (7)]. 5.5 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of tramadol hydrochloride extended-release tablets with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when tramadol hydrochloride extended-release tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined.  Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7), Patient Counseling Information (17)]. 5.6 Serotonin Syndrome Risk Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use of tramadol, including tramadol hydrochloride extended-release tablets, particularly during concomitant use with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. This may occur within the recommended dosage range. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected. 5.7 Increased Risk of Seizures Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Concomitant use of tramadol increases the seizure risk in patients taking: [see Drug Interactions (7)]. · Selective serotonin re-uptake inhibitors (SSRIs) and Serotonin-norepinephrine re-uptake inhibitors (SNRIs) antidepressants or anorectics, · Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), · Other opioids, · MAO inhibitors [see Warnings and Precautions (5.9), Drug Interactions (7)] · Neuroleptics, or · Other drugs that reduce the seizure threshold. Risk of seizures may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In tramadol overdose, naloxone administration may increase the risk of seizure. 5.8 Suicide Risk Do not prescribe tramadol hydrochloride extended-release tablets for patients who are suicidal or addiction-prone. Consideration should be given to the use of non-narcotic analgesics in patients who are suicidal or depressed. [see Drug Abuse and Dependence (9.2)] Prescribe tramadol hydrochloride extended-release tablets with caution for patients with a history of misuse and/or arecurrently taking CNS-active drugs including tranquilizers, or antidepressant drugs, or alcohol in excess, and patients who suffer from emotional disturbance or depression [see Drug Interactions (7)]. Inform patients not to exceed the recommended dose and to limit their intake of alcohol [see Dosage and Administration (2.1), Warnings and Precautions (5.5, 5.6, 5.12)]. 5.9 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.10 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of tramadol hydrochloride extended-release tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: Tramadol hydrochloride extended-release tablets-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of tramadol hydrochloride extended-release tablets [see Warnings and Precautions (5.2)]. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.2)]. Monitor such patients closely, particularly when initiating and titrating tramadol hydrochloride extended-release tablets and when tramadol hydrochloride extended-release tablets are given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2, 5.5)]. Alternatively, consider the use of non-opioid analgesics in these patients. 5.11 Severe Hypotension Tramadol hydrochloride extended-release tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of tramadol hydrochloride extended-release tablets. In patients with circulatory shock, tramadol hydrochloride extended-release tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of tramadol hydrochloride extended-release tablets in patients with circulatory shock. 5.12 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), tramadol hydrochloride extended-release tablets may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with tramadol hydrochloride extended-release tablets. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of tramadol hydrochloride extended-release tablets in patients with impaired consciousness or coma. 5.13 Risks of Use in Patients with Gastrointestinal Conditions Tramadol hydrochloride extended-release tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The tramadol in tramadol hydrochloride extended-release tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. 5.14 Anaphylaxis and Other Hypersensitivity Reactions Serious and rarely fatal hypersensitive reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose. Other reported hypersensitivity reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of hypersensitivity reactions to tramadol and other opioids may be at increased risk and therefore should not receive tramadol hydrochloride extended-release tablets. If anaphylaxis or other hypersensitivity occurs, stop administration of tramadol hydrochloride extended-release tablets immediately, discontinue tramadol hydrochloride extended-release tablets permanently, and do not rechallenge with any formulation of tramadol. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction [see Patient Counseling Information (17)]. 5.15 Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including tramadol hydrochloride extended-release tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7)]. When discontinuing tramadol hydrochloride extended-release tablets, gradually taper the dosage [see Dosage and Administration (2.4)]. Do not abruptly discontinue tramadol hydrochloride extended-release tablets [see Drug Abuse and Dependence (9.3)]. 5.16 Risks of Driving and Operating Machinery Tramadol hydrochloride extended-release tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of tramadol hydrochloride extended-release tablets and know how they will react to the medication [see Patient Counseling Information (17)].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Addiction, Abuse, and Misuse Inform patients that the use of tramadol hydrochloride extended-release tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share tramadol hydrochloride extended-release tablets with others and to take steps to protect tramadol hydrochloride extended-release tablets from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting tramadol hydrochloride extended-release tablets or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store tramadol hydrochloride extended-release tablets securely and to dispose of unused tramadol hydrochloride extended-release tablets in accordance with the local state guidelines and/or regulations. Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if tramadol hydrochloride extended-release tablets are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.5), Drug Interactions (7)]. Serotonin Syndrome Inform patients that tramadol could cause a rare but potentially life-threatening condition, particularly during concomitant use with serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare provider if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.6), Drug Interactions (7)]. Seizures Inform patients that tramadol hydrochloride extended-release tablets may cause seizures with concomitant use of serotonergic agents (including SSRIs, SNRIs, and triptans) or drugs that significantly reduce the metabolic clearance of tramadol [see Warnings and Precautions (5.7)]. MAOI Interaction Inform patients not to take tramadol hydrochloride extended-release tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking tramadol hydrochloride extended-release tablets [see Drug Interactions (7)]. Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.9)]. Important Administration Instructions Instruct patients how to properly take tramadol hydrochloride extended-release tablets, including the following: · Tramadol hydrochloride extended-release tablets are designed to work properly only if swallowed intact. Taking cut, broken, chewed, crushed, or dissolved tramadol hydrochloride extended-release tablets can result in a fatal overdose [see Dosage and Administration (2.1)]. · Advise patients not to exceed the single-dose and 24-hour dose limit and the time interval between doses, since exceeding these recommendations can result in respiratory depression, seizures, hepatic toxicity, and death. [see Dosage and Administration (2.1)]. · Do not discontinue tramadol hydrochloride extended-release tablets without first discussing the need for a tapering regimen with the prescriber [see Dosage and Administration (2.4)]. Hypotension Inform patients that tramadol hydrochloride extended-release tablets may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.11)]. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in tramadol hydrochloride extended-release tablets. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)]. Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of tramadol hydrochloride extended-release tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.3), Use in Specific Populations (8.1)]. Embryo-Fetal Toxicity Inform female patients of reproductive potential that tramadol hydrochloride extended-release tablets can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)]. Lactation Advise patients that breastfeeding is not recommended during treatment with tramadol hydrochloride extended-release tablets [see Use in Specific Populations (8.2)]. Infertility Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Use in Specific Populations (8.3)]. Driving or Operating Heavy Machinery Inform patients that tramadol hydrochloride extended-release tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.5)]. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.1)]. Disposal of Unused Tramadol Hydrochloride Extended-Release Tablets Advise patients to throw the unused tramadol hydrochloride extended-release tablets in the household trash following these steps. 1) Remove the drugs from their original containers and mix with an undesirable substance, such as used coffee grounds or kitty litter (this makes the drug less appealing to children and pets, and unrecognizable to people who may intentionally go through the trash seeking drugs). 2) Place the mixture in a sealable bag, empty can, or other container to prevent the drug from leaking or breaking out of a garbage bag.

DOSAGE AND ADMINISTRATION

2 DOSAGE & ADMINISTRATION To be prescribed only by healthcare providers knowledgeable in use of potent opioids for management of chronic pain. (2.1) Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (2.1). Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. (2.1) Do not exceed a daily dose of 300 mg tramadol. Do not use with other tramadol products. (2.1) For opioid-naïve and opioid non-tolerant patients, initiate tramadol hydrochloride extended-release tablets at a dose of 100 mg once daily, then titrate up by 100 mg increments every 5 days according to need and tolerance. (2.2) For patients currently on tramadol IR, calculate total 24-hr IR dose, and initiate tramadol hydrochloride extended-release tablets at a dose rounded down to next lower 100 mg increment; then adjust dose according to need and tolerance. See full prescribing information for instructions on conversion, titration, and maintenance of therapy. (2.2, 2.3) Do not abruptly discontinue tramadol hydrochloride extended-release tablets in a physically-dependent patient. (2.4) 2.1 Important Dosage and Administration Instructions Tramadol hydrochloride extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Do not use tramadol hydrochloride extended-release tablets concomitantly with other tramadol products [ see Warnings and Precautions (5.4), (5.12)]. Do not administer tramadol hydrochloride extended-release tablets at a dose exceeding 300 mg per day. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5.5)]. Initiate the dosing regimen for each patient individually, taking into account the patient’s severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)] Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with tramadol hydrochloride extended-release tablets and adjust the dosage accordingly [see Warnings and Precautions (5.2)]. Instruct patients to swallow tramadol hydrochloride extended-release tablets whole [see Patient Counseling Information (17)], and to take it with liquid. Crushing, chewing, splitting, or dissolving tramadol hydrochloride extended-release tablets will result in uncontrolled delivery of tramadol and can lead to overdose or death [see Warnings and Precautions (5.1)]. Tramadol hydrochloride extended-release tablets may be taken without regard to food, It is recommended that tramadol hydrochloride extended-release tablets be taken in a consistent manner [ see Clinical Pharmacology (12.3)]. 2.2 Initial Dosage Patients Not Currently on a Tramadol Product The initial dose of tramadol hydrochloride extended-release tablet is 100 mg once daily. Patients Currently on Tramadol Immediate-Release (IR) Products Calculate the 24-hour tramadol IR dose and initiate a total daily dose of tramadol hydrochloride extended-release tablets rounded down to the next lower 100 mg increment. The dose may subsequently be individualized according to patient need. Due to limitations in flexibility of dose selection with tramadol hydrochloride extended-release tablets, some patients maintained on tramadol IR products may not be able to convert to tramadol hydrochloride extended-release tablets. Conversion from Other Opioids to Tramadol Hydrochloride Extended-Release Tablets Discontinue all other around-the-clock opioid drugs when tramadol hydrochloride extended-release tablets therapy is initiated. There are no established conversion ratios for conversion from other opioids to tramadol hydrochloride extended-release tablets defined by clinical trials. Initiate dosing using tramadol hydrochloride extended-release tablet 100 mg once a day. 2.3 Titration and Maintenance of Therapy Individually titrate tramadol hydrochloride extended-release tablets by 100 mg every five days to a dose that provides adequate analgesia and minimizes adverse reactions. The maximum daily dose of tramadol hydrochloride extended-release tablets is 300 mg per day. Continually reevaluate patients receiving tramadol hydrochloride extended-release tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1)]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics. Patients who experience breakthrough pain may require a dosage adjustment of tramadol hydrochloride extended-release tablets, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the tramadol hydrochloride extended-release tablets dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid- related adverse reactions. 2.4 Discontinuation of Tramadol Hydrochloride Extended-Release Tablets When a patient no longer requires therapy with tramadol hydrochloride extended-release tablets, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue tramadol hydrochloride extended-release tablets [see Warnings and Precautions (5.15), Drug Abuse and Dependence (9.3)].

CeleBREX 200 MG Oral Capsule

Generic Name: CELECOXIB
Brand Name: CELEBREX
  • Substance Name(s):
  • CELECOXIB

DRUG INTERACTIONS

7. General: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 should be done with caution. Significant interactions may occur when celecoxib is administered together with drugs that inhibit CYP2C9. In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6. Concomitant use of CELEBREX and warfarin may result in increased risk of bleeding complications. (7.1) Concomitant use of CELEBREX increases lithium plasma levels. (7.2) Concomitant use of CELEBREX may reduce the antihypertensive effect of ACE Inhibitors and angiotensin II antagonists. Concomitant use of CELEBREX with ACE-Inhibitors in elderly or volume depleted or renally compromised patients may result in deterioration of renal function, including acute renal failure. (7.4) Use caution with drugs known to inhibit P450 2C9 or metabolized by 2D6 due to the potential for increased plasma levels (2.6, 8.4, 8.8, 12.3) 7.1 Warfarin Anticoagulant activity should be monitored, particularly in the first few days, after initiating or changing CELEBREX therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding complications. The effect of celecoxib on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily 2–5 mg doses of warfarin. In these subjects, celecoxib did not alter the anticoagulant effect of warfarin as determined by prothrombin time. However, in post-marketing experience, serious bleeding events, some of which were fatal, have been reported, predominantly in the elderly, in association with increases in prothrombin time in patients receiving CELEBREX concurrently with warfarin. 7.2 Lithium In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg twice daily with CELEBREX 200 mg twice daily as compared to subjects receiving lithium alone. Patients on lithium treatment should be closely monitored when CELEBREX is introduced or withdrawn. 7.3 Aspirin CELEBREX can be used with low-dose aspirin. However, concomitant administration of aspirin with CELEBREX increases the rate of GI ulceration or other complications, compared to use of CELEBREX alone [see Warnings and Precautions (5.1, 5.4) and Clinical Studies (14.6) ]. Because of its lack of platelet effects, CELEBREX is not a substitute for aspirin for cardiovascular prophylaxis [see Clinical Pharmacology (12.2) ]. 7.4 ACE-inhibitors and Angiotensin II Antagonists Reports suggest that NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme (ACE) inhibitors and angiotensin II antagonists. This interaction should be given consideration in patients taking CELEBREX concomitantly with ACE-inhibitors and angiotensin II antagonists [see Clinical Pharmacology (12.2 ]. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, may result in deterioration of renal function, including possible acute renal failure. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. 7.5 Fluconazole Concomitant administration of fluconazole at 200 mg once daily resulted in a two-fold increase in celecoxib plasma concentration. This increase is due to the inhibition of celecoxib metabolism via P450 2C9 by fluconazole [see Clinical Pharmacology (12.3) ]. CELEBREX should be introduced at the lowest recommended dose in patients receiving fluconazole. 7.6 Furosemide Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. 7.7 Methotrexate In an interaction study of rheumatoid arthritis patients taking methotrexate, CELEBREX did not have an effect on the pharmacokinetics of methotrexate [see Clinical Pharmacology (12.3) ]. 7.8 Concomitant NSAID Use The concomitant use of CELEBREX with any dose of a non-aspirin NSAID should be avoided due to the potential for increased risk of adverse reactions.

OVERDOSAGE

10. No overdoses of CELEBREX were reported during clinical trials. Doses up to 2400 mg/day for up to 10 days in 12 patients did not result in serious toxicity. Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. No information is available regarding the removal of celecoxib by hemodialysis, but based on its high degree of plasma protein binding (>97%) dialysis is unlikely to be useful in overdose. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

DESCRIPTION

11. CELEBREX (celecoxib) is chemically designated as 4-[5-(4-methylphenyl)- 3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide and is a diaryl-substituted pyrazole. The empirical formula is C17H14F3N3O2S, and the molecular weight is 381.38; the chemical structure is as follows: CELEBREX oral capsules contain either 50 mg, 100 mg, 200 mg or 400 mg of celecoxib, together with inactive ingredients including: croscarmellose sodium, edible inks, gelatin, lactose monohydrate, magnesium stearate, povidone and sodium lauryl sulfate. Chemical Structure

