InnoPran XL

1 INDICATIONS AND USAGE INNOPRAN XL 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 beta-blockers. 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 mm Hg 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. 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. INNOPRAN XL is a beta-adrenergic blocker 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. ( 1 )

2 DOSAGE AND ADMINISTRATION INNOPRAN XL should be administered once daily at bedtime and should be taken consistently either on an empty stomach or with food. Initiate dosing at 80 mg and titrate to 120 mg daily as needed for blood pressure control. Doses above 120 mg have no additional effects on blood pressure [see Clinical Studies ( 14.1 )] . Full antihypertensive response is usually achieved within 2 to 3 weeks. • Administer once daily at bedtime consistently either on an empty stomach or with food. ( 2 ) • Initiate dosage at 80 mg and titrate up to 120 mg if needed. ( 2 )

4 CONTRAINDICATIONS INNOPRAN XL is contraindicated in patients with: • Cardiogenic shock or decompensated heart failure • Sinus bradycardia, sick sinus syndrome, and greater than first-degree block unless a permanent pacemaker is in place • Bronchial asthma • Known hypersensitivity (e.g., anaphylactic reaction) to propranolol hydrochloride or any of the components of INNOPRAN XL • Cardiogenic shock and decompensated heart failure. ( 4 ) • Sinus bradycardia, sick sinus syndrome, and greater than first-degree block unless a permanent pacemaker is in place. ( 4 ) • Bronchial asthma. ( 4 ) • Hypersensitivity to propranolol or any of the components of INNOPRAN XL. ( 4 )

5 WARNINGS AND PRECAUTIONS • Abrupt cessation may exacerbate myocardial ischemia. ( 5.1 ) • May worsen congestive heart failure. ( 5.2 ) • Avoid discontinuing therapy prior to major surgery. ( 5.3 ) • Diabetes: May mask symptoms of hypoglycemia, and alter glucose levels; monitor. ( 5.4 ) • Bradycardia. ( 5.6 ) 5.1 Cardiac Ischemia after Abrupt Discontinuation Following abrupt discontinuation of therapy with beta-blockers, exacerbations of angina pectoris and myocardial infarction have occurred. When discontinuing chronically administered INNOPRAN XL, particularly in patients with ischemic heart disease, gradually reduce the dose over a period of 1-2 weeks and monitor the patients. If angina markedly worsens or acute coronary insufficiency develops, promptly resume therapy, at least temporarily and take other measures appropriate for the management of unstable angina. Warn patients against interruption or discontinuation of therapy without physician’s advice. Because coronary artery disease is common and may be unrecognized, avoid abrupt discontinuation of INNOPRAN XL therapy even in patients treated only for hypertension. 5.2 Cardiac Failure Beta-blockers, like INNOPRAN XL, can cause depression of myocardial contractility and may precipitate heart failure and cardiogenic shock. If signs or symptoms of heart failure develop, treat the patient according to recommended guidelines. It may be necessary to lower the dose of INNOPRAN XL or to discontinue it. 5.3 Maintain During Major Surgery Chronically administered beta-blocking therapy, including INNOPRAN XL, should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. 5.4 Hypoglycemia Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment. 5.5 Thyrotoxicosis INNOPRAN XL may mask clinical signs of hyperthyroidism, such as tachycardia. Avoid abrupt withdrawal of beta-blockade, which may precipitate a thyroid storm. 5.6 Bradycardia Bradycardia, including sinus pause, heart block, and cardiac arrest have occurred with the use of INNOPRAN XL. Patients with first-degree atrioventricular block, sinus node dysfunction, or conduction disorders (including Wolff-Parkinson-White) may be at increased risk. The concomitant use of beta-adrenergic blockers and non-dihydropyridine calcium channel blockers (e.g., verapamil and diltiazem), digoxin or clonidine increases the risk of significant bradycardia. Monitor heart rate and rhythm in patients receiving INNOPRAN XL. If severe bradycardia develops, reduce or stop INNOPRAN XL. 5.7 Reduced Effectiveness of Epinephrine in Treating Anaphylaxis Beta adrenergic blocker-treated patients treated with epinephrine for a severe anaphylactic reaction may be less responsive to the typical doses of epinephrine. In these patients, consider other medications (e.g., intravenous fluids, glucagon).

