Propranolol Hydrochloride (Page 4 of 5)

Drug Interactions

Caution should be exercised when propranolol hydrochloride tablets are administered with drugs that have an effect on CYP2D6, 1A2, or 2C19 metabolic pathways. Coadministration of such drugs with propranolol may lead to clinically relevant drug interactions and changes on its efficacy and/or toxicity (see Drug Interactions in PHARMACOKINETICS AND DRUG METABOLISM).

Cardiovascular Drugs

Antiarrhythmics

Propafenone has negative inotropic and beta-blocking properties that can be additive to those of propranolol. Quinidine increases the concentration of propranolol and produces greater degrees of clinical beta-blockade and may cause postural hypotension.

Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with β-blockers such as propranolol.

The clearance of lidocaine is reduced with administration of propranolol. Lidocaine toxicity has been reported following coadministration with propranolol.

Caution should be exercised when administering propranolol hydrochloride tablets with drugs that slow A-V nodal conduction, e.g. digitalis, lidocaine and calcium channel blockers.

Digitalis Glycosides

Both digitalis glycosides and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Calcium Channel Blockers

Caution should be exercised when patients receiving a beta blocker are administered a calcium-channel- blocking drug with negative inotropic and/or chronotropic effects. Both agents may depress myocardial contractility or atrioventricular conduction.

There have been reports of significant bradycardia, heart failure, and cardiovascular collapse with concurrent use of verapamil and beta blockers.

Coadministration of propranolol and diltiazem in patients with cardiac disease has been associated with bradycardia, hypotension, high-degree heart block, and heart failure.

ACE Inhibitors

When combined with beta blockers, ACE inhibitors can cause hypotension, particularly in the setting of acute myocardial infarction.

The antihypertensive effects of clonidine may be antagonized by beta blockers. Propranolol hydrochloride tablets should be administered cautiously to patients withdrawing from clonidine.

Alpha Blockers

Prazosin has been associated with prolongation of first dose hypotension in the presence of beta blockers. Postural hypotension has been reported in patients taking both beta blockers and terazosin or doxazosin.

Reserpine

Patients receiving catecholamine-depleting drugs, such as reserpine, should be closely observed for excessive reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension.

Inotropic Agents

Patients on long-term therapy with propranolol may experience uncontrolled hypertension if administered epinephrine as a consequence of unopposed alpha-receptor stimulation. Epinephrine is therefore not indicated in the treatment of propranolol overdose (see OVERDOSAGE).

Isoproterenol and Dobutamine

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. Also, propranolol may reduce sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial ischemia.

Non-Cardiovascular Drugs

Nonsteroidal Anti-Inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDS) have been reported to blunt the antihypertensive effect of beta-adrenoreceptor blocking agents.

Administration of indomethacin with propranolol may reduce the efficacy of propranolol in reducing blood pressure and heart rate.

Antidepressants

The hypotensive effects of MAO inhibitors or tricyclic antidepressants may be exacerbated when administered with beta blockers by interfering with the beta blocking activity of propranolol.

Anesthetic Agents

Methoxyflurane and trichloroethylene may depress myocardial contractility when administered with propranolol.

Warfarin

Propranolol when administered with warfarin increases the concentration of warfarin. Prothrombin time, therefore, should be monitored.

Neuroleptic Drugs

Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol.

Thyroxine

Thyroxine may result in a lower than expected T3 concentration when used concomitantly with propranolol.

Alcohol

Alcohol, when used concomitantly with propranolol, may increase plasma levels of propranolol.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In dietary administration studies in which mice and rats were treated with propranolol hydrochloride 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 hydrochloride. In a study in which both male and female rats were exposed to propranolol hydrochloride 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 hydrochloride in bacteria (S. typhimurium strain TA 1538).

Pregnancy

Teratogenic Effects

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 is administered to a nursing woman.

Pediatric Use

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.

Geriatric Use

Clinical studies of propranolol hydrochloride 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.

ADVERSE REACTIONS

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 lability, slightly clouded sensorium, and decreased performance on neuropsychometrics. For immediate- release formulations, fatigue, lethargy, and vivid dreams appear dose-related.

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