InnoPran XL®(propranolol hydrochloride) Extended Release Capsules

InnoPran XL (propranolol hydrochloride) is a nonselective, beta-adrenergic receptor-blocking agent for oral administration, available as an extended release product. InnoPran XL is available as 80 mg and 120 mg capsules which contain sustained-release beads. Each of the beads contains propranolol hydrochloride and is coated with dual membranes. These membranes are designed to retard release of propranolol hydrochloride for several hours after ingestion followed by the sustained release of propranolol.

The active ingredient in InnoPran XL is a synthetic beta-adrenergic receptor-blocking agent chemically described as 1-(Isopropylamino)-3-(1-naphthyloxy)-2-propanol hydrochloride. Its structural formula is:

Propranolol hydrochloride is a stable, white, crystalline solid, which is readily soluble in water and ethanol. Its molecular weight is 295.81. Each capsule for oral administration contains sugar spheres, ethylcellulose, povidone, hypromellose phthalate, diethyl pthalate, hypromellose, polyethylene glycol, gelatin, titanium dioxide and black iron oxide. In addition, InnoPran XL 120-mg capsules contain yellow iron oxide.

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. 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.

The mechanism of the antihypertensive effect of propranolol has not been established. Among factors that contribute to the antihypertensive action are: (1) decreased cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of tonic sympathetic nerve outflow from vasomotor centers in the brain. Although total peripheral resistance may increase initially, it readjusts to or below the pretreatment level with chronic use of propranolol. Effects of propranolol on plasma volume appear to be minor and somewhat variable.

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 reach 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 PM, increased the lag time from 3 to 5 hours and the time to reach the maximum concentration from 11.5 to 15.4 hours, under fed conditions, with no effect on the AUC. (See DOSAGE AND ADMINISTRATION).

Following multiple-dose administration of InnoPran XL at 10PM under fasting conditions, the steady state lag time was between 4-5 hours and propranolol peak plasma concentrations were reached approximately 12-14 hours after dosing. Propranolol trough levels were achieved 24-27 hours after dosing, and persisted for 3-5 hours after the next dose. The elimination half-life of propranolol was approximately 8 hours.

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 160-mg dose of InnoPran XL and propranolol hydrochloride long acting capsules did not differ significantly.

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.

Propranolol is extensively metabolized with most metabolites appearing in the urine. Propranolol is metabolized through three 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 four 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.

Of the two enantiomers of propranolol the S-enantiomer blocks beta adrenergic receptors. In normal subjects receiving oral doses of racemic propranolol, S-enantiomer concentrations exceeded those of the R-enantiomer by 40-90% as a result of stereoselective hepatic metabolism.

In a double-blind, parallel dose-response study in patients with mild-to-moderate hypertension (n=434), doses of InnoPran XL from 80 to 640 mg were taken once daily at approximately 10PM. InnoPran XL significantly lowered sitting systolic and diastolic blood pressure when measurements were taken approximately 16 hours later. The placebo-subtracted diastolic blood pressure effect for the 80 and 120 mg doses were -3.0 and -4.0 mm Hg, respectively. Higher doses of InnoPran XL (160, 640 mg) had no additional blood pressure lowering effect when compared with 120 mg. The antihypertensive effects of InnoPran XL were seen in the elderly (greater than or equal to 65 years old) and men and women. There were too few non-White patients to assess the efficacy of InnoPran XL in these patients.

InnoPran XL is indicated in the management of hypertension; it may be used alone or in combination with other antihypertensive agents.

Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than first-degree block; 3) bronchial asthma; and 4) in patients with known hypersensitivity to propranolol hydrochloride.

Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by beta-blockade may precipitate more severe failure. Although beta-blockers should be avoided in overt congestive heart failure, some have been shown to be highly beneficial when used with close follow-up in patients with a history of failure who are well compensated and are receiving additional therapies, including diuretics as needed. Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle.

In general, patients with bronchospastic lung disease should not receive beta-blockers. Propranolol should be administered with caution in this setting since it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta-receptors.

The necessity or desirability of withdrawal of beta-blocking therapy prior to major surgery is controversial. It should be noted, however, that the impaired ability of the heart to respond to reflex adrenergic stimuli in propranolol-treated patients may augment the risks of general anesthesia and surgical procedures.

Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension.

Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and blood pressure changes) of acute hypoglycemia, especially in labile insulin-dependent diabetics. In these patients, it may be more difficult to adjust the dosage of insulin.

Propranolol therapy, particularly in infants and children, diabetic or not, has been associated with hypoglycemia especially during fasting, as in preparation for surgery. Hypoglycemia has been reported with propranolol use after prolonged physical exertion and in patients with renal insufficiency.

Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism. Therefore, abrupt withdrawal of propranolol may be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm. Propranolol may change thyroid-function tests, increasing T₄ and reversing T₃, and decreasing T₃.

Beta-adrenergic blockade in patients with Wolf‑Parkinson-White syndrome and tachycardia has been associated with severe bradycardia requiring treatment with a pacemaker. In one case, this resulted after an initial dose of 5-mg propranolol.

Propranolol should be used with caution in patients with impaired hepatic or renal function. InnoPran XL is not indicated for the treatment of hypertensive emergencies.