7 DRUG INTERACTIONS • CYP2D6, 1A2, or 2C19 enzyme inhibitors increase propranolol levels. ( 7.1 ) • CYP1A2 and 2C19 inducers decrease propranolol levels. ( 7.1 ) • Monitor prothrombin time when propranolol is co-administered with warfarin. ( 7.1 ) 7.1 Pharmacokinetic Drug-Drug Interactions Impact of Propranolol on Other Drugs Warfarin: Warfarin concentrations are increased when administered with propranolol. Monitor prothrombin time accordingly [see Clinical Pharmacology ( 12.7 )] . Propafenone: Co-administration of propranolol increases the plasma concentrations of propafenone. Monitor patients for symptoms of excessive exposure to propafenone including bradycardia and postural hypotension [see Clinical Pharmacology ( 12.7 )] . Impact of Other Drugs on Propranolol CYP2D6, CYP1A2 and CYP2C19 Inhibitors: CYP2D6 inhibitors (e.g. bupropion, fluoxetine, paroxetine, quinidine), CYP1A2 inhibitors (e.g., ciprofloxacin, enoxamine, fluvoxamine) and CYP2C19 inhibitors (e.g., fluconazole, fluvoxamine, ticlopidine) increase exposure to propranolol when co-administered with INNOPRAN XL. Monitor patients for bradycardia and hypotension [see Clinical Pharmacology ( 12.7 )] . CYP1A2 and CYP2C19 Inducers: CYP1A2 inducers (e.g., phenytoin, montelukast, smoking) and CYP2C19 inducers (e.g. rifampin) decrease the plasma levels of propranolol resulting in a loss of efficacy [see Clinical Pharmacology ( 12.7 )] . Cholestyramine and Colestipol: Co-administered cholestyramine or colestipol significantly reduces the plasma concentrations of co-administered propranolol which may result in loss of efficacy [see Clinical Pharmacology ( 12.7 )] . 7.2 Pharmacodynamic Drug-Drug Interactions Adrenergic Agonists: Beta-blockers may antagonize the antihypertensive effects of clonidine, and rebound hypertension may result if clonidine is withdrawn abruptly. If clonidine and a beta-blocker are co-administered, withdraw the beta-blocker several days before the withdrawal of clonidine. Alpha Blockers: Co-administration of beta-blockers with alpha-blocker (e.g., prazosin) has been associated with prolongation of first dose hypotension and syncope. Dobutamine: Propranolol may reduce sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial ischemia. Antidepressants: The hypotensive effect of MAO inhibitors or tricyclic antidepressants may be exacerbated when administered with beta-blockers. Monitor patients for postural hypotension. Nonsteroidal Anti-Inflammatory Drugs: Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the antihypertensive effect of beta-adrenoreceptor blocking agents. Monitor blood pressure.

6 ADVERSE REACTIONS The most commonly reported adverse reactions (≥3% and greater than placebo) included the following: fatigue, dizziness, and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-800-308-6755 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions occurring at a rate of ≥3%, excluding those reported more commonly in placebo, encountered in the INNOPRAN XL placebo-controlled hypertension trials and plausibly related to treatment are shown in Table 1. Table 1. Treatment-Emergent Adverse Reactions Reported In ≥3% of Subjects Body System Placebo (N=88) INNOPRAN XL 80 mg (N=89) 120mg (N=85) Fatigue 3 (3%) 4 (5%) 6 (7%) Dizziness (except vertigo) 2 (2%) 6 (7%) 3 (4%) Constipation 0 3 (3%) 1 (1%) 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following reactions have been identified during post-marketing use of INNOPRAN XL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions were observed and have been reported with use of formulations of sustained- or immediate-release propranolol. Allergic: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions; pharyngitis and agranulocytosis; erythematous rash, fever combined with aching and sore throat, laryngospasm, and respiratory distress. Autoimmune: Systemic lupus erythematosus (SLE). Cardiovascular: exacerbation of peripheral arterial disease, arterial insufficiency, usually of the Raynaud type. Central Nervous System: Light-headedness, mental depression, insomnia, lassitude, weakness, fatigue, visual disturbances, hallucinations, vivid dreams, short-term memory loss, emotional lability, slightly clouded sensorium, paresthesia of hands. Gastrointestinal: Nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, mesenteric arterial thrombosis, ischemic colitis. Genitourinary: Male impotence; Peyronie’s disease. Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura. Musculoskeletal: Myopathy, myotonia. Skin and mucous membranes: Stevens-Johnson syndrome, toxic epidermal necrolysis, dry eyes, exfoliative dermatitis, erythema multiforme, urticaria, alopecia, SLE-like reactions, and psoriasisiform rashes.

8.1 Pregnancy Risk Summary Prolonged experience with propranolol in pregnant women over several decades, based on published interventional and observational studies, has not identified a drug associated risk of major birth defects, miscarriage, or other adverse maternal outcomes. Bradycardia, hypoglycemia, and respiratory depression have been observed with use of beta-blockers, including propranolol, in utero near the time of delivery. There are inconsistent reports of intrauterine growth restriction with beta-blocker use, including propranolol, during pregnancy. Untreated hypertension during pregnancy can lead to serious adverse outcomes for the mother and the fetus (see Clinical Considerations and Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage) Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal Adverse Reactions Propranolol crosses the placenta. Neonates born to mothers who are receiving propranolol during pregnancy, may be at risk for bradycardia, hypoglycemia, and respiratory depression. Monitor neonates exposed to propranolol during pregnancy and manage accordingly . Data Animal Data In a series of reproductive and developmental toxicology studies, propranolol was given to rats by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day, but not at doses of 80 mg/kg/day (equivalent to the maximum recommended human oral daily dose (MRHD) on a body surface area basis), treatment was associated with embryotoxicity (reduced litter size and increased resorption rates) as well as neonatal toxicity (deaths). Propranolol HCl was also administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (about 5 times the MRHD). No evidence of embryo or neonatal toxicity was noted.