CLINICAL STUDIES

14. 14.1 Osteoarthritis CELEBREX has demonstrated significant reduction in joint pain compared to placebo. CELEBREX was evaluated for treatment of the signs and the symptoms of OA of the knee and hip in placebo- and active-controlled clinical trials of up to 12 weeks duration. In patients with OA, treatment with CELEBREX 100 mg twice daily or 200 mg once daily resulted in improvement in WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, a composite of pain, stiffness, and functional measures in OA. In three 12-week studies of pain accompanying OA flare, CELEBREX doses of 100 mg twice daily and 200 mg twice daily provided significant reduction of pain within 24–48 hours of initiation of dosing. At doses of 100 mg twice daily or 200 mg twice daily the effectiveness of CELEBREX was shown to be similar to that of naproxen 500 mg twice daily. Doses of 200 mg twice daily provided no additional benefit above that seen with 100 mg twice daily. A total daily dose of 200 mg has been shown to be equally effective whether administered as 100 mg twice daily or 200 mg once daily. 14.2 Rheumatoid Arthritis CELEBREX has demonstrated significant reduction in joint tenderness/pain and joint swelling compared to placebo. CELEBREX was evaluated for treatment of the signs and symptoms of RA in placebo- and active-controlled clinical trials of up to 24 weeks in duration. CELEBREX was shown to be superior to placebo in these studies, using the ACR20 Responder Index, a composite of clinical, laboratory, and functional measures in RA. CELEBREX doses of 100 mg twice daily and 200 mg twice daily were similar in effectiveness and both were comparable to naproxen 500 mg twice daily. Although CELEBREX 100 mg twice daily and 200 mg twice daily provided similar overall effectiveness, some patients derived additional benefit from the 200 mg twice daily dose. Doses of 400 mg twice daily provided no additional benefit above that seen with 100–200 mg twice daily. 14.3 Juvenile Rheumatoid Arthritis In a 12-week, randomized, double-blind active-controlled, parallel-group, multicenter, non-inferiority study, patients from 2 years to 17 years of age with pauciarticular, polyarticular course JRA or systemic onset JRA (with currently inactive systemic features), received one of the following treatments: celecoxib 3 mg/kg (to a maximum of 150 mg) twice daily; celecoxib 6 mg/kg (to a maximum of 300 mg) twice daily; or naproxen 7.5 mg/kg (to a maximum of 500 mg) twice daily. The response rates were based upon the JRA Definition of Improvement greater than or equal to 30% (JRA DOI 30) criterion, which is a composite of clinical, laboratory, and functional measures of JRA. The JRA DOI 30 response rates at week 12 were 69%, 80% and 67% in the celecoxib 3 mg/kg BID, celecoxib 6 mg/kg BID, and naproxen 7.5 mg/kg BID treatment groups, respectively. The efficacy and safety of CELEBREX for JRA have not been studied beyond six months. The long-term cardiovascular toxicity in children exposed to CELEBREX has not been evaluated and it is unknown if the long-term risk may be similar to that seen in adults exposed to CELEBREX or other COX-2 selective and non-selective NSAIDs [(see Boxed Warning, Warnings and Precautions (5.12) ]. 14.4 Ankylosing Spondylitis CELEBREX was evaluated in AS patients in two placebo- and active-controlled clinical trials of 6 and 12 weeks duration. CELEBREX at doses of 100 mg twice daily, 200 mg once daily and 400 mg once daily was shown to be statistically superior to placebo in these studies for all three co-primary efficacy measures assessing global pain intensity (Visual Analogue Scale), global disease activity (Visual Analogue Scale) and functional impairment (Bath Ankylosing Spondylitis Functional Index). In the 12-week study, there was no difference in the extent of improvement between the 200 mg and 400 mg CELEBREX doses in a comparison of mean change from baseline, but there was a greater percentage of patients who responded to CELEBREX 400 mg, 53%, than to CELEBREX 200 mg, 44%, using the Assessment in Ankylosing Spondylitis response criteria (ASAS 20). The ASAS 20 defines a responder as improvement from baseline of at least 20% and an absolute improvement of at least 10 mm, on a 0 to 100 mm scale, in at least three of the four following domains: patient global pain, Bath Ankylosing Spondylitis Functional Index, and inflammation. The responder analysis also demonstrated no change in the responder rates beyond 6 weeks. 14.5 Analgesia, including Primary Dysmenorrhea In acute analgesic models of post-oral surgery pain, post-orthopedic surgical pain, and primary dysmenorrhea, CELEBREX relieved pain that was rated by patients as moderate to severe. Single doses [see Dosage and Administration (2.5) ] of CELEBREX provided pain relief within 60 minutes. 14.6 Special Studies Adenomatous Polyp Prevention Studies : Cardiovascular safety was evaluated in two randomized, double-blind, placebo-controlled, three year studies involving patients with Sporadic Adenomatous Polyps treated with CELEBREX: the APC trial (Adenoma Prevention with Celecoxib) and the PreSAP trial (Prevention of Spontaneous Adenomatous Polyps). In the APC trial, there was a dose-related increase in the composite endpoint (adjudicated) of cardiovascular death, myocardial infarction, or stroke with celecoxib compared to placebo over 3 years of treatment. The PreSAP trial did not demonstrate a statistically significant increased risk for the same composite endpoint (adjudicated): In the APC trial, the hazard ratios compared to placebo for a composite endpoint (adjudicated) of cardiovascular death, myocardial infarction, or stroke were 3.4 (95% CI 1.4 – 8.5) with celecoxib 400 mg twice daily and 2.8 (95% CI 1.1 – 7.2) with celecoxib 200 mg twice daily. Cumulative rates for this composite endpoint over 3 years were 3.0% (20/671 subjects) and 2.5% (17/685 subjects), respectively, compared to 0.9% (6/679 subjects) with placebo treatment. The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction. In the PreSAP trial, the hazard ratio for this same composite endpoint (adjudicated) was 1.2 (95% CI 0.6 – 2.4) with celecoxib 400 mg once daily compared to placebo. Cumulative rates for this composite endpoint over 3 years were 2.3% (21/933 subjects) and 1.9% (12/628 subjects), respectively. Clinical trials of other COX-2 selective and non-selective NSAIDs of up to three-years duration have shown an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. As a result, all NSAIDs are considered potentially associated with this risk. Celecoxib Long-Term Arthritis Safety Study (CLASS): This was a prospective, long-term, safety outcome study conducted post-marketing in approximately 5,800 OA patients and 2,200 RA patients. Patients received CELEBREX 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily (common therapeutic doses). Median exposures for CELEBREX (n = 3,987) and diclofenac (n = 1,996) were 9 months while ibuprofen (n = 1,985) was 6 months. The primary endpoint of this outcome study was the incidence of complicated ulcers (gastrointestinal bleeding, perforation or obstruction). Patients were allowed to take concomitant low-dose (≤ 325 mg/day) aspirin (ASA) for cardiovascular prophylaxis (ASA subgroups: CELEBREX, n = 882; diclofenac, n = 445; ibuprofen, n = 412). Differences in the incidence of complicated ulcers between CELEBREX and the combined group of ibuprofen and diclofenac were not statistically significant. Patients on CELEBREX and concomitant low-dose ASA (N=882) experienced 4-fold higher rates of complicated ulcers compared to those not on ASA (N=3105). The Kaplan-Meier rate for complicated ulcers at 9 months was 1.12% versus 0.32% for those on low-dose ASA and those not on ASA, respectively [see Warnings and Precautions (5.4) ]. The estimated cumulative rates at 9 months of complicated and symptomatic ulcers for patients treated with CELEBREX 400 mg twice daily are described in Table 4. Table 4 also displays results for patients less than or greater than 65 years of age. The difference in rates between CELEBREX alone and CELEBREX with ASA groups may be due to the higher risk for GI events in ASA users. Table 4: Complicated and Symptomatic Ulcer Rates in Patients Taking CELEBREX 400 mg Twice Daily (Kaplan-Meier Rates at 9 months [%]) Based on Risk Factors All Patients CELEBREX alone (n=3105) 0.78 CELEBREX with ASA (n=882) 2.19 Patients <65 Years CELEBREX alone (n=2025) 0.47 CELEBREX with ASA (n=403) 1.26 Patients ≥65 Years CELEBREX alone (n=1080) 1.40 CELEBREX with ASA (n=479) 3.06 In a small number of patients with a history of ulcer disease, the complicated and symptomatic ulcer rates in patients taking CELEBREX alone or CELEBREX with ASA were, respectively, 2.56% (n=243) and 6.85% (n=91) at 48 weeks. These results are to be expected in patients with a prior history of ulcer disease [see Warnings and Precautions (5.4) and Adverse Reactions (6.1) ]. Cardiovascular safety outcomes were also evaluated in the CLASS trial. Kaplan-Meier cumulative rates for investigator-reported serious cardiovascular thromboembolic adverse events (including MI, pulmonary embolism, deep venous thrombosis, unstable angina, transient ischemic attacks, and ischemic cerebrovascular accidents) demonstrated no differences between the CELEBREX, diclofenac, or ibuprofen treatment groups. The cumulative rates in all patients at nine months for CELEBREX, diclofenac, and ibuprofen were 1.2%, 1.4%, and 1.1%, respectively. The cumulative rates in non-ASA users at nine months in each of the three treatment groups were less than 1%. The cumulative rates for myocardial infarction in non-ASA users at nine months in each of the three treatment groups were less than 0.2%. There was no placebo group in the CLASS trial, which limits the ability to determine whether the three drugs tested had no increased risk of CV events or if they all increased the risk to a similar degree. Endoscopic Studies : The correlation between findings of short-term endoscopic studies with CELEBREX and the relative incidence of clinically significant serious upper GI events with long-term use has not been established. Serious clinically significant upper GI bleeding has been observed in patients receiving CELEBREX in controlled and open-labeled trials [see Warnings and Precautions (5.4) and Clinical Studies (14.6) ] A randomized, double-blind study in 430 RA patients was conducted in which an endoscopic examination was performed at 6 months. The incidence of endoscopic ulcers in patients taking CELEBREX 200 mg twice daily was 4% vs. 15% for patients taking diclofenac SR 75 mg twice daily. However, CELEBREX was not statistically different than diclofenac for clinically relevant GI outcomes in the CLASS trial [see Clinical Studies (14.6) ]. The incidence of endoscopic ulcers was studied in two 12-week, placebo-controlled studies in 2157 OA and RA patients in whom baseline endoscopies revealed no ulcers. There was no dose relationship for the incidence of gastroduodenal ulcers and the dose of CELEBREX (50 mg to 400 mg twice daily). The incidence for naproxen 500 mg twice daily was 16.2 and 17.6% in the two studies, for placebo was 2.0 and 2.3%, and for all doses of CELEBREX the incidence ranged between 2.7%–5.9%. There have been no large, clinical outcome studies to compare clinically relevant GI outcomes with CELEBREX and naproxen. In the endoscopic studies, approximately 11% of patients were taking aspirin (≤ 325 mg/day). In the CELEBREX groups, the endoscopic ulcer rate appeared to be higher in aspirin users than in non-users. However, the increased rate of ulcers in these aspirin users was less than the endoscopic ulcer rates observed in the active comparator groups, with or without aspirin.

HOW SUPPLIED

16. /STORAGE AND HANDLING Repackaged by Aphena Pharma Solutions – TN. See Repackaging Information for available configurations. CELEBREX 50 mg capsules are white, with reverse printed white on red band of body and cap with markings of 7767 on the cap and 50 on the body, supplied as: NDC Number Size 0025-1515-01 bottle of 60 CELEBREX 100 mg capsules are white, with reverse printed white on blue band of body and cap with markings of 7767 on the cap and 100 on the body, supplied as: NDC Number Size 0025-1520-31 bottle of 100 0025-1520-51 bottle of 500 0025-1520-34 carton of 100 unit dose CELEBREX 200 mg capsules are white, with reverse printed white on gold band with markings of 7767 on the cap and 200 on the body, supplied as: NDC Number Size 0025-1525-31 bottle of 100 0025-1525-51 bottle of 500 0025-1525-34 carton of 100 unit dose CELEBREX 400 mg capsules are white, with reverse printed white on green band with markings of 7767 on the cap and 400 on the body, supplied as: NDC Number Size 0025-1530-02 bottle of 60 0025-1530-01 carton of 100 unit dose Storage : Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]

GERIATRIC USE

8.5 Geriatric Use Of the total number of patients who received CELEBREX in pre-approval clinical trials, more than 3,300 were 65–74 years of age, while approximately 1,300 additional patients were 75 years and over. No substantial differences in effectiveness were observed between these subjects and younger subjects. In clinical studies comparing renal function as measured by the GFR, BUN and creatinine, and platelet function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers. However, as with other NSAIDs, including those that selectively inhibit COX-2, there have been more spontaneous post-marketing reports of fatal GI events and acute renal failure in the elderly than in younger patients [see Warnings and Precautions (5.4 , 5.6)].

DOSAGE FORMS AND STRENGTHS

3. Capsules: 50 mg, 100 mg, 200 mg and 400 mg Capsules: 50 mg, 100 mg, 200 mg and 400 mg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action CELEBREX is a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of CELEBREX is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2), and at therapeutic concentrations in humans, CELEBREX does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme. In animal colon tumor models, CELEBREX reduced the incidence and multiplicity of tumors.

INDICATIONS AND USAGE

1. Carefully consider the potential benefits and risks of CELEBREX and other treatment options before deciding to use CELEBREX. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5) ] CELEBREX is a nonsteroidal anti-inflammatory drug indicated for: Osteoarthritis (OA) (1.1) Rheumatoid Arthritis (RA) (1.2) Juvenile Rheumatoid Arthritis (JRA) in patients 2 years and older (1.3) Ankylosing Spondylitis (AS) (1.4) Acute Pain (AP) (1.5) Primary Dysmenorrhea (PD) (1.6) 1.1 Osteoarthritis (OA) CELEBREX is indicated for relief of the signs and symptoms of OA [see Clinical Studies (14.1) ] 1.2 Rheumatoid Arthritis (RA) CELEBREX is indicated for relief of the signs and symptoms of RA [see Clinical Studies (14.2) ] 1.3 Juvenile Rheumatoid Arthritis (JRA) CELEBREX is indicated for relief of the signs and symptoms of JRA in patients 2 years and older [see Clinical Studies (14.3) ] 1.4 Ankylosing Spondylitis (AS) CELEBREX is indicated for the relief of signs and symptoms of AS [see Clinical Studies (14.4) ] 1.5 Acute Pain (AP) CELEBREX is indicated for the management of AP in adults [see Clinical Studies (14.5) ] 1.6 Primary Dysmenorrhea (PD) CELEBREX is indicated for the treatment of PD [see Clinical Studies (14.5) ]

PEDIATRIC USE

8.4 Pediatric Use CELEBREX is approved for relief of the signs and symptoms of Juvenile Rheumatoid Arthritis in patients 2 years and older. Safety and efficacy have not been studied beyond six months in children. The long-term cardiovascular toxicity in children exposed to CELEBREX has not been evaluated and it is unknown if long-term risks may be similar to that seen in adults exposed to CELEBREX or other COX-2 selective and non-selective NSAIDs [(see Boxed Warning, Warnings and Precautions (5.12), and Clinical Studies (14.3) ]. The use of celecoxib in patients 2 years to 17 years of age with pauciarticular, polyarticular course JRA or in patients with systemic onset JRA was studied in a 12-week, double-blind, active controlled, pharmacokinetic, safety and efficacy study, with a 12-week open-label extension. Celecoxib has not been studied in patients under the age of 2 years, in patients with body weight less than 10 kg (22 lbs), and in patients with active systemic features. Patients with systemic onset JRA (without active systemic features) appear to be at risk for the development of abnormal coagulation laboratory tests. In some patients with systemic onset JRA, both celecoxib and naproxen were associated with mild prolongation of activated partial thromboplastin time (APTT) but not prothrombin time (PT). NSAIDs including celecoxib should be used only with caution in patients with systemic onset JRA, due to the risk of disseminated intravascular coagulation. Patients with systemic onset JRA should be monitored for the development of abnormal coagulation tests [see Dosage and Administration (2.3), Warnings and Precautions (5.12), Adverse Reactions (6.3), Animal Toxicology (13.2), Clinical Studies (14.3) ]. Alternative therapies for treatment of JRA should be considered in pediatric patients identified to be CYP2C9 poor metabolizers [see Poor Metabolizers of CYP2C9 substrates (8.8) ].

PREGNANCY

8.1 Pregnancy Pregnancy Category C. Pregnancy category D from 30 weeks of gestation onward. Teratogenic effects : Celecoxib at oral doses ≥150 mg/kg/day (approximately 2-fold human exposure at 200 mg twice daily as measured by AUC0–24), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 6-fold human exposure based on the AUC0–24 at 200 mg twice daily) throughout organogenesis. There are no studies in pregnant women. CELEBREX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic effects: Celecoxib produced pre-implantation and post-implantation losses and reduced embryo/fetal survival in rats at oral dosages ≥50 mg/kg/day (approximately 6-fold human exposure based on the AUC0–24 at 200 mg twice daily). These changes are expected with inhibition of prostaglandin synthesis and are not the result of permanent alteration of female reproductive function, nor are they expected at clinical exposures. No studies have been conducted to evaluate the effect of celecoxib on the closure of the ductus arteriosus in humans. Therefore, use of CELEBREX during the third trimester of pregnancy should be avoided.

NUSRING MOTHERS

8.3 Nursing Mothers Limited data from 3 published reports that included a total of 12 breastfeeding women showed low levels of CELEBREX in breast milk. The calculated average daily infant dose was 10–40 mcg/kg/day, less than 1% of the weight-based therapeutic dose for a two-year old-child. A report of two breastfed infants 17 and 22 months of age did not show any adverse events. Caution should be exercised when CELEBREX is administered to a nursing woman.

BOXED WARNING

WARNING: CARDIOVASCULAR AND GASTROINTESTINAL RISKS WARNING: CARDIOVASCULAR AND GASTROINTESTINAL RISKS See full prescribing information for complete boxed warning Cardiovascular Risk CELEBREX may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs may have a similar risk. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. (5.1,14.6) CELEBREX is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1) Gastrointestinal Risk NSAIDs, including CELEBREX, 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. (5.4) Cardiovascular Risk CELEBREX may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. All nonsteroidal anti-inflammatory drugs (NSAIDs) may have a similar risk. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. (5.1,14.6) CELEBREX is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1) Gastrointestinal Risk NSAIDs, including CELEBREX, 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 events. (5.4)