Beta-adrenergic receptor blockade can cause reduction of intraocular pressure. Patients should be told that InnoPran XL may interfere with the glaucoma screening test. Withdrawal may lead to a return of intraocular pressure.

Risk of Anaphylactic Reaction. While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

In patients with hypertension, use of propranolol has been associated with elevated levels of serum potassium, and serum transaminases and alkaline phosphatase. In severe heart failure, the use of propranolol has been associated with increases in Blood Urea Nitrogen.

Caution should be exercised when InnoPran XL is administered with drugs that have an effect on CYP2D6, 1A2 or 2C19 metabolic pathways. Co-administration of such drugs with propranolol may lead to clinically relevant drug interactions and changes on its efficacy and/or toxicity (see DRUG INTERACTIONS in CLINICAL PHARMACOLOGY).

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 maximum recommended human oral daily dose (MRHD) of 640 mg propranolol HCI. In a study in which both male and female rats were exposed to propranolol HCI 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 two 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 HCI in bacteria (S. typhimurium strain TA 1538).

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 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 HCI also was administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (about 5 times the maximum recommended human oral daily dose). No evidence of embryo or neonatal toxicity was noted.

There are no adequate and well-controlled studies in pregnant women. Intrauterine growth retardation has been reported for neonates whose mothers received propranolol HCI during pregnancy. Neonates whose mothers received propranolol HCI at parturition have exhibited bradycardia, hypoglycemia, and respiratory depression. Adequate facilities for monitoring such infants at birth should be available. InnoPran XL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Propranolol is excreted in human milk. Caution should be exercised when InnoPran XL is administered to a nursing woman.

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

Clinical studies of InnoPran XL did not include sufficient numbers of subjects ages 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.

Adverse events occurring at a rate of ≥3%, excluding those reported more commonly in placebo encountered in the InnoPran XL placebo-controlled hypertension trials and are plausibly related to treatment are shown in Table 1.

 The following adverse events were observed and have been reported with use of formulations of sustained- or immediate-release propranolol.

Bradycardia; congestive heart failure; intensification of AV block; hypotension; paresthesia of hands; thrombocytopenic purpura; arterial insufficiency, usually of the Raynaud type.

Light-headedness, mental depression manifested by insomnia, lassitude, weakness, fatigue; reversible mental depression progressing to catatonia; visual disturbances; hallucinations; vivid dreams; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics. For immediate-release formulations, fatigue, lethargy, and vivid dreams appear dose related.

Nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, constipation, mesenteric arterial thrombosis, ischemic colitis.

Pharyngitis and agranulocytosis; erythematous rash, fever combined with aching and sore throat; laryngospasm, and respiratory distress.

Bronchospasm.

Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.

In extremely rare instances, systemic lupus erythematosus has been reported.

Alopecia, LE-like reactions, psoriasiform rashes, dry eyes, male impotence, and Peyronie’s disease have been reported rarely. Oculomucocutaneous reactions involving the skin, serous membranes, and conjunctivae reported for a beta blocker (practolol) have not been associated with propranolol.

InnoPran XL should be administered once daily at bedtime (approximately 10 PM) and should be taken consistently either on an empty stomach or with food. The starting dose is 80 mg but dosage should be individualized and titration may be needed to a dose of 120 mg. In the clinical trial, doses of InnoPran XL above 120 mg had no additional effects on blood pressure (See PHARMACODYNAMICS AND CLINICAL EFFECTS). The time needed for full antihypertensive response is variable, but is usually achieved within 2-3 weeks.

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

Propranolol is not significantly dialyzable. In the event of overdose or exaggerated response, the following measures should be employed:

Decontamination: Gastric lavage

Supportive Therapy

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.

The electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output balance must be monitored. Isoproterenol and aminophylline may be used for bronchospasm.

InnoPran XL (propranolol hydrochloride) Extended Release Capsules

Each gray/white capsule, imprinted with “80”, 2 segmented bands, “InnoPran XL”, and Reliant logo contains 80 mg of propranolol hydrochloride in bottles of 30 (NDC 65726-250-10), bottles of 100 (NDC 65726-250-25), bottles of 500 (NDC 65726-250-35), and a Unit Dose package of 100 (NDC 65726-250-90).

Each gray/off-white capsule, imprinted with “120”, 3 segmented bands, “InnoPran XL”, and Reliant logo contains 120 mg of propranolol hydrochloride in bottles of 30 (NDC 65726-251-10) bottles of 100 (NDC 65726-251-25), bottles of 500 (NDC 65726-251-35), and a Unit Dose package of 100 (NDC 65726-251-90).

Store at 25ºC (77ºF); excursions permitted to 15 - 30ºC (59 - 86ºF) [see USP Controlled Room Temperature] in a tightly closed container. The unit dose packaging should be stored in the carton.

Rx only

January, 2005

Manufactured for:

Reliant Pharmaceuticals, Inc.

Liberty Corner, NJ 07938, USA

By:

Eurand America, Inc.

Vandalia, OH 45377, USA

Address Medical Inquiries to:

Reliant Pharmaceuticals, Inc.

Medical Affairs

110 Allen Road

Liberty Corner, NJ 07938, USA

©2005 Reliant Pharmaceuticals, Inc.

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