InnoPran XL

Dosage Forms And Strengths

INNOPRAN XL Extended-Release Capsules are supplied as capsules containing either 80 mg, or 120 mg of propranolol hydrochloride imprinted with “InnoPran XL”. In addition, the 80 mg strength is a gray/white capsule imprinted with “80” and 2 segmented bands, while the 120 mg strength is a gray/off-white capsule imprinted with “120” and 3 segmented bands.

Storage And Handling

INNOPRAN XL (propranolol hydrochloride) Extended Release Capsules are supplied as capsules containing either 80 mg, or 120 mg propranolol hydrochloride imprinted with “InnoPran XL”.

Storage

Store at 25°C (77°F); excursions permitted to 15° and 30°C (59° and 86°F) in a tightly closed container.

Manufactured for: Akrimax Pharmaceuticals, LLC Cranford, NJ 07016 By: Aptalis Pharmatech, Inc. Vandalia, OH 45377. Marketed and distributed by: Akrimax Pharmaceuticals, LLC Cranford, NJ 07016 Innopran XL®, a Diffucaps ® Drug Delivery Product Manufactured By Aptalis Pharmatech, Inc. Revised: Nov 2013

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 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.

Some antihypertensive drugs have smaller blood pressure effects (as montherapy) 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 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. The time needed for full antihypertensive response is variable, but is usually achieved within 2 to 3 weeks.

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.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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.

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.

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.

Masked Signs Of Hypoglycemia

Beta-blockers, like Innopran XL, may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.

Thyrotoxicosis

Innopran XL may mask clinical signs of hyperthyroidism, such as tachycardia. Avoid abrupt withdrawal of beta-blockade, which may precipitate a thyroid storm.

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.

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).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

In dietary administration studies in which mice and rats were treated with propranolol HCl for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis. On a body surface area basis, this dose in the mouse and rat is, respectively, about equal to and about twice the MRHD of 640 mg propranolol HCl. In a study in which both male and female rats were exposed to propranolol HCl in their diets at concentrations of up to 0.05% (about 50 mg/kg body weight and less than the MRHD), from 60 days prior to mating and throughout pregnancy and lactation for 2 generations, there were no effects on fertility. Based on differing results from Ames tests performed by different laboratories, there is equivocal evidence for a genotoxic effect of propranolol HCl in bacteria (S. typhimurium strain TA 1538).

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well controlled studies in pregnant women. Intrauterine growth retardation, small placentas, and congenital anomalies have been reported for neonates whose mothers received propranolol HCl during pregnancy.

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.

Labor And Delivery

Neonates whose mothers received propranolol HCl at parturition have exhibited bradycardia, hypoglycemia, and/or respiratory depression. Adequate facilities for monitoring such infants at birth should be available.

Nursing Mothers

Propranolol is excreted in human milk.

Pediatric Use

Safety and effectiveness of propranolol in pediatric patients have not been established.

Geriatric Use

Clinical studies of INNOPRAN XL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal Impairment

The exposure to propranolol is increased in patients with renal impairment. Initiate INNOPRAN XL therapy in patients with impaired renal function at the lowest dose (80 mg) once daily and monitor patients for marked bradycardia and hypotension.

Hepatic Impairment

The exposure to propranolol is increased in patients with hepatic impairment. Initiate INNOPRAN XL therapy in patients with impaired hepatic function at the lowest dose (80 mg) once daily and monitor patients for marked bradycardia and hypotension.

SIDE EFFECTS

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

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.

DRUG INTERACTIONS

Pharmacokinetic Drug-Drug Interactions

Impact of Propranolol on Other Drugs

Warfarin: Warfarin concentrations are increased when administered with propranolol. Monitor prothrombin time accordingly.

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.

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.

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.

Cholestyramine and Colestipol: Co-administered cholestyramine or colestipol significantly reduces the plasma concentrations of co-administered propranolol which may result in loss of efficacy.

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.

Pregnancy Category C

There are no adequate and well controlled studies in pregnant women. Intrauterine growth retardation, small placentas, and congenital anomalies have been reported for neonates whose mothers received propranolol HCl during pregnancy.

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.

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

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.