WARNING AND CAUTIONS

5. WARNINGS AND PRECAUTIONS Serious and potentially fatal cardiovascular (CV) thrombotic events, myocardial infarction, and stroke. Patients with known CV disease/risk factors may be at greater risk (5.1, 14.6, 17.2). Serious gastrointestinal (GI) adverse events, which can be fatal. The risk is greater in patients with a prior history of ulcer disease or GI bleeding, and in patients at high risk for GI events, especially the elderly. CELEBREX should be used with caution in these patients (5.4, 8.5, 14.6, 17.3). Elevated liver enzymes and, rarely, severe hepatic reactions. Discontinue use of CELEBREX immediately if abnormal liver enzymes persist or worsen (5.5, 17.4). New onset or worsening of hypertension. Blood pressure should be monitored closely during treatment with CELEBREX (5.2, 7.4, 17.2). Fluid retention and edema. CELEBREX should be used with caution in patients with fluid retention or heart failure (5.3, 17.6). Renal papillary necrosis and other renal injury with long term use. Use CELEBREX with caution in the elderly, those with impaired renal function, heart failure, liver dysfunction, and those taking diuretics, ACE-inhibitors, or angiotensin II antagonists (5.6, 7.4, 8.7, 17.6). Anaphylactoid reactions. Do not use CELEBREX in patients with the aspirin triad (5.7, 10, 17.7). Serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal and can occur without warning even without known prior sulfa allergy. Discontinue CELEBREX at first appearance of rash or skin reactions (5.8, 17.5). 5.1 Cardiovascular Thrombotic Events Chronic use of CELEBREX may cause an increased risk of serious adverse cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. In the APC (Adenoma Prevention with Celecoxib) trial, the hazard ratio for the composite endpoint of cardiovascular death, MI, or stroke was 3.4 (95% CI 1.4 – 8.5) for CELEBREX 400 mg twice daily and 2.8 (95% CI 1.1 – 7.2) with CELEBREX 200 mg twice daily compared to placebo. Cumulative rates for this composite endpoint over 3 years were 3.0% (20/671 subjects) and 2.5% (17/685 subjects), respectively, compared to 0.9% (6/679 subjects) with placebo treatment. The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction [see Clinical Studies (14.6) ]. All NSAIDs, both COX-2 selective and non-selective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with CELEBREX, the lowest effective dose should be used for the shortest duration consistent with individual patient treatment goals. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV toxicity 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 CELEBREX does increase the risk of serious GI events [see Warnings and Precautions (5.4) ]. Two large, controlled, clinical trials of a different COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke [see Contraindications (4) ]. 5.2 Hypertension As with all NSAIDs, CELEBREX can lead to the 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 CELEBREX, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with CELEBREX and throughout the course of therapy. The rates of hypertension from the CLASS trial in the CELEBREX, ibuprofen and diclofenac-treated patients were 2.4%, 4.2% and 2.5%, respectively [see Clinical Studies (14.6) ]. 5.3 Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs, including CELEBREX [see Adverse Reactions (6.1) ]. In the CLASS study [see Clinical Studies (14.6) ], the Kaplan-Meier cumulative rates at 9 months of peripheral edema in patients on CELEBREX 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily and diclofenac 75 mg twice daily were 4.5%, 6.9% and 4.7%, respectively. CELEBREX should be used with caution in patients with fluid retention or heart failure. 5.4 Gastrointestinal (GI) Effects Risk of GI Ulceration, Bleeding, and Perforation NSAIDs, including CELEBREX, can cause serious gastrointestinal events including 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. Complicated and symptomatic ulcer rates were 0.78% at nine months for all patients in the CLASS trial, and 2.19% for the subgroup on low-dose ASA. Patients 65 years of age and older had an incidence of 1.40% at nine months, 3.06% when also taking ASA [see Clinical Studies (14.6) ]. With longer duration of use of NSAIDs, there is a trend for 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 patients 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 of 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, the lowest effective dose should be used for the shortest duration consistent with individual patient treatment goals. Physicians and patients should remain alert for signs and symptoms of GI ulceration and bleeding during CELEBREX therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered. Celebrex is contraindicated in patients with active GI bleeding. 5.5 Hepatic Effects Borderline elevations of one or more liver-associated enzymes may occur in up to 15% of patients taking NSAIDs, and notable elevations of ALT or AST (approximately 3 or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure (some with fatal outcome) have been reported with NSAIDs, including CELEBREX [see Adverse Reactions (6.1) ]. In controlled clinical trials of CELEBREX, the incidence of borderline elevations (greater than or equal to 1.2 times and less than 3 times the upper limit of normal) of liver associated enzymes was 6% for CELEBREX and 5% for placebo, and approximately 0.2% of patients taking CELEBREX and 0.3% of patients taking placebo had notable elevations of ALT and AST. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with CELEBREX. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), CELEBREX should be discontinued. 5.6 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 an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, ACE-inhibitors, angiotensin II receptor antagonists, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Clinical trials with CELEBREX have shown renal effects similar to those observed with comparator NSAIDs. No information is available from controlled clinical studies regarding the use of CELEBREX in patients with advanced renal disease. Therefore, treatment with CELEBREX is not recommended in these patients with advanced renal disease. If CELEBREX therapy must be initiated, close monitoring of the patient’s renal function is advisable. 5.7 Anaphylactoid Reactions As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to CELEBREX. In post-marketing experience, rare cases of anaphylactic reactions and angioedema have been reported in patients receiving CELEBREX. CELEBREX 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 (4), Warnings and Precautions (5.7) ]. Emergency help should be sought in cases where an anaphylactoid reaction occurs. 5.8 Skin Reactions CELEBREX is a sulfonamide and 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 can occur without warning and in patients without prior known sulfa allergy. 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. 5.9 Pregnancy In late pregnancy, starting at 30 weeks gestation, CELEBREX should be avoided because it may cause premature closure of the ductus arteriosus [see Use in Specific Populations (8.1) ]. 5.10 Corticosteroid Treatment CELEBREX cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. 5.11 Hematological Effects Anemia is sometimes seen in patients receiving CELEBREX. In controlled clinical trials the incidence of anemia was 0.6% with CELEBREX and 0.4% with placebo. Patients on long-term treatment with CELEBREX should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss. CELEBREX does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT), and does not inhibit platelet aggregation at indicated dosages [see Clinical Pharmacology (12.2) ]. 5.12 Disseminated Intravascular Coagulation (DIC) CELEBREX should be used only with caution in pediatric patients with systemic onset JRA due to the risk of disseminated intravascular coagulation. 5.13 Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, CELEBREX should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. 5.14 Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have a CBC and a chemistry profile checked periodically. If abnormal liver tests or renal tests persist or worsen, CELEBREX should be discontinued. In controlled clinical trials, elevated BUN occurred more frequently in patients receiving CELEBREX compared with patients on placebo. This laboratory abnormality was also seen in patients who received comparator NSAIDs in these studies. The clinical significance of this abnormality has not been established. 5.15 Inflammation The pharmacological activity of CELEBREX in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infectious complications of presumed noninfectious, painful conditions. 5.16 Concomitant NSAID Use The concomitant use of CELEBREX with any dose of a non-aspirin NSAID should be avoided due to the potential for increased risk of adverse reactions.

INFORMATION FOR PATIENTS

17. PATIENT COUNSELING INFORMATION Patients should be informed of the following information before initiating therapy with CELEBREX and periodically during the course of ongoing therapy. 17.1 Medication Guide Patients should be informed of the availability of a Medication Guide for NSAIDs that accompanies each prescription dispensed, and should be instructed to read the Medication Guide prior to using CELEBREX. 17.2 Cardiovascular Effects Patients should be informed that CELEBREX may cause serious CV side effects such as MI or stroke, which may result in hospitalization and even death. Patients should be informed of the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and to seek immediate medical advice if they observe any of these signs or symptoms. [see Warnings and Precautions (5.1) ]. Patients should be informed that CELEBREX can lead to the onset of new hypertension or worsening of preexisting hypertension, and that CELEBREX may impair the response of some antihypertensive agents. Patients should be instructed on the proper follow up for monitoring of blood pressure. [see Warnings and Precautions (5.2) and Drug Interactions (7.4) ]. 17.3 Gastrointestinal Effects Patients should be informed that CELEBREX can cause gastrointestinal discomfort and more serious side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Patients should be informed of the signs and symptoms of ulcerations and bleeding, and to seek immediate medical advice if they observe any signs or symptoms that are indicative of these disorders, including epigastric pain, dyspepsia, melena, and hematemesis. [see Warnings and Precautions (5.4) ]. 17.4 Hepatic Effects 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). Patients should be instructed that they should stop therapy and seek immediate medical therapy if these signs and symptoms occur [see Warnings and Precautions (5.5), Use in Specific Populations (8.6) ]. 17.5 Adverse Skin Reactions Patients should be informed that CELEBREX is a sulfonamide and can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be informed of the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and seek immediate medical advice when observing any indicative signs or symptoms. Patients should be advised to stop CELEBREX immediately if they develop any type of rash and contact their physician as soon as possible. Patients with prior history of sulfa allergy should not take CELEBREX [see Warnings and Precautions (5.8) ]. 17.6 Weight Gain and Edema Long-term administration of NSAIDs including CELEBREX has resulted in renal injury. Patients at greatest risk are those taking diuretics, ACE-inhibitors, angiotensin II antagonists, or with renal or liver dysfunction, heart failure, and the elderly [see Warnings and Precautions (5.3 , 5.6), Use in Specific Populations (8) ]. Patients should be instructed to promptly report to their physicians signs or symptoms of unexplained weight gain or edema following treatment with CELEBREX [see Warnings and Precautions (5.3) ]. 17.7 Anaphylactoid Reactions Patients should be informed of the signs and symptoms of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). Patients should be instructed to seek immediate emergency assistance if they develop any of these signs and symptoms [see Warnings and Precautions (5.7) ]. 17.8 Effects During Pregnancy Patients should be informed that in late pregnancy CELEBREX should be avoided because it may cause premature closure of the ductus arteriosus [see Warnings and Precautions (5.9), Use in Specific Populations (8.1) ]. 17.9 Preexisting Asthma Patients should be instructed to tell their physicians if they have a history of asthma or aspirin-sensitive asthma because the use of NSAIDs in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Patients with this form of aspirin sensitivity should be instructed not to take Celebrex. Patients with preexisting asthma should be instructed to seek immediate medical attention if their asthma worsens after taking Celebrex [see Warnings and Precautions (5.13) ].

DOSAGE AND ADMINISTRATION

2. Use lowest effective dose for the shortest duration consistent with treatment goals for the individual patient. These doses can be given without regard to timing of meals. Use lowest effective dose for the shortest duration consistent with treatment goals for the individual patient. (1, 5.1, 5.4) OA: 200 mg once daily or 100 mg twice daily (2.1, 14.1) RA: 100 to 200 mg twice daily (2.2, 14.2) JRA: 50 mg twice daily in patients 10–25 kg. 100 mg twice daily in patients more than 25 kg (2.3, 14.3) AS: 200 mg once daily single dose or 100 mg twice daily. If no effect is observed after 6 weeks, a trial of 400 mg (single or divided doses) may be of benefit (2.4, 14.4) AP and PD: 400 mg initially, followed by 200 mg dose if needed on first day. On subsequent days, 200 mg twice daily as needed (2.5, 14.5) Reduce daily dose by 50% in patients with moderate hepatic impairment (Child-Pugh Class B). Consider a dose reduction by 50% (or alternative management for JRA) in patients who are known or suspected to be CYP2C9 poor metabolizers, (2.6, 8.4, 8.8, 12.3). 2.1 Osteoarthritis For relief of the signs and symptoms of OA the recommended oral dose is 200 mg per day administered as a single dose or as 100 mg twice daily. 2.2 Rheumatoid Arthritis For relief of the signs and symptoms of RA the recommended oral dose is 100 to 200 mg twice daily. 2.3 Juvenile Rheumatoid Arthritis For the relief of the signs and symptoms of JRA the recommended oral dose for pediatric patients (age 2 years and older) is based on weight. For patients ≥10 kg to ≤25 kg the recommended dose is 50 mg twice daily. For patients >25 kg the recommended dose is 100 mg twice daily. For patients who have difficulty swallowing capsules, the contents of a CELEBREX capsule can be added to applesauce. The entire capsule contents are carefully emptied onto a level teaspoon of cool or room temperature applesauce and ingested immediately with water. The sprinkled capsule contents on applesauce are stable for up to 6 hours under refrigerated conditions (2–8° C/ 35–45° F). 2.4 Ankylosing Spondylitis For the management of the signs and symptoms of AS, the recommended dose of CELEBREX is 200 mg daily in single (once per day) or divided (twice per day) doses. If no effect is observed after 6 weeks, a trial of 400 mg daily may be worthwhile. If no effect is observed after 6 weeks on 400 mg daily, a response is not likely and consideration should be given to alternate treatment options. 2.5 Management of Acute Pain and Treatment of Primary Dysmenorrhea The recommended dose of CELEBREX is 400 mg initially, followed by an additional 200 mg dose if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily as needed. 2.6 Special Populations Hepatic insufficiency : The daily recommended dose of CELEBREX capsules in patients with moderate hepatic impairment (Child-Pugh Class B) should be reduced by 50%. The use of CELEBREX in patients with severe hepatic impairment is not recommended [see Warnings and Precautions (5.5), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Poor Metabolizers of CYP2C9 Substrates: Patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) should be administered celecoxib with caution. Consider starting treatment at half the lowest recommended dose in poor metabolizers (i.e. CYP2C9*3/*3). Consider using alternative management in JRA patients who are poor metabolizers. [see Use in Specific populations (8.8), and Clinical Pharmacology (12.5)].

torsemide 20 MG Oral Tablet

Generic Name: TORSEMIDE
Brand Name: Demadex
  • Substance Name(s):
  • TORSEMIDE

DRUG INTERACTIONS

7 •Non-steroidal anti-inflammatory drugs (NSAIDs): Reduced diuretic, natriuretic, and antihypertensive effects; risk of renal impairment. (7.1) •CYP2C9: Concomitant use with CYP2C9 inhibitors can decrease torsemide clearance. Torsemide may affect the efficacy and safety of sensitive CYP2C9 substrates or of substrates with a narrow therapeutic range, such as warfarin or phenytoin. (7.2) •Cholestyramine: Decreased exposure of DEMADEX. (7.3) •Organic anion drugs: may decrease diuretic activity of DEMADEX. (7.4) •Lithium: Risk of lithium toxicity. (7.5) •Renin-angiotensin inhibitors: Increased risk of hypotension and renal impairment. (7.7) •Radiocontrast agents: Increased risk of renal toxicity. (7.8) •Corticosteroids and ACTH: Increased risk of hypokalemia. (7.9) 7.1 Nonsteroidal Anti-inflammatory Drugs Because DEMADEX and salicylates compete for secretion by renal tubules, patients receiving high doses of salicylates may experience salicylate toxicity when DEMADEX is concomitantly administered. Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and torsemide has been associated with the development of acute renal failure. The antihypertensive and diuretic effects of DEMADEX can be reduced by NSAIDs. Partial inhibition of the natriuretic effect of DEMADEX by concomitant administration of indomethacin has been demonstrated for DEMADEX under conditions of dietary sodium restriction (50 mEq/day) but not in the presence of normal sodium intake (150 mEq/day). 7.2 Cytochrome P450 2C9 Inhibitors and Inducers Torsemide is a substrate of CYP2C9. Concomitant use of CYP2C9 inhibitors (e.g., amiodarone, fluconazole, miconazole, oxandrolone) can decrease torsemide clearance and increase torsemide plasma concentrations. Concomitant use of CYP2C9 inducers (e.g., rifampin) increase torsemide clearance and decrease plasma torsemide concentrations. Monitor diuretic effect and blood pressure when used in combination with CYP2C9 inhibitor or inducer. Adjust torsemide dose if necessary. Because of its inhibition of CYP2C9 metabolism, torsemide may affect the efficacy and safety of sensitive CYP2C9 substrates, such as celecoxib, or of substrates with a narrow therapeutic range, such as warfarin or phenytoin. Monitor patients and adjust dosages if necessary. 7.3 Cholestyramine Concomitant use of torsemide and cholestyramine has not been studied in humans but, in a study in animals, coadministration of cholestyramine decreased the absorption of orally administered torsemide. If DEMADEX and cholestyramine should be coadministered, administer DEMADEX at least one hour before or 4 to 6 h after cholestyramine administration. 7.4 Organic Anion Drugs Coadministration of organic anion drugs (e.g., probenecid) that undergo significant renal tubular secretion have the potential to reduce secretion of DEMADEX into the proximal tubule and thereby decreases the diuretic activity of DEMADEX. Monitor diuretic effect and blood pressure during coadministration. 7.5 Lithium Like other diuretics, torsemide reduces the renal clearance of lithium, inducing a high risk of lithium toxicity. Monitor lithium levels periodically when torsemide is coadministered. 7.6 Ototoxic Drugs Loop diuretics increase the ototoxic potential of other ototoxic drugs, including aminoglycoside antibiotics and ethacrynic acid. This effect has been reported with concomitant use of torsemide and gentamycin. Avoid concomitant use of DEMADEX and aminoglycoside antibiotics, if possible. 7.7 Renin-angiotensin Inhibitors Coadministration of DEMADEX with ACE inhibitors or angiotensin receptor blockers can increase the risk of hypotension and renal impairment. 7.8 Radiocontrast Agents DEMEDEX can increase the risk of renal toxicity related to administration of radiocontrast agents. 7.9 Corticosteroids and ACTH Concomitant use with DEMEDEX may increase risk of hypokalemia.

OVERDOSAGE

10 The signs and symptoms of overdosage can be anticipated to include those of excessive pharmacologic effect: dehydration, hypovolemia, hypotension, hyponatremia, hypokalemia, hypochloremic alkalosis, and hemoconcentration. Treatment of overdosage should consist of fluid and electrolyte replacement. Laboratory determinations of serum levels of torsemide and its metabolites are not widely available. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of torsemide and its metabolites. Torsemide is not dialyzable, so hemodialysis will not accelerate elimination.

DESCRIPTION

11 DEMADEX® (torsemide) is a diuretic of the pyridine-sulfonylurea class. Its chemical name is 1-isopropyl-3-[(4-m-toluidino-3-pyridyl) sulfonyl] urea and its structural formula is: Its empirical formula is C16H20N4O3S, its pKa is 7.1, and its molecular weight is 348.43. Torsemide is a white to off-white crystalline powder. The tablets for oral administration also contain lactose NF, crospovidone NF, povidone USP, microcrystalline cellulose NF, and magnesium stearate NF. Torsemide Structural Formula

HOW SUPPLIED

16 /STORAGE AND HANDLING DEMADEX for oral administration is available as white, scored tablets as follows: Dose Shape Debossing NDC 0037-xxxx-xx Side 1 Side 2 Bottle/100 5 mg elliptical 5 5005 3505-01 10 mg elliptical 10 5010 3510-01 20 mg elliptical 20 5020 3520-01 100 mg capsule shaped 100 5001 3500-01 Store at 15° to 30°C (59° to 86°F).

GERIATRIC USE

8.5 Geriatric Use Of the total number of patients who received DEMADEX in United States clinical studies, 24% were 65 or older while about 4% were 75 or older. No specific age-related differences in effectiveness or safety were observed between younger patients and elderly patients.

