ProNorm

Each film-coated tablet contains: Propranolol (as hydrochloride), USP 10 mg or 40 mg.
Beta blockers (beta-adrenoceptor blocking drugs or antagonists) are competitive antagonists of catecholamines at beta-adrenergic receptors in a wide range of tissues. Although they have broadly similar properties they differ in their affinity for beta1 or beta2 receptor subtypes, intrinsic sympathomimetic activity, membrane-stabilising activity, blockade of alpha-adrenergic receptors, and pharmacokinetic properties including differences in lipid solubility. These differences may affect the choice of drug in specific situation.

Pharmacology: Pharmacodynamics: The substance has no β-1 receptor selectivity (cardioselectivity) and has no intrinsic sympathomimetic activity (ISA). Propranolol is a strongly lipophilic substance and has a membrane stabilising effect.
Pharmacokinetics: Absorption: Propranolol is highly lipophilic and 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. Peak plasma concentrations occur about 1 to 4 hours after an oral dose.
Administration of protein-rich foods increase the bioavailability of propranolol by about 50% with no change in time to peak concentration, plasma binding, half-life, or the amount of unchanged drug in the urine.
Distribution: Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha 1 acid glycoprotein). The binding is enantiomer-selective. The S(-)-enantiomer is preferentially bound to alpha 1 glycoprotein and the R(+)-enantiomer preferentially bound to albumin. The volume of distribution of propranolol is approximately 4 liters/kg. Propranolol crosses the blood-brain barrier and the placenta, and is distributed into breast milk.
Metabolism and Elimination: 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 of CYP2C19 and a substrate for the intestinal efflux transporter, p-glycoprotein (p-gp). Studies suggest however that p-gpis 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 of 4-hydroxy propranolol was significantly higher and of naphthyloxylactic acid significantly lower in Ems than PMs. The plasma half-life of propranolol is from 3 to 6 hours.

Management of hypertension, angina pectoris, cardiac arrhythmias, coronary insufficiency, migraine prophylaxis and benign essential tremor.

For Hypertension: 40 mg initially 2 tablets, then increased if necessary to 80 mg twice daily, maximum dose 320 mg/day or as prescribed by the physician.
For Angina Pectoris: Initially 10 mg-20 mg 3-4 times a day according to response, maximum dose 400 mg/day or as prescribed by the physician.
For Arrhythmias: 10 mg-30 mg 3 to 4 times a day or as prescribed by the physician.
For Migraine: Initially 40 mg twice a day, gradually increased to 80-160 mg/day or as prescribed by the physician.
For Hypertrophic Subaortic Stenosis: 20 mg to 40 mg 3 to 4 times a day or as prescribed by the physician.

Propranolol is not significantly dialyzable. In the event of overdosage or exaggerated response, the following measures should be employed: General: If ingestion is or may have been recent, evacuate gastric contents, taking care to prevent pulmonary aspiration.
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 mcg/kg to 150 mcg/kg intravenously followed by continuous drip of 1 mg/hour to 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.

Bronchospasm, including bronchial asthma; allergic rhinitis during the pollen season; sinus bradycardia and greater than first degree block; cardiogenic shock; right ventricular failure secondary to pulmonary hypertension; congestive heart failure, unless the failure is secondary to a tachyarrhythmia treatable with propranolol.

This product contains FD & C Yellow Lake #5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons.

Propranolol should not be given to patients with bronchospasm or asthma or to those with history of obstructive airways disease.
Use in Children: Safety and effectiveness of propranolol in pediatric patients have not been established.
Bronchospasm and congestive heart failure have been reported coincident with the administration of propranolol therapy in pediatric patients.
Use in the Elderly: Clinical studies of propranolol hydrochloride tablets 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.

Pregnancy: Category C: In a series of reproductive and developmental toxicology studies, propranolol hydrochloride 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 hydrochloride 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, small placentas, and congenital abnormalities have been reported in neonates whose mothers received propranolol during pregnancy. Neonates whose mothers received propranolol at parturition have exhibited bradycardia, hypoglycemia, and/or respiratory depression. Adequate facilities for monitoring such infants at birth should be available. Propranolol hydrochloride tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: Propranolol is excreted in human milk. Caution should be exercised when propranolol hydrochloride tablets are administered to a nursing woman.

The following adverse events were observed and have been reported in patients using propranolol.
Cardiovascular: bradycardia, congestive heart failure, intensification of AV block, hypotension, paresthesia of hands, thrombocytopenic purpura, arterial insufficiency, usually of the Raynaud type.
Central Nervous System: light-headedness, mental depression, manifested by insomnia, lassitude, weakness, fatigue, catatonia; visual disturbances, hallucinations, vivid dreams, an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional liability, slightly clouded sensorium, and decreased performance on neuropsychometrics. For immediate-release formulations, fatigue, lethargy, and vivid dreams appear dose-related.
Gastrointestinal: nausea, vomiting epigastric distress, abdominal cramping, diarrhea, constipation, mesenteric, arterial thrombosis, ischemic colitis.
Allergic: hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, pharyngitis and agranulocytosis, erythematous rash, fever combined with aching and sore throat, laryngospasm, and respiratory distress.
Respiratory: bronchospasm.
Hematologic: agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.
Autoimmune: Systemic Lupus Erythematosus (SLE).
Skin and Mucous Membranes: Stevens-Johnson Syndrome, toxic epidermal necrolysis, dry eyes, exfoliative dermatitis, erythema multiforme, urticaria, alopecia, SLE-like reactions, and psoriasiform rashes. Oculomucocutaneous syndrome involving the skin, serous membranes and conjunctive reported for a beta blocker have not been associated with propranolol.
Genitourinary: male impotence, Peyronie's disease.

Both pharmacodynamic and pharmacokinetic interactions have been reported with beta blockers. Pharmacodynamic interactions may occur with drugs whose actions enhance or antagonise the various effects of beta blockers at beta1 receptors, including their antihypertensive effect, cardiodepressant effect, effect on carbohydrate metabolism, or effect on bronchial beta2 receptors. The characteristics of the individual beta blocker must therefore be borne in mind when considering likely interactions.

Store at temperatures not exceeding 30°C.

Beta-Blockers

C07AA05 - propranolol ; Belongs to the class of non-selective beta-blocking agents. Used in the treatment of cardiovascular diseases.

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