Most overdoses of propranolol are mild and respond to supportive care.

Propranolol is not significantly dialyzable.

Hypotension and bradycardia have been reported following propranolol overdose and should be treated appropriately. Glucagon can exert potent inotropic and chronotropic effects and may be particularly useful for the treatment of hypotension or depressed myocardial function after a propranolol overdose.

Glucagon should be administered as 50-150 mcg/kg intravenously followed by continuous drip of 1-5 mg/hour for positive chronotropic effect. Isoproterenol, dopamine or phosphodiesterase inhibitors may also be useful. Epinephrine, however, may provoke uncontrolled hypertension. Bradycardia can be treated with atropine or isoproterenol. Serious bradycardia may require temporary cardiac pacing.

Monitor the electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output balance. Isoproterenol and aminophylline may be used for bronchospasm.

Propranolol is a nonselective, beta-adrenergic receptor-blocking agent possessing no other autonomic nervous system activity. It specifically competes with beta-adrenergic receptor-stimulating agents for available receptor sites. Of the 2 enantiomers of propranolol, the S-enantiomer blocks beta-adrenergic receptors. When access to beta-receptor sites is blocked by propranolol, chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased proportionately. At dosages greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action, which affects the cardiac action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain.

Absorption

Propranolol is highly lipophilic and is almost completely absorbed after oral administration. However, it undergoes high first-pass metabolism by the liver, and, on average, only about 25% of propranolol reaches the systemic circulation.

A single-dose, food-effect study in 36 healthy subjects showed that a high fat meal administered with INNOPRAN XL at 10 p.m., increased the lag time from 3 to 5 hours and the time to reach the maximum concentration from 11.5 to 15.4 hours, with no effect on the AUC.

Following multiple-dose administration of INNOPRAN XL at 10 p.m. under fasting conditions, the steady state lag time was between 4 and 5 hours and propranolol peak plasma concentrations were reached approximately 12 to 14 hours after dosing. Propranolol trough levels were achieved 24 to 27 hours after dosing, and persisted for 3 to 5 hours after the next dose.

The plasma levels of propranolol showed dose-proportional increases after single and multiple administration of 80-, 120-, and 160-mg of INNOPRAN XL.

At steady state, the bioavailability of a 160-mg dose of INNOPRAN XL and propranolol hydrochloride long-acting capsules did not differ significantly.

Distribution

Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha1 acid glycoprotein). The binding is enantiomer-selective. The S-isomer is preferentially bound to alpha1 glycoprotein and the R-isomer preferentially bound to albumin. The volume of distribution of propranolol is approximately 4 liters.

Metabolism and Elimination

Propranolol is extensively metabolized with most metabolites appearing in the urine. Propranolol is metabolized through 3 primary routes: Aromatic hydroxylation (mainly 4-hydroxylation), N-dealkylation followed by further side-chain oxidation, and direct glucuronidation. It has been estimated that the percentage contributions of these routes to total metabolism are 42%, 41%, and 17%, respectively, but with considerable variability between individuals. The 4 major metabolites are propranolol glucuronide, naphthyloxylactic acid, and glucuronic acid and sulfate conjugates of 4-hydroxy propranolol.

In vitro studies have indicated that the aromatic hydroxylation of propranolol is catalyzed mainly by polymorphic CYP2D6. Side-chain oxidation is mediated mainly by CYP1A2 and to some extent by CYP2D6. 4-hydroxy propranolol is a weak inhibitor of CYP2D6.

Propranolol is also a substrate for CYP2C19 and a substrate for the intestinal efflux transporter, p-glycoprotein (p-gp). Studies suggest however that p-gp is not dose-limiting for intestinal absorption of propranolol in the usual therapeutic dose range.

In healthy subjects, no difference was observed between CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) with respect to oral clearance or elimination half-life. Partial clearance to 4-hydroxy propranolol was significantly higher and to naphthyloxylactic acid was significantly lower in EMs than PMs.

In normal subjects receiving oral doses of racemic propranolol, S-enantiomer concentrations exceeded those of the R-enantiomer by 40 to 90% as a result of stereoselective hepatic metabolism.

The elimination half-life of propranolol was approximately 8 hours.