DOSAGE FORMS AND STRENGTHS

3 DEMADEX is available as white scored tablets in 5-, 10-, 20-, and 100-mg strengths. Tablets: 5 mg, 10 mg, 20 mg and 100 mg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action Micropuncture studies in animals have shown that torsemide acts from within the lumen of the thick ascending portion of the loop of Henle, where it inhibits the Na+/K+/2Cl–-carrier system. Clinical pharmacology studies have confirmed this site of action in humans, and effects in other segments of the nephron have not been demonstrated. Diuretic activity thus correlates better with the rate of drug excretion in the urine than with the concentration in the blood. Torsemide increases the urinary excretion of sodium, chloride, and water, but it does not significantly alter glomerular filtration rate, renal plasma flow, or acid-base balance.

INDICATIONS AND USAGE

1 DEMADEX is a loop diuretic indicated for: •the treatment of edema associated with heart failure, renal disease or hepatic disease. (1.1) •the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. (1.2) 1.1 Edema DEMADEX is indicated for the treatment of edema associated with heart failure, renal disease or hepatic disease. 1.2 Hypertension DEMADEX is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with DEMADEX. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. The antihypertensive effects of DEMADEX are on the average greater in black patients than in nonblack patients [see Clinical Pharmacology (12.2)]. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. DEMADEX can be used alone or in combination with other antihypertensive agents.

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Administration of another loop diuretic to premature infants has been associated with the precipitation of nephrocalcinosis/nephrolithiasis. Nephrocalcinosis/nephrolithiasis has also been observed in children under 4 years of age with no history of prematurity who have been treated chronically with the other loop diuretic. The other loop diuretic, when administered during the first weeks of life, has also been reported to increase the risk of persistent patent ductus arteriosus. The use of DEMADEX in such patients has not been studied.

PREGNANCY

8.1 Pregnancy Risk Summary There are no available data on use of DEMADEX in pregnant women and the risk of major birth defects or miscarriage. In pregnant rats and rabbits dosed, on a mg/m2 basis, with 10 and 1.7 times a human dose of 20 mg/day, respectively, there was no fetotoxicity or teratogenicity. However, in pregnant rats and rabbits administered 50 and 6.8 times the human dose, respectively, decreases in body weight, decreased fetal resorption and delayed fetal ossification was observed. 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 malformations and miscarriage in clinically recognized pregnancies is 2-4%, and 15-20%, respectively. Data There was no fetotoxicity or teratogenicity in rats treated with up to 5 mg/kg/day of torsemide (on a mg/kg basis, this is 15 times a human dose of 20 mg/day; on a mg/m2 basis, the animal dose is 10 times the human dose), or in rabbits, treated with 1.6 mg/kg/day (on a mg/kg basis, 5 times the human dose of 20 mg/kg/day; on a mg/m2 basis, 1.7 times this dose). Fetal and maternal toxicity (decrease in average body weight, increase in fetal resorption and delayed fetal ossification) occurred in rabbits and rats given doses 4 (rabbits) and 5 (rats) times larger.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS •Hypotension and worsening renal function: monitor volume status and renal function periodically (5.1) •Electrolyte and metabolic abnormalities: monitor serum electrolytes and blood glucose periodically. (5.2) •Ototoxicity (5.3, 7.6) 5.1 Hypotension and Worsening Renal Function Excessive diuresis may cause potentially symptomatic dehydration, blood volume reduction and hypotension and worsening renal function, including acute renal failure particularly in salt-depleted patients or those taking renin-angiotensin aldosterone inhibitors. Worsening of renal function can also occur with concomitant use of nephrotoxic drugs (e.g., aminoglycosides, cisplatin, and NSAIDs). Monitor volume status and renal function periodically. 5.2 Electrolyte and Metabolic Abnormalities DEMADEX can cause potentially symptomatic hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, and hypochloremic alkalosis. Treatment with DEMADEX can cause an increase in blood glucose levels and hyperglycemia. Asymptomatic hyperuricemia can occur and gout may rarely be precipitated. Monitor serum electrolytes and blood glucose periodically. 5.3 Ototoxicity Tinnitus and hearing loss (usually reversible) have been observed with loop diuretics, including DEMADEX. Higher than recommended doses, severe renal impairment, and hypoproteinemia, appear to increase the risk of ototoxicity.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Symptomatic Hypotension: Advise patients receiving DEMADEX that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. The patients should be told that if syncope occurs, DEMADEX should be discontinued until the physician has been consulted. All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope [see Warnings and Precautions (5.1)]. Non-Steroidal Anti-inflammatory Drugs (NSAID): Advise patients to discuss with their physician before taking NSAID medications concomitantly [see Drug Interactions (7.1)]. MEDA PHARMACEUTICALS and DEMADEX are registered trademarks of Meda AB. Any other trademarks are the property of their respective owners. Manufactured By: Meda Manufacturing GmbH, Cologne, Germany For: Meda Pharmaceuticals Meda Pharmaceuticals Inc. Somerset, NJ 08873-4120 Made in Germany Printed in USA © 2017 Meda Pharmaceuticals Inc. IN-3500-02

DOSAGE AND ADMINISTRATION

2 Edema associated with: •Heart failure: Initial dose is 10 or 20 mg once daily. Titrate by factors of two; doses above 200 mg have not been studied. (2.1) •Chronic Renal Failure: Initial dose is 20 mg once daily. Titrate by factors of two; doses above 200 mg have not been studied. (2.1) •Hepatic Cirrhosis: Initial dose is 5 or 10 mg once daily. Titrate by factors of two; doses above 40 mg have not been studied. (2.1) Hypertension: •The recommended initial dose is 5 mg once daily. After 4-6 weeks, increase to 10 mg once daily, if needed. If 10 mg is insufficient, consider adding another agent. (2.2) 2.1 Treatment of Edema Edema associated with heart failure The recommended initial dose is 10 mg or 20 mg oral DEMADEX once daily. If the diuretic response is inadequate, titrate upward by approximately doubling until the desired diuretic response is obtained. Doses higher than 200 mg have not been adequately studied. Edema associated with chronic renal failure The recommended initial dose is 20 mg oral DEMADEX once daily. If the diuretic response is inadequate, titrate upward by approximately doubling until the desired diuretic response is obtained. Doses higher than 200 mg have not been adequately studied. Edema associated with hepatic cirrhosis The recommended initial dose is 5 mg or 10 mg oral DEMADEX once daily, administered together with an aldosterone antagonist or a potassium-sparing diuretic. If the diuretic response is inadequate, titrate upward by approximately doubling until the desired diuretic response is obtained. Doses higher than 40 mg have not been adequately studied in this population. 2.2 Treatment of Hypertension The recommended initial dose is 5 mg once daily. If the 5 mg dose does not provide adequate reduction in blood pressure within 4 to 6 weeks, increase to 10 mg once daily. If the response to 10 mg is insufficient, add another antihypertensive agent to the treatment regimen.

Simvastatin 10 MG Oral Tablet

Generic Name: SIMVASTATIN
Brand Name: simvastatin
  • Substance Name(s):
  • SIMVASTATIN

DRUG INTERACTIONS

7. Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3) Interacting Agents Prescribing Recommendations Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. Grapefruit juice Avoid grapefruit juice Other Lipid-lowering Medications: Use with other fibrate products or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with simvastatin. ( 5.1, 7.2, 7.4) Coumarin anticoagulants: Concomitant use with simvastatin tablets prolongs INR. Achieve stable INR prior to starting simvastatin tablets. Monitor INR frequently until stable upon initiation or alteration of simvastatin tablets therapy. ( 7.6) 7.1 Strong CYP3A4 Inhibitors, Cyclosporine, or Danazol Strong CYP3A4 inhibitors: Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of CYP3A4. Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Elevated plasma levels of HMG-CoA reductase inhibitory activity increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).] Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated [see Contraindications (4)] . If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated. [see Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)] . 7.2 Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone Gemfibrozil: Contraindicated with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1)] . Other fibrates: Caution should be used when prescribing with simvastatin [ see Warnings and Precautions (5.1)] . 7.3 Amiodarone, Dronedarone, Ranolazine, or Calcium Channel Blockers The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amiodarone, dronedarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem, or amlodipine [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) and Table 3 in Clinical Pharmacology (12.3)]. 7.4 Niacin Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥ 1 g/day niacin) of niacin-containing products. In particular, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)] . 7.5 Digoxin In one study, concomitant administration of digoxin with simvastatin resulted in a slight elevation in digoxin concentrations in plasma. Patients taking digoxin should be monitored appropriately when simvastatin is initiated [see Clinical Pharmacology (12.3)] . 7.6 Coumarin Anticoagulants In two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients, simvastatin 20 to 40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. With other statins, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants. 7.7 Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine.

OVERDOSAGE

10. Significant lethality was observed in mice after a single oral dose of 9 g/m 2. No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100 g/m 2, respectively. No specific diagnostic signs were observed in rodents. At these doses the only signs seen in dogs were emesis and mucoid stools. A few cases of overdosage with simvastatin tablets have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. Supportive measures should be taken in the event of an overdose. The dialyzability of simvastatin and its metabolites in man is not known at present.

DESCRIPTION

11. Simvastatin is a lipid-lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus. After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol. Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2 H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1 S-[1α,3α,7β,8β(2 S*,4 S*),-8aβ]]. The empirical formula of simvastatin is C 25H 38O 5 and its molecular weight is 418.57. Its structural formula is: Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol. Simvastatin tablets USP for oral administration contain either 5 mg, 10 mg, 20 mg, 40 mg or 80 mg of simvastatin and the following inactive ingredients: microcrystalline cellulose, hydroxypropyl cellulose, hypromellose E5, croscarmellose sodium, ferric oxide red, lactose monohydrate, magnesium stearate, maize starch, talc, titanium dioxide, butylated hydroxyanisole , ascorbic acid, citric acid monohydrate, and triethyl citrate. Simvastatin

CLINICAL STUDIES

14. 14.1 Clinical Studies in Adults Reductions in Risk of CHD Mortality and Cardiovascular Events In 4S, the effect of therapy with simvastatin tablets on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212 to 309 mg/dL (5.5 to 8.0 mmol/L). In this multicenter, randomized, double-blind, placebo-controlled study, patients were treated with standard care, including diet, and either simvastatin tablets 20 to 40 mg/day (n=2,221) or placebo (n=2,223) for a median duration of 5.4 years. Over the course of the study, treatment with simvastatin tablets led to mean reductions in total-C, LDL-C and TG of 25%, 35%, and 10%, respectively, and a mean increase in HDL-C of 8%. Simvastatin tablets significantly reduced the risk of mortality by 30% (p=0.0003, 182 deaths in the simvastatin tablets group vs 256 deaths in the placebo group). The risk of CHD mortality was significantly reduced by 42% (p=0.00001, 111 vs 189 deaths). There was no statistically significant difference between groups in non-cardiovascular mortality. Simvastatin tablets significantly decreased the risk of having major coronary events (CHD mortality plus hospital-verified and silent non-fatal myocardial infarction [MI]) by 34% (p<0.00001, 431 vs 622 patients with one or more events). The risk of having a hospital-verified non-fatal MI was reduced by 37%. Simvastatin tablets significantly reduced the risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37% (p<0.00001, 252 vs 383 patients). Simvastatin tablets significantly reduced the risk of fatal plus non-fatal cerebrovascular events (combined stroke and transient ischemic attacks) by 28% (p=0.033, 75 vs 102 patients). Simvastatin tablets reduced the risk of major coronary events to a similar extent across the range of baseline total and LDL cholesterol levels. Because there were only 53 female deaths, the effect of simvastatin tablets on mortality in women could not be adequately assessed. However, simvastatin tablets significantly lessened the risk of having major coronary events by 34% (60 vs 91 women with one or more event). The randomization was stratified by angina alone (21% of each treatment group) or a previous MI. Because there were only 57 deaths among the patients with angina alone at baseline, the effect of simvastatin tablets on mortality in this subgroup could not be adequately assessed. However, trends in reduced coronary mortality, major coronary events and revascularization procedures were consistent between this group and the total study cohort. Additionally, simvastatin tablets resulted in similar decreases in relative risk for total mortality, CHD mortality, and major coronary events in elderly patients (≥65 years) , compared with younger patients. The Heart Protection Study (HPS) was a large, multi-center, placebo-controlled, double-blind study with a mean duration of 5 years conducted in 20,536 patients (10,269 on simvastatin tablets 40 mg and 10,267 on placebo). Patients were allocated to treatment using a covariate adaptive method D.R. Taves, Minimization: a new method of assigning patients to treatment and control groups. Clin. Pharmacol. Ther. 15 (1974), pp. 443-453 which took into account the distribution of 10 important baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients had a mean age of 64 years (range 40 to 80 years), were 97% Caucasian and were at high risk of developing a major coronary event because of existing CHD (65%), diabetes (Type 2, 26%; Type 1, 3%), history of stroke or other cerebrovascular disease (16%), peripheral vessel disease (33%), or hypertension in males ≥65 years (6%). At baseline, 3,421 patients (17%) had LDL-C levels below 100 mg/dL, of whom 953 (5%) had LDL-C levels below 80 mg/dL; 7,068 patients (34%) had levels between 100 and 130 mg/dL; and 10,047 patients (49%) had levels greater than 130 mg/dL. The HPS results showed that simvastatin tablets 40 mg/day significantly reduced: total and CHD mortality; non-fatal MI, stroke, and revascularization procedures (coronary and non-coronary) (see Table 4). Table 4: Summary of Heart Protection Study Results Endpoint Simvastatin Tablets (N=10,269) n(%) n = number of patients with indicated event Placebo (N=10,267) n (%) Risk Reduction (%) (95% CI) p-Value Primary Mortality 1,328 (12.9) 1,507 (14.7) 13 (6 to 19) p=0.0003 CHD mortality 587 (5.7) 707 (6.9) 18 (8 to 26) p=0.0005 Secondary Non-fatal MI 357 (3.5) 574 (5.6) 38 (30 to 46) p<0.0001 Stroke 444 (4.3) 585 (5.7) 25 (15 to 34) p<0.0001 Tertiary Coronary revascularization 513 (5) 725 (7.1) 30 (22 to 38) p<0.0001 Peripheral and other non-coronary revascularization 450 (4.4) 532 (5.2) 16 (5 to 26) p=0.006 Two composite endpoints were defined in order to have sufficient events to assess relative risk reductions across a range of baseline characteristics (see Figure 1). A composite of major coronary events (MCE) was comprised of CHD mortality and non-fatal MI (analyzed by time-to-first event; 898 patients treated with simvastatin tablets had events and 1,212 patients on placebo had events). A composite of major vascular events (MVE) was comprised of MCE, stroke and revascularization procedures including coronary, peripheral and other non-coronary procedures (analyzed by time-to-first event; 2,033 patients treated with simvastatin tablets had events and 2,585 patients on placebo had events). Significant relative risk reductions were observed for both composite endpoints (27% for MCE and 24% for MVE, p 200 mg/dL, respectively. Patients with TG > 350 mg/dL were excluded 664 -36 -47 8 -24 Multi-Center Combined Hyperlipidemia Study mean baseline LDL-C 156 mg/dL and median baseline TG 391 mg/dL. (Mean % Change at Week 6) Placebo 125 1 2 3 -4 Simvastatin Tablets 40 mg q.p.m. 123 -25 -29 13 -28 Simvastatin Tablets 80 mg q.p.m. 124 -31 -36 16 -33 Hypertriglyceridemia (Frederickson type IV) The results of a subgroup analysis in 74 patients with type lV hyperlipidemia from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 6. Table 6: Six-week, Lipid-lowering Effects of Simvastatin in Type lV Hyperlipidemia Median Percent Change (25 th and 75 th percentile) from Baseline The median baseline values (mg/dL) for the patients in this study were: total-C = 254, LDL-C = 135, HDL-C = 36, TG = 404, VLDL-C = 83, and non-HDL-C = 215 TREATMENT N Total-C LDL-C HDL-C TG VLDL-C Non-HDL-C Placebo 74 +2 (-7, +7) +1 (-8, +14) +3 (-3, +10) -9 (-25, +13) -7 (-25, +11) +1 (-9, +8) Simvastatin Tablets 40 mg/day 74 -25 (-34, -19) -28 (-40, -17) +11 (+5, +23) -29 (-43, -16) -37 (-54, -23) -32 (-42, -23) Simvastatin Tablets 80 mg/day 74 -32 (-38, -24) -37 (-46, -26) +15 (+5, +23) -34 (-45, -18) -41 (-57, -28) -38 (-49, -32) Dysbetalipoproteinemia (Fredrickson type lll) The results of a subgroup analysis in 7 patients with type lll hyperlipidemia (dysbetalipoproteinemia) (apo E2/2) (VLDL-C/TG>0.25) from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 7. Table 7: Six-week, Lipid-lowering Effects of Simvastatin in Type lll Hyperlipidemia Median Percent Change (min, max) from Baseline The median baseline values (mg/dL) were: total-C = 324, LDL-C = 121, HDL-C = 31, TG = 411, VLDL-C = 170, and non-HDL-C = 291. TREATMENT N Total-C LDL-C + IDL HDL-C TG VLDL-C+IDL Non-HDL-C Placebo 7 -8 (-24, +34) -8(-27, +23) -2(-21, +16) +4(-22, +90) -4(-28, +78) -8 (-26, -39) Simvastatin Tablets 40 mg/day 7 -50 (-66, -39) -50(-60, -31) +7(-8, +23) -41(-74, -16) -58(-90, -37) -57(-72, -44) Simvastatin Tablets 80 mg/day 7 -52 (-55, -41) -51(-57, -28) +7(-5, +29) -38(-58, +2) -60 (-72, -39) -59 (-61, -46) Homozygous Familial Hypercholesterolemia In a controlled clinical study, 12 patients 15 to 39 years of age with homozygous familial hypercholesterolemia received simvastatin 40 mg/day in a single dose or in 3 divided doses, or 80 mg/day in 3 divided doses. In 11 patients with reductions in LDL-C, the mean LDL-C changes for the 40- and 80-mg doses were 14% (range 8% to 23%, median 12%) and 30% (range 14% to 46%, median 29%), respectively. One patient had an increase of 15% in LDL-C. Another patient with absent LDL-C receptor function had an LDL-C reduction of 41% with the 80-mg dose. Endocrine Function In clinical studies, simvastatin did not impair adrenal reserve or significantly reduce basal plasma cortisol concentration. Small reductions from baseline in basal plasma testosterone in men were observed in clinical studies with simvastatin, an effect also observed with other statins and the bile acid sequestrant cholestyramine. There was no effect on plasma gonadotropin levels. In a placebo-controlled, 12-week study there was no significant effect of simvastatin 80 mg on the plasma testosterone response to human chorionic gonadotropin. In another 24-week study, simvastatin 20 to 40 mg had no detectable effect on spermatogenesis. In 4S, in which 4,444 patients were randomized to simvastatin 20 to 40 mg/day or placebo for a median duration of 5.4 years, the incidence of male sexual adverse events in the two treatment groups was not significantly different. Because of these factors, the small changes in plasma testosterone are unlikely to be clinically significant. The effects, if any, on the pituitary-gonadal axis in pre-menopausal women are unknown. Simvastatin 14.2 Clinical Studies in Adolescents In a double-blind, placebo-controlled study, 175 patients (99 adolescent boys and 76 post-menarchal girls) 10 to 17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (HeFH) were randomized to simvastatin (n=106) or placebo (n=67) for 24 weeks (base study). Inclusion in the study required a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with an LDL-C level >189 mg/dL. The dosage of simvastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24-week extension, 144 patients elected to continue therapy with simvastatin 40 mg or placebo. Simvastatin tablets significantly decreased plasma levels of total-C, LDL-C, and Apo B (see Table 8). Results from the extension at 48 weeks were comparable to those observed in the base study. Table 8: Lipid-Lowering Effects of Simvastatin in Adolescent Patients with Heterozygous Familial Hypercholesterolemia (Mean Percent Change from Baseline) Dosage Duration N Total-C LDL-C HDL-C TG median percent change Apo B Placebo 24 Weeks 67 % Change from Baseline (95% CI) 1.6 (-2.2, 5.3) 1.1 (-3.4, 5.5) 3.6 (-0.7, 8.0) -3.2 (-11.8, 5.4) -0.5 (-4.7, 3.6) Mean baseline, mg/dL (SD) 278.6(51.8) 211.9(49.0) 46.9(11.9) 90.0(50.7) 186.3(38.1) Simvastatin Tablets 24 Weeks 106 % Change from Baseline (95% CI) -26.5 (-29.6, -23.3) -36.8 (-40.5, -33.0) 8.3 (4.6, 11.9) -7.9 (-15.8, 0.0) -32.4 (-35.9, -29.0) Mean baseline, mg/dL (SD) 270.2(44.0) 203.8(41.5) 47.7(9.0) 78.3(46.0) 179.9(33.8) After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64.0 to 289.0 mg/dL) in the simvastatin tablets 40 mg group compared to 207.8 mg/dL (range: 128.0 to 334.0 mg/dL) in the placebo group. The safety and efficacy of doses above 40 mg daily have not been studied in children with HeFH. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

HOW SUPPLIED

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RECENT MAJOR CHANGES

Contraindication ( 4) 02/2014 Warnings and Precautions Myopathy/Rhabdomyolysis ( 5.1) 02/2014

GERIATRIC USE

8.5 Geriatric Use Of the 2,423 patients who received simvastatin tablets in Phase III clinical studies and the 10,269 patients in the Heart Protection Study who received simvastatin tablets, 363 (15%) and 5,366 (52%), respectively were ≥65 years old. In HPS, 615 (6%) were ≥75 years old. 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, but greater sensitivity of some older individuals cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, simvastatin tablets should be prescribed with caution in the elderly. [See Clinical Pharmacology (12.3).] A pharmacokinetic study with simvastatin showed the mean plasma level of statin activity to be approximately 45% higher in elderly patients between 70 to 78 years of age compared with patients between 18 to 30 years of age. In 4S, 1,021 (23%) of 4,444 patients were 65 or older. Lipid-lowering efficacy was at least as great in elderly patients compared with younger patients, and simvastatin tablets significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD. In HPS, 52% of patients were elderly (4,891 patients 65 to 69 years and 5,806 patients 70 years or older). The relative risk reductions of CHD death, non-fatal MI, coronary and non-coronary revascularization procedures, and stroke were similar in older and younger patients [see Clinical Studies (14.1)]. In HPS, among 32,145 patients entering the active run-in period, there were 2 cases of myopathy/rhabdomyolysis; these patients were aged 67 and 73. Of the 7 cases of myopathy/rhabdomyolysis among 10,269 patients allocated to simvastatin, 4 were aged 65 or more (at baseline), of whom one was over 75. There were no overall differences in safety between older and younger patients in either 4S or HPS. Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, simvastatin tablets should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age. [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)] .

DOSAGE FORMS AND STRENGTHS

3. Simvastatin tablets 5 mg are brick red colored, round shaped, biconvex, film coated tablet debossed “SI” on one side and plain on other side. Simvastatin tablets 10 mg are brick red colored,oval shaped, biconvex,film-coated tablets, debossed “S 4” on one side and plain on the other side Simvastatin tablets 20 mg are brick red colored,oval shaped, biconvex,film-coated tablets, debossed “S 5” on one side and plain on the other side. Simvastatin tablets 40 mg are brick red colored,oval shaped, biconvex,film-coated tablets,debossed “S 6” on one side and plain on the other side Simvastatin tablets 80 mg are brick red colored, capsule-shaped, biconvex, film-coated tablets, debossed with “SMV” on one side and “80” on the other side Tablets: 5 mg; 10 mg; 20 mg; 40.0#160;mg; 80 mg ( 3)

MECHANISM OF ACTION

12.1 Mechanism of Action Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C.

INDICATIONS AND USAGE

1. Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with coronary heart disease (CHD) or at high risk of CHD, simvastatin tablets can be started simultaneously with diet. Simvastatin tablets are an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet to: Reduce the risk of total mortality by reducing CHD deaths and reduce the risk of non-fatal myocardial infarction, stroke, and the need for revascularization procedures in patients at high risk of coronary events. ( 1.1) Reduce elevated total-C, LDL-C, Apo B, TG and increase HDL-C in patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia. ( 1.2) Reduce elevated TG in patients with hypertriglyceridemia and reduce TG and VLDL-C in patients with primary dysbeta-lipoproteinemia. ( 1.2) Reduce total-C and LDL-C in adult patients with homozygous familial hypercholesterolemia. ( 1.2 ) Reduce elevated total-C, LDL-C, and Apo B in boys and postmenarchal girls, 10 to 17 years of age with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy. ( 1.2, 1.3) Limitations of Use Simvastatin tablets have not been studied in Fredrickson Types I and V dyslipidemias. ( 1.4) 1.1 Reductions in Risk of CHD Mortality and Cardiovascular Events In patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, simvastatin tablets are indicated to: Reduce the risk of total mortality by reducing CHD deaths. Reduce the risk of non-fatal myocardial infarction and stroke. Reduce the need for coronary and non-coronary revascularization procedures. 1.2 Hyperlipidemia Simvastatin tablets are indicated to: Reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb). Reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type lV hyperlipidemia). Reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson type III hyperlipidemia). Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable. 1.3 Adolescent Patients with Heterozygous Familial Hypercholesterolemia (HeFH) Simvastatin tablets are indicated as an adjunct to diet to reduce total-C, LDL-C, and Apo B levels in adolescent boys and girls who are at least one year post-menarche, 10 to 17 years of age, with HeFH, if after an adequate trial of diet therapy the following findings are present: LDL cholesterol remains ≥190 mg/dL; or LDL cholesterol remains ≥160 mg/dL and There is a positive family history of premature cardiovascular disease (CVD) or Two or more other CVD risk factors are present in the adolescent patient. The minimum goal of treatment in pediatric and adolescent patients is to achieve a mean LDL-C <130 mg/dL. The optimal age at which to initiate lipid-lowering therapy to decrease the risk of symptomatic adulthood CAD has not been determined. 1.4 Limitations of Use Simvastatin tablets have not been studied in conditions where the major abnormality is elevation of chylomicrons (i.e., hyperlipidemia Fredrickson types I and V).

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness of simvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys and in girls who were at least 1 year post-menarche. Patients treated with simvastatin had an adverse reaction profile similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls. [See Dosage and Administration (2.5), Adverse Reactions (6.1), Clinical Studies (14.2).] Adolescent females should be counseled on appropriate contraceptive methods while on simvastatin therapy [see Contraindications (4) and Use in Specific Populations (8.1)]. Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-menarchal girls.

PREGNANCY

8.1 Pregnancy Pregnancy Category X [See Contraindications (4).] Simvastatin tablets are contraindicated in women who are or may become pregnant. Lipid lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of use with simvastatin tablets during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero. Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, simvastatin tablets may cause fetal harm when administered to a pregnant woman. If simvastatin tablets are used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. There are rare reports of congenital anomalies following intrauterine exposure to statins. In a review Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy, Reproductive Toxicology,, 10(6):439-446, 1996. of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related statin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed those expected in the general population. However, the study was only able to exclude a 3- to 4-fold increased risk of congenital anomalies over the background rate. In 89% of these cases, drug treatment was initiated prior to pregnancy and was discontinued during the first trimester when pregnancy was identified. Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m 2 surface area. However, in studies with another structurally-related statin, skeletal malformations were observed in rats and mice. Women of childbearing potential, who require treatment with simvastatin tablets for a lipid disorder, should be advised to use effective contraception. For women trying to conceive, discontinuation of simvastatin tablets should be considered. If pregnancy occurs, simvastatin tablets should be immediately discontinued.

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether simvastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not nurse their infants. A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother [see Contraindications (4)] .

WARNING AND CAUTIONS

5. WARNINGS AND PRECAUTIONS Patients should be advised of the increased risk of myopathy including rhabdomyolysis with the 80-mg dose. ( 5.1) Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with higher doses and concomitant use of certain medicines. Predisposing factors include advanced age (≥65), female gender, uncontrolled hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. ( 4, 5.1, 8.5, 8.6) Patients should be advised to report promptly any unexplained and/or persistent muscle pain, tenderness, or weakness. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. See Drug Interaction table. ( 5.1) Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter. ( 5.2) 5.1 Myopathy/Rhabdomyolysis Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of statin activity in plasma. Predisposing factors for myopathy include advanced age (≥65 years),female gender, uncontrolled hypothyroidism, and renal impairment. The risk of myopathy, including rhabdomyolysis, is dose related. In a clinical trial database in which 41,413 patients were treated with simvastatin. 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses. In these trials, patients were carefully monitored and some interacting medicinal products were excluded In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded. The risk of myopathy, including rhabdomyolysis, is greater in patients on simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-lowering efficacy and compared with lower doses of simvastatin. Therefore, the 80-mg dose of simvastatin should be used only in patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [See Dosage and Administration, Restricted Dosing for 80 mg (2.2).] If, however, a patient who is currently tolerating the 80-mg dose of simvastatin needs to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin with less potential for the drug-drug interaction. Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, and to report promptly any unexplained muscle pain, tenderness or weakness. If symptoms occur, treatment should be discontinued immediately. [See Warnings and Precautions (5.2).] There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing simvastatin. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with simvastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy. Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Simvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Simvastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy. Drug Interactions The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, posaconazole, voriconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, cobicistat-containing products, or grapefruit juice [See Clinical Pharmacology (12.3).] . Combination of these drugs with simvastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with simvastatin must be suspended during the course of treatment. [See Contraindications (4) and Drug Interactions (7.1).] The combined use of simvastatin with gemfibrozil, cyclosporine, or danazol is contraindicated [See Contraindications (4) and Drug Interactions (7.1 and 7.2).] Caution should be used when prescribing other fibrates with simvastatin, as these agents can cause myopathy when given alone and the risk is increased when they are coadministered [see Drug Interactions (7.2).] Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine [see Drug Interactions (7.7).] The benefits of the combined use of simvastatin with the following drugs should be carefully weighed against the potential risks of combinations: other lipid-lowering drugs (other fibrates, ≥1 g/day of niacin, or, for patients with HoFH, lomitapide), amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine [see Drug Interactions (7.3) and Table 3 in Clinical Pharmacology (12.3)] [also see Dosage and Administration, Patients with Homozygous Familial Hypercholesterolemia (2.4)] Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In an ongoing, double-blind, randomized cardiovascular outcomes trial, an independent safety monitoring committee identified that the incidence of myopathy is higher in Chinese compared with non-Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses of a niacin-containing product. Caution should be used when treating Chinese patients with simvastatin in doses exceeding 20 mg/day coadministered with lipid- modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin- containing products. It is unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients [see Drug Interactions (7.4)] . Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (2.3, 2.4) Drug Interactions (7), Clinical Pharmacology (12.3)]. Table 1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis Interacting Agents Prescribing Recommendations Strong CYP3A4 Inhibitors, e.g.: Itraconazole Ketoconazole Posaconazole Voriconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Boceprevir Telaprevir Nefazodone Cobicistat-containing products Gemfibrozil Cyclosporine Danazol Contraindicated with simvastatin Verapamil Diltiazem Dronedarone Do not exceed 10 mg simvastatin daily Amiodarone Amlodipine Ranolazine Do not exceed 20 mg simvastatin daily Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. Grapefruit juice Avoid grapefruit juice 5.2 Liver Dysfunction Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies. When drug treatment was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity. In the Scandinavian Simvastatin Survival Study (4S) [see Clinical Studies (14.1)] , the number of patients with more than one transaminase elevation to > 3X ULN, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 [0.7%] vs. 12 [0.6%]). Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2,221) and 5 in the placebo group (n=2,223). Of the 1,986 simvastatin treated patients in 4S with normal liver function tests (LFTs) at baseline, 8 (0.4%) developed consecutive LFT elevations to > 3X ULN and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study. Among these 8 patients, 5 initially developed these abnormalities within the first year. All of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg. In 2 controlled clinical studies in 1,105 patients, the 12-month incidence of persistent hepatic transaminase elevation without regard to drug relationship was 0.9% and 2.1% at the 40- and 80-mg dose, respectively. No patients developed persistent liver function abnormalities following the initial 6 months of treatment at a given dose. It is recommended that liver function tests be performed before the initiation of treatment, and thereafter when clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with simvastatin, promptly interrupt therapy. If an alternate etiology is not found do not restart simvastatin. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy [see Warnings and Precautions (5.1)] . The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of simvastatin. Moderate (less than 3X ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and did not require interruption of treatment. 5.3 Endocrine Function Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including simvastatin.

INFORMATION FOR PATIENTS

17. PATIENT COUNSELING INFORMATION Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel. Patients should be advised about substances they should not take concomitantly with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1)]. Patients should also be advised to inform other healthcare professionals prescribing a new medication or increasing the dose of an existing medication that they are taking simvastatin tablets. 17.1 Muscle Pain All patients starting therapy with simvastatin tablets should be advised of the risk of myopathy , including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing simvastatin tablets. Patients using the 80-mg dose should be informed that the risk of myopathy, including rhabdomyolysis, is increased with use of the 80-mg dose. The risk of myopathy, including rhabdomyolysis, occurring with use of simvastatin tablets are increased when taking certain types of medication or consuming grapefruit juice. Patients should discuss all medication, both prescription and over the counter, with their healthcare professional. 17.2 Liver Enzymes It is recommended that liver function tests be performed before the initiation of simvastatin tablets, and thereafter when clinically indicated. All patients treated with simvastatin tablets should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. 17.3 Pregnancy Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using simvastatin tablets. Discuss future pregnancy plans with your patients, and discuss when to stop taking simvastatin tablets if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking simvastatin tablets and call their healthcare professional. 17.4 Breastfeeding Women who are breastfeeding should not use simvastatin tablets. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professional. Manufactured For: Accord Healthcare, Inc., 1009, Slater Road, Suite 210-B, Durham, NC 27703, USA Manufactured By: Intas Pharmaceuticals Limited, Ahmedabad -380 009, India. 10 9351 1 659550 Issued February 2015

DOSAGE AND ADMINISTRATION

2. Dose range is 5 to 40 mg/day. ( 2.1) Recommended usual starting dose is 10 or 20 mg once a day in the evening. ( 2.1) Recommended starting dose for patients at high risk of CHD is 40 mg/day. ( 2.1) Due to the increased risk of myopathy, including rhabdomyolysis, use of the 80-mg dose of simvastatin tablets should be restricted to patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. ( 2.2) Patients who are currently tolerating the 80-mg dose of simvastatin tablets who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin with less potential for the drug-drug interaction. ( 2.2) Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80-mg dose of simvastatin tablets, patients unable to achieve their LDL-C goal utilizing the 40-mg dose of simvastatin tablets should not be titrated to the 80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering. ( 2.2) Adolescents (10 to 17 years of age) with HeFH: starting dose is 10 mg/day; maximum recommended dose is 40 mg/day. ( 2.5) 2.1 Recommended Dosing The usual dosage range is 5 to 40 mg/day. In patients with CHD or at high risk of CHD, simvastatin tablets can be started simultaneously with diet. The recommended usual starting dose is 10 or 20 mg once a day in the evening. For patients at high risk for a CHD event due to existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, the recommended starting dose is 40 mg/day. Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter. 2.2 Restricted Dosing for 80 mg Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 80-mg dose of simvastatin tablets should be restricted to patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. [see Warnings and Precautions (5.1)] Patients who are currently tolerating the 80-mg dose of simvastatin tablets who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin with less potential for the drug-drug interaction. Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80-mg dose of simvastatin tablets, patients unable to achieve their LDL-C goal utilizing the 40-mg dose of simvastatin tablets should not be titrated to the 80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering. 2.3 Coadministration with Other Drugs Patients taking Verapamil, Diltiazem, or Dronedarone The dose of simvastatin tablets should not exceed 10 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)]. . Patients taking Amiodarone, Amlodipine or Ranolazine The dose of simvastatin tablets should not exceed 20 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)]. 2.4 Patients with Homozygous Familial Hypercholesterolemia The recommended dosage is 40 mg/day in the evening [see Dosage and Administration, Restricted Dosing for 80 mg (2.2)] . Simvastatin tablets should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable. Simvastatin exposure is approximately doubled with concomitant use of lomitapide; therefore, the dose of simvastatin tablets should be reduced by 50% if initiating lomitapide. Simvastatin tablets dosage should not exceed 20 mg/day (or 40 mg/day for patients who have previously taken simvastatin tablets 80 mg/day chronically, e.g., for 12 months or more, without evidence of muscle toxicity) while taking lomitapide. 2.5 Adolescents (10 to 17 years of age) with Heterozygous Familial Hypercholesterolemia The recommended usual starting dose is 10 mg once a day in the evening. The recommended dosing range is 10 to 40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy [see NCEP Pediatric Panel Guidelines National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics 89(3):495-501. 1992. and Clinical Studies (14.2) ]. Adjustments should be made at intervals of 4 weeks or more. 2.6 Patients with Renal Impairment Because simvastatin tablets do not undergo significant renal excretion, modification of dosage should not be necessary in patients with mild to moderate renal impairment. However, caution should be exercised when simvastatin tablets are administered to patients with severe renal impairment; such patients should be started at 5 mg/day and be closely monitored [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. 2.7 Chinese Patients Taking Lipid-Modifying Doses (greater than or equal to 1 g/day Niacin) of Niacin-Containing Products Because of an increased risk for myopathy, in Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses (greater than or equal to 1 g/day niacin) of niacin-containing products, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. The cause of the increased risk of myopathy is not known. It is also unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients. [see Warnings and Precautions (5.1)]

pramipexole dihydrochloride 0.375 MG 24 HR Extended Release Oral Tablet

Generic Name: PRAMIPEXOLE DIHYDROCHLORIDE
Brand Name: Pramipexole dihydrochloride
  • Substance Name(s):
  • PRAMIPEXOLE DIHYDROCHLORIDE

DRUG INTERACTIONS

7 Dopamine antagonists: May diminish the effectiveness of pramipexole (7.1). 7.1 Dopamine Antagonists Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of pramipexole dihydrochloride extended-release tablets.

OVERDOSAGE

10 There is no clinical experience with significant overdosage. One patient took 11 mg/day of pramipexole for 2 days in a clinical trial for an investigational use. Blood pressure remained stable, although pulse rate increased to between 100 and 120 beats/minute. No other adverse reactions were reported related to the increased dose. There is no known antidote for overdosage of a dopamine agonist. If signs of central nervous system stimulation are present, a phenothiazine or other butyrophenone neuroleptic agent may be indicated; the efficacy of such drugs in reversing the effects of overdosage has not been assessed. Management of overdose may require general supportive measures along with gastric lavage, intravenous fluids, and electrocardiogram monitoring.

DESCRIPTION

11 pramipexole dihydrochloride extended-release tablets contain pramipexole, a non-ergot dopamine agonist. The chemical name of pramipexole dihydrochloride is (S)-2-amino-4,5,6,7-tetrahydro-6(propylamino)benzothiazole dihydrochloride monohydrate. Its molecular formula is C10 H17 N3 S · 2HCl · H2O, and its molecular weight is 302.26. The structural formula is: Pramipexole dihydrochloride USP is a white to almost white, crystalline powder. It is freely soluble in water, soluble in methanol, slightly soluble in alcohol (99.6%) and practically insoluble in methylene chloride. Melting occurs in the range of 293°C to 306°C, with decomposition. Pramipexole dihydrochloride extended-release tablets, for oral administration, contain 0.375 mg, 0.75 mg, 1.5 mg, 3 mg, or 4.5 mg of pramipexole dihydrochloride monohydrate. Inactive ingredients are carbomer homopolymer, colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose and pregelatinized starch.

CLINICAL STUDIES

14 The effectiveness of pramipexole dihydrochloride extended-release tablets in the treatment of Parkinson’s disease was supported by clinical pharmacokinetic data [see Clinical Pharmacology (12.3) ] and two randomized, double-blind, placebo-controlled, multicenter clinical trials in early and advanced Parkinson’s disease. In both randomized studies, the Unified Parkinson’s Disease Rating Scale (UPDRS) served as a primary outcome assessment measure. The UPDRS is a four-part multi-item rating scale intended to evaluate mentation (Part I), activities of daily living (Part II), motor performance (Part III), and complications of therapy (Part IV). Part II of the UPDRS contains 13 questions related to activities of daily living, which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52. Part III of the UPDRS contains 14 items designed to assess the severity of the cardinal motor findings in patients with Parkinson’s disease (e.g., tremor, rigidity, bradykinesia, postural instability, etc.), scored for different body regions and has a maximum (worst) score of 108. Early Parkinson’s Disease The effectiveness of pramipexole dihydrochloride extended-release tablets in early Parkinson’s disease patients (Hoehn & Yahr Stages I-III) who were not on levodopa therapy was established in a randomized, double-blind, placebo-controlled, 3-parallel-group clinical study. Patients were treated with pramipexole dihydrochloride extended-release tablets, immediate-release pramipexole tablets, or placebo; those treated with pramipexole extended-release tablets or immediate-release pramipexole tablets had a starting dose of 0.375 mg/day followed by a flexible up-titration, based on efficacy and tolerability, up to 4.5 mg/day. Levodopa was permitted during the study as rescue medication. Stable doses of concomitant MAO-B inhibitors, anticholinergics, or amantadine, individually or in combination, were allowed. The primary efficacy endpoint was the mean change from baseline in the UPDRS Parts II+III score for pramipexole dihydrochloride extended-release tablets versus placebo following 18 weeks of treatment. At 18 weeks of treatment, the mean change from baseline UPDRS Parts II+III score was –8.1 points in patients receiving pramipexole dihydrochloride extended-release tablets (n=102) and –5.1 points in patients receiving placebo (n=50), a difference that was statistically significant (p<0.03). Seven patients treated with placebo (14%) and 3 patients treated with pramipexole dihydrochloride extended-release tablets (3%) received levodopa rescue medication. At 18 weeks, the mean dose of pramipexole dihydrochloride extended-release was 3 mg/day. At 33-weeks the adjusted mean improvement from baseline UPDRS Parts II+III score was –8.6 points in patients receiving pramipexole dihydrochloride extended-release tablets (n=213), compared to –3.8 points in patients receiving placebo (n=103). At 18 and 33 weeks, the mean dose of pramipexole dihydrochloride extended-release tablets was approximately 3 mg/day. Twenty-two patients treated with placebo (21%) and 15 patients treated with pramipexole dihydrochloride extended-release tablets (7%) received levodopa rescue medication before the final assessment No differences in effectiveness based on age or gender were detected. Patients receiving MAOB-I, anticholinergics, or amantadine had responses similar to patients not receiving these drugs. Advanced Parkinson’s Disease The effectiveness of pramipexole dihydrochloride extended-release tablets in advanced Parkinson's disease patients (Hoehn & Yahr Stages II-IV at "on" time) who were on concomitant levodopa therapy (at an optimized dose) and who had motor fluctuations (at least 2 cumulative hours of "off" time per day) was established in a randomized, double-blind, placebo-controlled, 3-parallel-group clinical study. Patients were treated with pramipexole extended-release tablets, immediate-release pramipexole tablets, or placebo; those treated with pramipexole extended-release tablets or immediate-release pramipexole tablets had a starting dose of 0.375 mg/day followed by a flexible up-titration over 7 weeks, based on efficacy and tolerability, up to 4.5 mg/day, followed by a 26 week maintenance period. Levodopa dosage reduction was permitted only in the case of dopaminergic adverse events. The primary efficacy endpoint was the adjusted mean change from baseline in the UPDRS Parts II+III score for pramipexole dihydrochloride extended-release tablets versus placebo following 18 weeks of treatment. At 18 weeks of treatment, the adjusted mean improvement from baseline UPDRS Parts II+III score was – 11 points in patients receiving pramipexole dihydrochloride extended-release tablets (n=161) and – 6.1 points in patients receiving placebo (n=174), (p=0.0001). At week 18, the adjusted mean improvement from baseline in “off" time was -2.1 hours for pramipexole dihydrochloride extended-release and -1.4 hours for placebo (p=0.0199). At 33-weeks the adjusted mean improvement from baseline UPDRS Parts II+III score was –11.1 points in patients receiving pramipexole dihydrochloride extended-release tablets (n=117) and –6.8 points in patients receiving placebo (n=136) (p=0.0135). At both 18 and 33 weeks the mean daily dose of pramipexole dihydrochloride extended-release was 2.6 mg/day. At week 18, 4 patients (3%) in the placebo group and 14 patients (11%) in the pramipexole dihydrochloride extended-release tablets group had decreased their levodopa daily dose compared to baseline due to dopaminergic adverse events. No clinically relevant difference in effectiveness was observed in the sub-group analyses based on gender, age, race (White vs. Asian), or concomitant use of antiparkinsonian treatment (MAOB-I, amantadine or anticholinergics).

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 How Supplied Pramipexole dihydrochloride extended-release tablets are available as follows: 0. 375 mg: Off white, round shaped, biconvex, uncoated tablet, debossed with ‘RDY’ on one one side and ‘611’ on other side and are supplied in bottle of 30’s count. Bottles of 30 NDC 55111-611-30 0.75 mg: Off white, round shaped, biconvex, uncoated tablet, debossed with ‘RDY’ on one one side and ‘612’ on other side and are supplied in bottle of 30’s count. Bottles of 30 NDC 55111-612-30 1.5 mg: Off white, oval shaped, biconvex, uncoated tablet, debossed with ‘RDY’ on one one side and ‘613’ on other side and are supplied in bottle of 30’s count. Bottles of 30 NDC 55111-613-30 3 mg: Off white, oval shaped, biconvex, uncoated tablet, debossed with ‘RDY’ on one one side and ‘614’ on other side and are supplied in bottle of 30’s count. Bottles of 30 NDC 55111-614-30 4.5 mg: Off white, oval shaped, biconvex, uncoated tablet, debossed with ‘RDY’ on one one side and ‘615’ on other side and are supplied in bottle of 30’s count. Bottles of 30 NDC 55111-615-30 16.2 Storage and Handling ­­Store at 20°-25°C (68°-77°F); [see USP Controlled Room Temperature]. Protect from exposure to high humidity. Store in a safe place out of the reach of children.

GERIATRIC USE

8.5 Geriatric Use Pramipexole total oral clearance is approximately 30% lower in subjects older than 65 years compared with younger subjects, because of a decline in pramipexole renal clearance due to an age-related reduction in renal function. This resulted in an increase in elimination half-life from approximately 8.5 hours to 12 hours. In a placebo-controlled clinical trial of pramipexole dihydrochloride extended-release tablets in early Parkinson’s disease, 47% of the 259 patients were ≥65 years of age. Among patients receiving pramipexole dihydrochloride extended-release tablets, hallucinations were more common in the elderly, occurring in 13% of the patients ≥ 65 years of age compared to 2% of the patients <65 years of age.

DOSAGE FORMS AND STRENGTHS

3 0. 375 mg: Off white, round shaped, biconvex, un coated tablet, debossed with ‘RDY’ on one side and ‘611’ on other side. 0.75 mg: Off white, round shaped, biconvex, un coated tablet, debossed with ‘RDY’ on one side and ‘612’ on other side. 1.5 mg: Off white, oval shaped, biconvex, un coated tablet, debossed with ‘RDY’ on one side and ‘613’ on other side. 3 mg: Off white, oval shaped, biconvex, un coated tablet, debossed with ‘RDY’ on one side and ‘614’ on other side. 4.5 mg: Off white, oval shaped, biconvex, un coated tablet, debossed with ‘RDY’ on one side and ‘615’ on other side. Extended-release tablets: 0.375 mg, 0.75 mg, 1.5 mg, 3 mg, and 4.5 mg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action Pramipexole is a non-ergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors, binding with higher affinity to D3 than to D2 or D4 receptor subtypes. The precise mechanism of action of pramipexole as a treatment for Parkinson’s disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum. This conclusion is supported by electrophysiologic studies in animals that have demonstrated that pramipexole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum. The relevance of D3 receptor binding in Parkinson’s disease is unknown.

INDICATIONS AND USAGE

1 Pramipexole dihydrochloride extended-release tablets are indicated for the treatment of Parkinson’s disease. Pramipexole dihydrochloride extended-release is a non-ergot dopamine agonist indicated for the treatment of Parkinson’s disease (PD) (1)

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness of pramipexole dihydrochloride extended-release tablets in pediatric patients have not been evaluated.

PREGNANCY

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of pramipexole dihydrochloride extended-release in pregnant women. No adverse developmental effects were observed in animal studies in which pramipexole was administered to rabbits during pregnancy. Effects on embryofetal development could not be adequately assessed in pregnant rats; however, postnatal growth was inhibited at clinically relevant exposures [see Data]. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Oral administration of pramipexole (0.1, 0.5, or 1.5 mg/kg/day) to pregnant rats during the period of organogenesis resulted in a high incidence of total resorption of embryos at the highest dose tested. This increase in embryolethality is thought to result from the prolactin-lowering effect of pramipexole; prolactin is necessary for implantation and maintenance of early pregnancy in rats but not in rabbits or humans. Because of pregnancy disruption and early embryonic loss in this study, the teratogenic potential of pramipexole could not be adequately assessed in rats. The highest no-effect dose for embryolethality in rats was associated with maternal plasma drug exposures (AUC) approximately equal to those in humans receiving the maximum recommended human dose (MRHD) of 4.5 mg/day. There were no adverse effects on embryo-fetal development following oral administration of pramipexole (0.1, 1, or 10 mg/kg/day) to pregnant rabbits during organogenesis (plasma AUC up to approximately 70 times that in humans at the MRHD). Postnatal growth was inhibited in the offspring of rats treated with pramipexole (0.1, 0.5, or 1.5 mg/kg/day) during the latter part of pregnancy and throughout lactation. The no-effect dose for adverse effects on offspring growth (0.1 mg/kg/day) was associated with maternal plasma drug esposure lower than that in humans at the MRHD.

NUSRING MOTHERS

8.2 Lactation Risk Summary There are no data on the presence of pramipexole in human milk, the effects of pramipexole on the breastfed infant, or the effects of pramipexole on milk production. However, inhibition of lactation is expected because pramipexole inhibits secretion of prolactin in humans. Pramipexole or metabolites, or both, are present in rat milk [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for pramipexole dihydrochloride extended-release and any potential adverse effects on the breastfed infant from pramipexole dihydrochloride extended-release or from the underlying maternal condition. Data In a study of radiolabeled pramipexole, pramipexole or metabolites, or both, were present in rat milk at concentrations three to six times higher than those in maternal plasma.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Falling asleep during activities of daily living: Sudden onset of sleep may occur without warning; advise patients to report symptoms. (5.1) Symptomatic orthostatic hypotension: Monitor closely especially during dose escalation (5.2) Impulse control/Compulsive behaviors: Patients may experience compulsive behaviors and other intense urges (5.3) Hallucinations and Psychotic-like Behavior: May occur. Risk increases with age (5.4) Dyskinesia: May be caused or exacerbated by pramipexole dihydrochloride extended-release (5.5) Events reported with dopaminergic therapy: Include withdrawal-emergent hyperpyrexia and confusion, fibrotic complications, and melanoma. (5.9) 5.1 Falling Asleep During Activities of Daily Living and Somnolence Patients treated with pramipexole have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on pramipexole tablets, some perceived that they had no warning signs (sleep attack) such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events had been reported as late as one year after the initiation of treatment. In placebo-controlled clinical trials in Parkinson’s disease, the sudden onset of sleep or sleep attacks were reported in 8 of 387 (2%) patients treated with pramipexole dihydrochloride extended-release tablets compared to 2 of 281 (1%) patients on placebo. In early Parkinson’s disease, somnolence was reported in 36% of 223 patients treated with pramipexole dihydrochloride extended-release, median dose 3 mg/day, compared to 15% of 103 patients on placebo. In advanced Parkinson’s disease, somnolence was reported in 15% of 164 patients treated with pramipexole dihydrochloride extended-release tablets, median dose 3 mg/day, compared to 16% of 178 patients on placebo. It has been reported that falling asleep while engaged in activities of daily living usually occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Before initiating treatment with pramipexole dihydrochloride extended-release tablets, advise patients of the potential to develop drowsiness, and specifically ask about factors that may increase the risk for somnolence such as the use of concomitant sedating medications or alcohol, the presence of sleep disorders, and concomitant medications that increase pramipexole plasma levels (e.g., cimetidine) [see Clinical Pharmacology (12.3) ]. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), pramipexole dihydrochloride extended-release tablets should ordinarily be discontinued. If a decision is made to continue pramipexole dihydrochloride extended-release tablets, advise patients not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent. While dose reduction reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. 5.2 Symptomatic Orthostatic Hypotension Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. Parkinson’s disease patients, in addition, appear to have an impaired capacity to respond to an orthostatic challenge. For these reasons, Parkinson’s disease patients being treated with dopaminergic agonists, including pramipexole dihydrochloride extended-release, ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk. In placebo-controlled clinical trials in Parkinson’s disease, symptomatic orthostatic hypotension was reported in 10 of 387 (3%) patients treated with pramipexole dihydrochloride extended-release tablets compared to 3 of 281 (1%) patients on placebo. One patient of 387 on pramipexole dihydrochloride extended-release tablets discontinued treatment due to hypotension. 5.3 Impulse Control/Compulsive Behaviors Case reports and the results of cross-sectional studies suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including pramipexole dihydrochloride extended-release, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with pramipexole dihydrochloride extended-release. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking pramipexole dihydrochloride extended-release. A total of 1056 patients with Parkinson’s disease who participated in two pramipexole dihydrochloride extended-release placebo-controlled studies of up to 33 weeks duration were specifically asked at each visit about the occurrence of these symptoms. A total of 14 of 387 (4%) treated with pramipexole dihydrochloride extended-release tablets, 12 of 388 (3%) treated with immediate-release pramipexole tablets, and 4 of 281 (1%) treated with placebo reported compulsive behaviors, including pathological gambling, hypersexuality, and/or compulsive buying. 5.4 Hallucinations and Psychotic-like Behavior In placebo-controlled clinical trials in Parkinson’s disease, hallucinations (visual or auditory or mixed) were reported in 25 of 387 (6%) patients treated with pramipexole dihydrochloride extended-release tablets compared to 5 of 281 (2%) patients receiving placebo. Hallucinations led to discontinuation of treatment in 5 of 387 (1%) patients on pramipexole dihydrochloride extended-release tablets. Age appears to increase the risk of hallucinations attributable to pramipexole. In placebo-controlled clinical trials in Parkinson’s disease, hallucinations were reported in 15 of 162 (9%)patients ≥ 65 years of age taking pramipexole dihydrochloride extended-release tablets compared to 10 of 225 (4%)patients <65 years of age taking pramipexole dihydrochloride extended-release tablets. Postmarketing reports with dopamine agonists, including pramipexole dihydrochloride extended-release, indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with pramipexole dihydrochloride extended-release or after starting or increasing the dose of pramipexole dihydrochloride extended-release. Other drugs prescribed to improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. Patients with a major psychotic disorder should ordinarily not be treated with dopamine agonists, including pramipexole dihydrochloride extended-release, because of the risk of exacerbating the psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of pramipexole dihydrochloride extended-release [see Drug Interactions ( 7.1 )]. 5.5 Dyskinesia Pramipexole dihydrochloride extended-release tablets may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia. 5.6 Renal Impairment The elimination of pramipexole is dependent on renal function [see Clinical Pharmacology (12.3) ]. Patients with mild renal impairment (a creatinine clearance above 50 mL/min) require no reduction in daily dose. Pramipexole dihydrochloride extended-release tablets have not been studied in patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) or on hemodialysis [see Dosage and Administration (2.2) , Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ]. 5.7 Rhabdomyolysis In the clinical development program for immediate-release pramipexole tablets, a single case of rhabdomyolysis occurred in a 49 year old male with advanced Parkinson's disease. The patient was hospitalized with an elevated CPK (10,631 IU/L). The symptoms resolved with discontinuation of the medication. Advise patients to contact a physician if they experience any unexplained muscle pain, tenderness, or weakness, as these may be symptoms of rhabdomyolysis. 5.8 Retinal Pathology Human Data A two-year open-label, randomized, parallel-group safety study of retinal deterioration and vision compared immediate-release pramipexole tablets and immediate-release ropinirole. Two hundred thirty four Parkinson’s disease patients (115 on pramipexole, mean dose 3 mg/day and 119 on ropinirole, mean dose 9.5 mg/day) were evaluated using a panel of clinical ophthalmological assessments. Of 234 patients who were evaluable, 196 had been treated for two years and 29 were judged to have developed clinical abnormalities that were considered meaningful (19 patients in each treatment arm had received treatment for less than two years). There was no statistical difference in retinal deterioration between the treatment arms; however, the study was only capable of detecting a very large difference between treatments. In addition, because the study did not include an untreated comparison group (placebo treated), it is unknown whether the findings reported in patients treated with either drug are greater than the background rate in an aging population. Animal Data Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in a 2 year carcinogenicity study. While retinal degeneration was not diagnosed in pigmented rats treated for 2 years, a thinning in the outer nuclear layer of the retina was slightly greater in rats given drug compared with controls. Evaluation of the retinas of albino mice, monkeys, and minipigs did not reveal similar changes. The potential significance of this effect for humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved [see Nonclinical Toxicology (13.2) ]. 5.9 Events Reported with Dopaminergic Therapy Although the events enumerated below may not have been reported with the use of pramipexole in its development program, they are associated with the use of other dopaminergic drugs. The expected incidence of these events, however, is so low that even if pramipexole caused these events at rates similar to those attributable to other dopaminergic therapies, it would be unlikely that even a single case would have occurred in a cohort of the size exposed to pramipexole in studies to date. Hyperpyrexia and Confusion Although not reported with pramipexole in the clinical development program, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy. If possible, avoid sudden discontinuation or rapid dose reduction in patients taking pramipexole dihydrochloride extended-release tablets. If the decision is made to discontinue pramipexole dihydrochloride extended-release tablets, the dose should be tapered to reduce the risk of hyperpyrexia and confusion [see Dosage and Administration ( 2.2 )]. Fibrotic Complications Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, non-ergot derived dopamine agonists can cause them is unknown. Cases of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis have been reported in the postmarketing experience with immediate-release pramipexole tablets. While the evidence is not sufficient to establish a causal relationship between pramipexole and these fibrotic complications, a contribution of pramipexole cannot be completely ruled out. Melanoma Epidemiologic studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the observed increased risk was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear. For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using pramipexole dihydrochloride extended-release tablets for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Dosing Instructions Instruct patients to take pramipexole dihydrochloride extended-release tablets only as prescribed. If a dose is missed, pramipexole dihydrochloride extended-release tablets should be taken as soon as possible, but no later than 12 hours after the regularly scheduled time. After 12 hours, the missed dose should be skipped and the next dose should be taken on the following day at the regularly scheduled time. Pramipexole dihydrochloride extended-release tablets can be taken with or without food. If patients develop nausea, advise that taking pramipexole dihydrochloride extended-release tablets with food may reduce the occurrence of nausea. Inform patients that residue in stool which may resemble a swollen original pramipexole dihydrochloride extended-release tablet or swollen pieces of the original tablet have been reported [see Adverse Reactions (6.2)]. Instruct patients to contact their physician if this occurs. Pramipexole dihydrochloride extended-release tablets should be swallowed whole. They should not be chewed, crushed, or divided [see Dosage and Administration ( 2.1 )]. Pramipexole is the active ingredient that is in both pramipexole dihydrochloride extended-release tablets and immediate-release pramipexole tablets. Ensure that patients do not take both immediate-release pramipexole and extended-release pramipexole. Sedating Effects Alert patients to the potential sedating effects of pramipexole dihydrochloride extended-release tablets, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse reaction with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with pramipexole dihydrochloride extended-release tablets to gauge whether or not it affects their mental and/or motor performance adversely. Advise patients that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., conversations or eating) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Because of possible additive effects, advise caution when patients are taking other sedating medications or alcohol in combination with pramipexole dihydrochloride extended-release and when taking concomitant medications that increase plasma levels of pramipexole (e.g., cimetidine) [see Warnings and Precautions ( 5.1 )]. Impulse Control Symptoms Including Compulsive Behaviors Alert patients and their caregivers to the possibility that they may experience intense urges to spend money, intense urges to gamble, increased sexual urges, binge eating and/or other intense urges and the inability to control these urges while taking pramipexole dihydrochloride extended-release tablets. [See Warnings and Precautions ( 5.3 )]. Hallucinations and Psychotic-like Behavior Inform patients that hallucinations and other psychotic-like behavior can occur and that the elderly are at a higher risk than younger patients with Parkinson’s disease [see Warnings and Precautions ( 5.4 )]. Postural (Orthostatic) Hypotension Advise patients that they may develop postural (orthostatic) hypotension, with or without symptoms such as dizziness, nausea, fainting, or blackouts, and sometimes, sweating. Hypotension may occur more frequently during initial therapy. Accordingly, caution patients against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with pramipexole dihydrochloride extended-release [see Warnings and Precautions ( 5.2 )]. Pregnancy Because the teratogenic potential of pramipexole has not been completely established in laboratory animals, and because experience in humans is limited, advise women to notify their physicians if they become pregnant or intend to become pregnant during therapy [see Use in Specific Populations ( 8.1 )]. Lactation Because of the possibility that pramipexole may be excreted in breast milk, advise women to notify their physicians if they intend to breast-feed or are breast-feeding an infant [see Use in Specific Populations ( 8.2 )].

DOSAGE AND ADMINISTRATION

2 Pramipexole dihydrochloride extended-release tablets are taken once daily, with or without food (2.1) Tablets must be swallowed whole and must not be chewed, crushed, or divided (2.1) Starting dose is 0.375 mg given once daily (2.2) Dose may be increased gradually, not more frequently than every 5 to 7 days, first to 0.75 mg per day and then by 0.75 mg increments up to a maximum recommended dose of 4.5 mg per day. Assess therapeutic response and tolerability at a minimal interval of 5 days or longer after each dose increment. (2.2) Patients may be switched overnight from immediate-release pramipexole tablets to extended-release pramipexole tablets at the same daily dose. Dose adjustment may be needed in some patients (2.3) Pramipexole dihydrochloride extended-release tablets should be discontinued gradually. (2.2) 2.1 General Dosing Considerations Pramipexole dihydrochloride extended-release tablets are taken orally once daily, with or without food. Pramipexole dihydrochloride extended-release tablets must be swallowed whole and must not be chewed, crushed, or divided. If a significant interruption in therapy with pramipexole dihydrochloride extended-release tablets has occurred, re-titration of therapy may be warranted. 2.2 Dosing for Parkinson’s Disease The starting dose is 0.375 mg given once per day. Based on efficacy and tolerability, dosages may be increased gradually, not more frequently than every 5 to 7 days, first to 0.75 mg per day and then by 0.75 mg increments up to a maximum recommended dose of 4.5 mg per day. In clinical trials, dosage was initiated at 0.375 mg/day and gradually titrated based on individual therapeutic response and tolerability. Doses greater than 4.5 mg/day have not been studied in clinical trials. Patients should be assessed for therapeutic response and tolerability at a minimal interval of 5 days or longer after each dose increment [see Clinical Studies ( 14) ]. Due to the flexible dose design used in clinical trials, specific dose-response information could not be determined [see Clinical Studies (14) ]. Pramipexole dihydrochloride extended-release tablets may be tapered off at a rate of 0.75 mg per day until the daily dose has been reduced to 0.75 mg. Thereafter, the dose may be reduced by 0.375 mg per day [see Warnings and Precautions (5.9)]. Dosing in Patients with Renal Impairment: In patients with moderate renal impairment (creatinine clearance between 30 and 50 mL/min), pramipexole dihydrochloride extended-release tablets should initially be taken every other day. Caution should be exercised and careful assessment of therapeutic response and tolerability should be made before increasing to daily dosing after one week, and before any additional titration in 0.375 mg increments up to 2.25 mg per day. Dose adjustment should occur no more frequently than at weekly intervals. Pramipexole dihydrochloride extended-release tablets have not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min) or patients on hemodialysis, and are not recommended in these patients. 2.3 Switching from Immediate-Release Pramipexole Tablets to Extended-Release Pramipexole Tablets Patients may be switched overnight from immediate-release pramipexole tablets to extended-release pramipexole tablets at the same daily dose. When switching between immediate-release pramipexole tablets and extended-release pramipexole tablets, patients should be monitored to determine if dosage adjustment is necessary.

sildenafil 25 MG (as sildenafil citrate) Oral Tablet

Generic Name: SILDENAFIL CITRATE
Brand Name: Viagra
  • Substance Name(s):
  • SILDENAFIL CITRATE

DRUG INTERACTIONS

7 VIAGRA can potentiate the hypotensive effects of nitrates, alpha blockers, and anti-hypertensives (4.1, 5.5, 7.1, 7.2, 7.3, 12.2) With concomitant use of alpha blockers, initiate VIAGRA at 25 mg dose (2.3) CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, erythromycin): Increase VIAGRA exposure (2.4, 7.4, 12.3) Ritonavir: Do not exceed a maximum single dose of 25 mg in a 48 hour period (2.4, 5.6) Erythromycin or strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, saquinavir): Consider a starting dose of 25 mg (2.4, 7.4) 7.1 Nitrates Administration of VIAGRA with nitric oxide donors such as organic nitrates or organic nitrites in any form is contraindicated. Consistent with its known effects on the nitric oxide/cGMP pathway, VIAGRA was shown to potentiate the hypotensive effects of nitrates [see Dosage and Administration (2.3), Contraindications (4.1), Clinical Pharmacology (12.2) ]. 7.2 Alpha-blockers Use caution when co-administering alpha-blockers with VIAGRA because of potential additive blood pressure-lowering effects. When VIAGRA is co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating VIAGRA treatment and VIAGRA should be initiated at the lowest dose [see Dosage and Administration (2.3),Warnings and Precautions (5.5), Clinical Pharmacology (12.2) ]. 7.3 Amlodipine When VIAGRA 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic [see Warnings and Precautions (5.5), Clinical Pharmacology (12.2) ]. 7.4 Ritonavir and other CYP3A4 inhibitors Co-administration of ritonavir, a strong CYP3A4 inhibitor, greatly increased the systemic exposure of sildenafil (11-fold increase in AUC). It is therefore recommended not to exceed a maximum single dose of 25 mg of VIAGRA in a 48 hour period [see Dosage and Administration (2.4), Warnings and Precautions (5.6), Clinical Pharmacology (12.3) ]. Co-administration of erythromycin, a moderate CYP3A4 inhibitor, resulted in a 160% and 182% increases in sildenafil Cmax and AUC, respectively. Co-administration of saquinavir, a strong CYP3A4 inhibitor, resulted in 140% and 210% increases in sildenafil Cmax and AUC, respectively. Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole could be expected to have greater effects than seen with saquinavir. A starting dose of 25 mg of VIAGRA should be considered in patients taking erythromycin or strong CYP3A4 inhibitors (such as saquinavir, ketoconazole, itraconazole) [see Dosage and Administration (2.4), Clinical Pharmacology (12.3) ]. 7.5 Alcohol In a drug-drug interaction study sildenafil 50 mg given with alcohol 0.5 g/kg in which mean maximum blood alcohol levels of 0.08% was achieved, sildenafil did not potentiate the hypotensive effect of alcohol in healthy volunteers [see Clinical Pharmacology (12.2) ].

OVERDOSAGE

10 In studies with healthy volunteers of single doses up to 800 mg, adverse reactions were similar to those seen at lower doses but incidence rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.

DESCRIPTION

11 VIAGRA (sildenafil citrate), an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate and has the following structural formula: Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. VIAGRA is formulated as blue, film-coated rounded-diamond-shaped tablets equivalent to 25 mg, 50 mg and 100 mg of sildenafil for oral administration. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, lactose, triacetin, and FD & C Blue #2 aluminum lake. Chemical Structure

CLINICAL STUDIES

14 In clinical studies, VIAGRA was assessed for its effect on the ability of men with erectile dysfunction (ED) to engage in sexual activity and in many cases specifically on the ability to achieve and maintain an erection sufficient for satisfactory sexual activity. VIAGRA was evaluated primarily at doses of 25 mg, 50 mg and 100 mg in 21 randomized, double-blind, placebo-controlled trials of up to 6 months in duration, using a variety of study designs (fixed dose, titration, parallel, crossover). VIAGRA was administered to more than 3,000 patients aged 19 to 87 years, with ED of various etiologies (organic, psychogenic, mixed) with a mean duration of 5 years. VIAGRA demonstrated statistically significant improvement compared to placebo in all 21 studies. The studies that established benefit demonstrated improvements in success rates for sexual intercourse compared with placebo. Efficacy Endpoints in Controlled Clinical Studies The effectiveness of VIAGRA was evaluated in most studies using several assessment instruments. The primary measure in the principal studies was a sexual function questionnaire (the International Index of Erectile Function – IIEF) administered during a 4-week treatment-free run-in period, at baseline, at follow-up visits, and at the end of double-blind, placebo-controlled, at-home treatment. Two of the questions from the IIEF served as primary study endpoints; categorical responses were elicited to questions about (1) the ability to achieve erections sufficient for sexual intercourse and (2) the maintenance of erections after penetration. The patient addressed both questions at the final visit for the last 4 weeks of the study. The possible categorical responses to these questions were (0) no attempted intercourse, (1) never or almost never, (2) a few times, (3) sometimes, (4) most times, and (5) almost always or always. Also collected as part of the IIEF was information about other aspects of sexual function, including information on erectile function, orgasm, desire, satisfaction with intercourse, and overall sexual satisfaction. Sexual function data were also recorded by patients in a daily diary. In addition, patients were asked a global efficacy question and an optional partner questionnaire was administered. Efficacy Results from Controlled Clinical Studies The effect on one of the major end points, maintenance of erections after penetration, is shown in Figure 6, for the pooled results of 5 fixed-dose, dose-response studies of greater than one month duration, showing response according to baseline function. Results with all doses have been pooled, but scores showed greater improvement at the 50 and 100 mg doses than at 25 mg. The pattern of responses was similar for the other principal question, the ability to achieve an erection sufficient for intercourse. The titration studies, in which most patients received 100 mg, showed similar results. Figure 6 shows that regardless of the baseline levels of function, subsequent function in patients treated with VIAGRA was better than that seen in patients treated with placebo. At the same time, on-treatment function was better in treated patients who were less impaired at baseline. Figure 6. Effect of VIAGRA and Placebo on Maintenance of Erection by Baseline Score. The frequency of patients reporting improvement of erections in response to a global question in four of the randomized, double-blind, parallel, placebo-controlled fixed dose studies (1797 patients) of 12 to 24 weeks duration is shown in Figure 7. These patients had erectile dysfunction at baseline that was characterized by median categorical scores of 2 (a few times) on principal IIEF questions. Erectile dysfunction was attributed to organic (58%; generally not characterized, but including diabetes and excluding spinal cord injury), psychogenic (17%), or mixed (24%) etiologies. Sixty-three percent, 74%, and 82% of the patients on 25 mg, 50 mg and 100 mg of VIAGRA, respectively, reported an improvement in their erections, compared to 24% on placebo. In the titration studies (n=644) (with most patients eventually receiving 100 mg), results were similar. Overall treatment p<0.0001 Figure 7. Percentage of Patients Reporting an Improvement in Erections. The patients in studies had varying degrees of ED. One-third to one-half of the subjects in these studies reported successful intercourse at least once during a 4-week, treatment-free run-in period. In many of the studies, of both fixed dose and titration designs, daily diaries were kept by patients. In these studies, involving about 1600 patients, analyses of patient diaries showed no effect of VIAGRA on rates of attempted intercourse (about 2 per week), but there was clear treatment-related improvement in sexual function: per patient weekly success rates averaged 1.3 on 50–100 mg of VIAGRA vs 0.4 on placebo; similarly, group mean success rates (total successes divided by total attempts) were about 66% on VIAGRA vs about 20% on placebo. During 3 to 6 months of double-blind treatment or longer-term (1 year), open-label studies, few patients withdrew from active treatment for any reason, including lack of effectiveness. At the end of the long-term study, 88% of patients reported that VIAGRA improved their erections. Men with untreated ED had relatively low baseline scores for all aspects of sexual function measured (again using a 5-point scale) in the IIEF. VIAGRA improved these aspects of sexual function: frequency, firmness and maintenance of erections; frequency of orgasm; frequency and level of desire; frequency, satisfaction and enjoyment of intercourse; and overall relationship satisfaction. One randomized, double-blind, flexible-dose, placebo-controlled study included only patients with erectile dysfunction attributed to complications of diabetes mellitus (n=268). As in the other titration studies, patients were started on 50 mg and allowed to adjust the dose up to 100 mg or down to 25 mg of VIAGRA; all patients, however, were receiving 50 mg or 100 mg at the end of the study. There were highly statistically significant improvements on the two principal IIEF questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) on VIAGRA compared to placebo. On a global improvement question, 57% of VIAGRA patients reported improved erections versus 10% on placebo. Diary data indicated that on VIAGRA, 48% of intercourse attempts were successful versus 12% on placebo. One randomized, double-blind, placebo-controlled, crossover, flexible-dose (up to 100 mg) study of patients with erectile dysfunction resulting from spinal cord injury (n=178) was conducted. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of VIAGRA. On a global improvement question, 83% of patients reported improved erections on VIAGRA versus 12% on placebo. Diary data indicated that on VIAGRA, 59% of attempts at sexual intercourse were successful compared to 13% on placebo. Across all trials, VIAGRA improved the erections of 43% of radical prostatectomy patients compared to 15% on placebo. Subgroup analyses of responses to a global improvement question in patients with psychogenic etiology in two fixed-dose studies (total n=179) and two titration studies (total n=149) showed 84% of VIAGRA patients reported improvement in erections compared with 26% of placebo. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of VIAGRA. Diary data in two of the studies (n=178) showed rates of successful intercourse per attempt of 70% for VIAGRA and 29% for placebo. Figure 6 Figure 6 Figure 7 Efficacy Results in Subpopulations in Controlled Clinical Studies A review of population subgroups demonstrated efficacy regardless of baseline severity, etiology, race and age. VIAGRA was effective in a broad range of ED patients, including those with a history of coronary artery disease, hypertension, other cardiac disease, peripheral vascular disease, diabetes mellitus, depression, coronary artery bypass graft (CABG), radical prostatectomy, transurethral resection of the prostate (TURP) and spinal cord injury, and in patients taking antidepressants/antipsychotics and anti-hypertensives/diuretics.

HOW SUPPLIED

16 /STORAGE AND HANDLING VIAGRA (sildenafil citrate) is supplied as blue, film-coated, rounded-diamond-shaped tablets containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil and debossed on the obverse and reverse sides as follows: 25 mg 50 mg 100 mg Obverse VGR25 VGR50 VGR100 Reverse PFIZER PFIZER PFIZER Bottle of 30 NDC-0069-4200-30 NDC-0069-4210-30 NDC-0069-4220-30 Bottle of 100 N/A NDC-0069-4210-66 NDC-0069-4220-66 Carton of 30 (1 tablet per Single Pack ) N/A NDC 0069-4210-33 NDC 0069-4220-33 Recommended Storage: Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].

RECENT MAJOR CHANGES

Contraindications, Concomitant Guanylate Cyclase (GC) Stimulators (4.3)

GERIATRIC USE

8.5 Geriatric Use Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy young volunteers (18–45 years) [see Clinical Pharmacology (12.3) ]. Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively [see Clinical Pharmacology (12.3) ]. Of the total number of subjects in clinical studies of Viagra, 18% were 65 years and older, while 2% were 75 years and older. No overall differences in safety or efficacy were observed between older (≥ 65 years of age) and younger (< 65 years of age) subjects. However, since higher plasma levels may increase the incidence of adverse reactions, a starting dose of 25 mg should be considered in older subjects due to the higher systemic exposure [see Dosage and Administration (2.5) ].

DOSAGE FORMS AND STRENGTHS

3 VIAGRA is supplied as blue, film-coated, rounded-diamond-shaped tablets containing sildenafil citrate equivalent to 25 mg, 50 mg, or 100 mg of sildenafil. Tablets are debossed with PFIZER on one side and VGR25, VGR50 or VGR100 on the other to indicate the dosage strengths. Tablets: 25 mg, 50 mg, 100 mg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation. Binding Characteristics Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). Sildenafil is approximately 4,000-fold more selective for PDE5 compared to PDE3. PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision [see Clinical Pharmacology (12.2) ]. In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle. The inhibition of PDE5 in some of these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of NO observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo.

INDICATIONS AND USAGE

1 VIAGRA is indicated for the treatment of erectile dysfunction. VIAGRA is a phosphodiesterase-5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction (ED) (1)

PEDIATRIC USE

8.4 Pediatric Use VIAGRA is not indicated for use in pediatric patients. Safety and effectiveness have not been established in pediatric patients.

PREGNANCY

8.1 Pregnancy Pregnancy Category B. VIAGRA is not indicated for use in women. There are no adequate and well-controlled studies of sildenafil in pregnant women. Risk Summary Based on animal data, VIAGRA is not predicted to increase the risk of adverse developmental outcomes in humans. Animal Data No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received up to 200 mg/kg/day during organogenesis. These doses represent, respectively, about 20 and 40 times the Maximum Recommended Human Dose (MRHD) on a mg/m2 basis in a 50 kg subject. In the rat pre- and postnatal development study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days. In the nonpregnant rat the AUC at this dose was about 20 times human AUC.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Patients should not use VIAGRA if sexual activity is inadvisable due to cardiovascular status (5.1) Patients should seek emergency treatment if an erection lasts >4 hours. Use VIAGRA with caution in patients predisposed to priapism (5.2) Patients should stop VIAGRA and seek medical care if a sudden loss of vision occurs in one or both eyes, which could be a sign of non arteritic anterior ischemic optic neuropathy (NAION). VIAGRA should be used with caution, and only when the anticipated benefits outweigh the risks, in patients with a history of NAION. Patients with a “crowded” optic disc may also be at an increased risk of NAION. (5.3) Patients should stop VIAGRA and seek prompt medical attention in the event of sudden decrease or loss of hearing (5.4) Caution is advised when VIAGRA is co-administered with alpha-blockers or anti-hypertensives. Concomitant use may lead to hypotension (5.5) Decreased blood pressure, syncope, and prolonged erection may occur at higher sildenafil exposures. In patients taking strong CYP inhibitors, such as ritonavir, sildenafil exposure is increased. Decrease in VIAGRA dosage is recommended (2.4, 5.6) 5.1 Cardiovascular There is a potential for cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Therefore, treatments for erectile dysfunction, including VIAGRA, should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status. The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following a complete medical assessment. VIAGRA has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 8.4/5.5 mmHg), [see Clinical Pharmacology (12.2) ]. While this normally would be expected to be of little consequence in most patients, prior to prescribing VIAGRA, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity. Use with caution in patients with the following underlying conditions which can be particularly sensitive to the actions of vasodilators including VIAGRA – those with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure. There are no controlled clinical data on the safety or efficacy of VIAGRA in the following groups; if prescribed, this should be done with caution. Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months; Patients with resting hypotension (BP 170/110 mmHg); Patients with cardiac failure or coronary artery disease causing unstable angina. 5.2 Prolonged Erection and Priapism Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of VIAGRA. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result. VIAGRA should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia). However, there are no controlled clinical data on the safety or efficacy of VIAGRA in patients with sickle cell or related anemias. 5.3 Effects on the Eye Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including VIAGRA, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision including permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors. Based on published literature, the annual incidence of NAION is 2.5–11.8 cases per 100,000 in males aged ≥ 50. An observational study evaluated whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of NAION. The results suggest an approximate 2 fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. From this information, it is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions (6.2) ]. Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including VIAGRA, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with “crowded” optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including VIAGRA, for this uncommon condition. There are no controlled clinical data on the safety or efficacy of VIAGRA in patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases); if prescribed, this should be done with caution. 5.4 Hearing Loss Physicians should advise patients to stop taking PDE5 inhibitors, including VIAGRA, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including VIAGRA. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions (6.1, 6.2) ]. 5.5 Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives Alpha-blockers Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including VIAGRA, and alpha-adrenergic blocking agents are both vasodilators with blood pressure lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may occur. In some patients, concomitant use of these two drug classes can lower blood pressure significantly [see Drug Interactions (7.2) and Clinical Pharmacology (12.2) ] leading to symptomatic hypotension (e.g., dizziness, lightheadedness, fainting). Consideration should be given to the following: Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors. Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor. In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose [see Dosage and Administration (2.3) ]. In those patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor. Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs. Anti-hypertensives VIAGRA has systemic vasodilatory properties and may further lower blood pressure in patients taking anti-hypertensive medications. In a separate drug interaction study, when amlodipine, 5 mg or 10 mg, and VIAGRA, 100 mg were orally administered concomitantly to hypertensive patients mean additional blood pressure reduction of 8 mmHg systolic and 7 mmHg diastolic were noted [see Drug Interactions (7.3) and Clinical Pharmacology (12.2) ]. 5.6 Adverse Reactions with the Concomitant Use of Ritonavir The concomitant administration of the protease inhibitor ritonavir substantially increases serum concentrations of sildenafil (11-fold increase in AUC). If VIAGRA is prescribed to patients taking ritonavir, caution should be used. Data from subjects exposed to high systemic levels of sildenafil are limited. Decreased blood pressure, syncope, and prolonged erection were reported in some healthy volunteers exposed to high doses of sildenafil (200–800 mg). To decrease the chance of adverse reactions in patients taking ritonavir, a decrease in sildenafil dosage is recommended [see Dosage and Administration (2.4), Drug Interactions (7.4), and Clinical Pharmacology (12.3) ]. 5.7 Combination with other PDE5 Inhibitors or Other Erectile Dysfunction Therapies The safety and efficacy of combinations of VIAGRA with other PDE5 Inhibitors, including REVATIO or other pulmonary arterial hypertension (PAH) treatments containing sildenafil, or other treatments for erectile dysfunction have not been studied. Such combinations may further lower blood pressure. Therefore, the use of such combinations is not recommended. 5.8 Effects on Bleeding There have been postmarketing reports of bleeding events in patients who have taken VIAGRA. A causal relationship between VIAGRA and these events has not been established. In humans, VIAGRA has no effect on bleeding time when taken alone or with aspirin. However, in vitro studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor). In addition, the combination of heparin and VIAGRA had an additive effect on bleeding time in the anesthetized rabbit, but this interaction has not been studied in humans. The safety of VIAGRA is unknown in patients with bleeding disorders and patients with active peptic ulceration. 5.9 Counseling Patients About Sexually Transmitted Diseases The use of VIAGRA offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), may be considered.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) Nitrates Physicians should discuss with patients the contraindication of VIAGRA with regular and/or intermittent use of nitric oxide donors, such as organic nitrates or organic nitrites in any form [see Contraindications (4.1) ]. Guanylate Cyclase (GC) Stimulators Physicians should discuss with patients the contraindication of VIAGRA with use of guanylate cyclase stimulators such as riociguat [see Contraindications (4.3) ]. Concomitant Use with Drugs Which Lower Blood Pressure Physicians should advise patients of the potential for VIAGRA to augment the blood pressure lowering effect of alpha-blockers and anti-hypertensive medications. Concomitant administration of VIAGRA and an alpha-blocker may lead to symptomatic hypotension in some patients. Therefore, when VIAGRA is co-administered with alpha-blockers, patients should be stable on alpha-blocker therapy prior to initiating VIAGRA treatment and VIAGRA should be initiated at the lowest dose [see Warnings and Precautions (5.5) ]. Cardiovascular Considerations Physicians should discuss with patients the potential cardiac risk of sexual activity in patients with preexisting cardiovascular risk factors. Patients who experience symptoms (e.g., angina pectoris, dizziness, nausea) upon initiation of sexual activity should be advised to refrain from further activity and should discuss the episode with their physician [see Warnings and Precautions (5.1) ]. Sudden Loss of Vision Physicians should advise patients to stop use of all PDE5 inhibitors, including VIAGRA, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including possible permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians should discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye. Physicians should also discuss with patients the increased risk of NAION among the general population in patients with a “crowded” optic disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitor, including VIAGRA, for this uncommon condition [see Warnings and Precautions (5.3) and Adverse Reactions (6.2) ]. Sudden Hearing Loss Physicians should advise patients to stop taking PDE5 inhibitors, including VIAGRA, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including VIAGRA. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Warnings and Precautions (5.4) and Adverse Reactions (6.2) ]. Priapism Physicians should warn patients that prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of VIAGRA. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result [see Warnings and Precautions (5.2) ]. Avoid Use with other PDE5 Inhibitors Physicians should inform patients not to take VIAGRA with other PDE5 inhibitors including REVATIO or other pulmonary arterial hypertension (PAH) treatments containing sildenafil. Sildenafil is also marketed as REVATIO for the treatment of PAH. The safety and efficacy of VIAGRA with other PDE5 inhibitors, including REVATIO, have not been studied [see Warnings and Precautions (5.7) ]. Sexually Transmitted Disease The use of VIAGRA offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), may be considered [see Warnings and Precautions (5.9) ].

DOSAGE AND ADMINISTRATION

2 For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. However, VIAGRA may be taken anywhere from 30 minutes to 4 hours before sexual activity (2.1) Based on effectiveness and toleration, may increase to a maximum of 100 mg or decrease to 25 mg (2.1) Maximum recommended dosing frequency is once per day (2.1) 2.1 Dosage Information For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. However, VIAGRA may be taken anywhere from 30 minutes to 4 hours before sexual activity. The maximum recommended dosing frequency is once per day. Based on effectiveness and toleration, the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. 2.2 Use with Food VIAGRA may be taken with or without food. 2.3 Dosage Adjustments in Specific Situations VIAGRA was shown to potentiate the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors such as organic nitrates or organic nitrites in any form is therefore contraindicated [see Contraindications (4.1), Drug Interactions (7.1), and Clinical Pharmacology (12.2) ]. When VIAGRA is co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating VIAGRA treatment and VIAGRA should be initiated at 25 mg [see Warnings and Precautions (5.5), Drug Interactions (7.2), and Clinical Pharmacology (12.2) ]. 2.4 Dosage Adjustments Due to Drug Interactions Ritonavir The recommended dose for ritonavir-treated patients is 25 mg prior to sexual activity and the recommended maximum dose is 25 mg within a 48 hour period because concomitant administration increased the blood levels of sildenafil by 11-fold [see Warnings and Precautions (5.6), Drug Interactions (7.4), and Clinical Pharmacology (12.3) ]. CYP3A4 Inhibitors Consider a starting dose of 25 mg in patients treated with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, or saquinavir) or erythromycin. Clinical data have shown that co-administration with saquinavir or erythromycin increased plasma levels of sildenafil by about 3 fold [see Drug Interactions (7.4) and Clinical Pharmacology (12.3) ]. 2.5 Dosage Adjustments in Special Populations Consider a starting dose of 25 mg in patients > 65 years, patients with hepatic impairment (e.g., cirrhosis), and patients with severe renal impairment (creatinine clearance <30 mL/minute) because administration of VIAGRA in these patients resulted in higher plasma levels of sildenafil [see Use in Specific Populations (8.5, 8.6, 8.7) and Clinical Pharmacology (12.3) ].