CATEGORIES: Hypertension, essential; Myocardial infarction; Tachycardia, ventricular; Angina pectoris; Headache, migraine, prophylaxis; Extrasystole, atrial; Extrasystole, premature ventricular; Pheochromocytoma, adjunct; Stenosis, hypertrophic subaortic; Tachycardia, digitalis-induced; Tachycardia, sinus; Tremor, essential; Wolff-Parkinson-White syndrome; Arrhythmia, atrial fibrillation; Arrhythmia, atrial flutter; Arrhythmia, paroxysmal atrial tachycardia; Arrhythmia, secondary to thyrotoxicosis; Arrhythmia, supraventricular; Pregnancy Category C; WHO Formulary; FDA Approved November 1967
Drug Classes: Antiadrenergics, beta blocking; Antiarrhythmics, class II
BRAND NAMES: Inderal; Inderal LA; InnoPran XL
FOREIGN BRAND AVAILABILITY:
Acifol (Mexico);
Adrexan (France);
Angilol (England, New Zealand);
Angilol LA (New Zealand);
Apo-Propranolol (Canada, New Zealand);
Apsolol (England);
Avlocardyl (France);
Becardin (Hong Kong);
Berkolol (England, Hong Kong, Ireland);
Betabloc (India);
Beta-Timelets (Germany);
Blocard (Indonesia);
Blocaryl (Argentina);
Cardinol (New Zealand);
Cardinol LA (New Zealand);
Ciplar (India);
Corbeta (India);
Deralin (Australia, Israel);
Dibudinate (Argentina);
Dociton (Germany);
Duranol (Philippines);
Elbrol (Germany);
Emforal (Thailand);
Farmadral (Indonesia);
Farprolol (Mexico);
Frekven (Denmark);
Frina (Hungary);
Hopranolol (Hong Kong);
Impral (Mexico);
Indicardin (South Africa);
Inpanol (Hong Kong);
Noloten (Argentina);
Oposim (Argentina);
Phanerol (Philippines);
Prestoral (Indonesia);
Prolol (Hong Kong, Israel, Thailand);
Prolol Plus (Hong Kong);
Propalong (Argentina);
Propayerst (Argentina);
Propral (Finland);
Reducor (Finland);
Rexigen (South Africa);
Slow Deralin (Israel);
Sumial (Spain);
Tenomal (Greece);
Tensiflex (Argentina);
Waucoton (Greece)
COST OF THERAPY:
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Note: The trade names have been used throughout this monograph for clarity.
Inderal (propranolol hydrochloride) is a synthetic beta-adrenergic receptor blocking agent chemically described as 1-(Isopropylamino)-3-(1-naphthyloxy)-2-propanol hydrochloride.
Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water and ethanol. Its molecular weight is 295.81.
Propranolol is available as 10, 20, 40, 60, and 80 mg tablets for oral administration and as a 1 mg/ml sterile injectable solution for intravenous administration.
The inactive ingredients contained in Inderal tablets are: Lactose, magnesium stearate, microcrystalline cellulose, and stearic acid. In addition, propranolol 10 mg and 80 mg tablets contain FD&C yellow no. 6 and D&C yellow no. 10; propranolol 20 mg tablets contain FD&C blue no. 1; propranolol 40 mg tablets contain FD&C blue no. 1, FD&C yellow no. 6, and D&C yellow no. 10; propranolol 60 mg tablets contain D&C red no. 30.
Long-Acting (LA) Capsules
Inderal LA capsules are formulated to provide a sustained release of propranolol hydrochloride. Inderal LA is available as 60, 80, 120, and 160 mg capsules.
Inderal LA capsules contain the following inactive ingredients: Cellulose, ethylcellulose, gelatin capsules, hypromellose, and titanium ddioxide. In addition, Inderal LA 60, 80, and 120 mg capsules contain D&C red no. 28 and FD&C blue no. 1; Inderal LA 160 mg capsules contain FD&C blue no. 1.
Extended-Release Capsules
InnoPran XL is a nonselective, beta-adrenergic receptor-blocking agent for oral administration, available as an extended release product. The capsules contain sustained-release beads available as 80 and 120 mg capsules. 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.
General
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 HCl, the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased proportionately.
Mechanism of Action
The mechanism of the antihypertensive effect of propranolol has not been established. Among the factors that may be involved in contributing 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. Effects on plasma volume appear to be minor and somewhat variable. Propranolol has been shown to cause a small increase in serum potassium concentration when used in the treatment of hypertensive patients.
In angina pectoris, propranolol generally reduces the oxygen requirement of the heart at any given level of effort by blocking the catecholamine-induced increases in the heart rate, systolic blood pressure, and the velocity and extent of myocardial contraction. Propranolol may increase oxygen requirements by increasing left ventricular fiber length, end diastolic pressure, and systolic ejection period. The net physiologic effect of beta-adrenergic blockade is usually advantageous and is manifested during exercise by delayed onset of pain and increased work capacity. Propranolol exerts its antiarrhythmic effects in concentrations associated with beta-adrenergic blockade, and this appears to be its principal antiarrhythmic mechanism of action. In 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 antimigraine effect of propranolol has not been established. Beta-adrenergic receptors have been demonstrated in the pial vessels of the brain.
The specific mechanism of propranolol HCl's antitremor effects has not been established, but beta-2 (noncardiac) receptors may be involved. A central effect is also possible. Clinical studies have demonstrated that propranolol is of benefit in exaggerated physiological and essential (familial) tremor.
Beta-receptor blockade can be useful in conditions in which, because of pathologic or functional changes, sympathetic activity is detrimental to the patient. But there are also situations in which sympathetic stimulation is vital. For example, in patients with severely damaged hearts, adequate ventricular function is maintained by virtue of sympathetic drive, which should be preserved. In the presence of A-V block greater than first degree, beta blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta blockade results in bronchial constriction by interfering with adrenergic bronchodilator activity, which should be preserved in patients subject to bronchospasm.
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. Peak effect occurs in 1 to 1.5 hours. The biologic half-life is approximately 4 hours.
There is no simple correlation between dose or plasma level and therapeutic effect, and the dose-sensitivity range as observed in clinical practice is wide. The principal reason for this is that sympathetic tone varies widely between individuals. Since there is no reliable test to estimate sympathetic tone or to determine whether total beta blockade has been achieved, proper dosage requires titration.
LA Capsules
Inderal LA capsules (60, 80, 120, and 160 mg) release propanolol HCl at a controlled and predictable rate. Peak blood levels following dosing with Inderal LA occur at about 6 hours, and the apparent plasma half-life is about 10 hours. When measured at steady-state over a 24 hour period the areas under the propranolol plasma concentration-time curve (AUCs) for the capsules are approximately 60-65% of the AUCs for a comparable divided daily dose of Inderal tablets. The lower AUCs for the capsules are due greater hepatic metabolism of propranolol, resulting from a slower rate of absorption of propranolol. Over a 24 hour period, blood levels are fairly constant for about 12 hours, then decline exponentially.
Inderal LA should not be considered a simple mg-for-mg substitute for conventional propanolol and the blood levels achieved do not match (are lower than) those of 2-4 times daily dosing with the same dose. When changing to Inderal LA from conventional propranolol, a possible need for retitration upwards should be considered, especially to maintain effectiveness at the end of the dosing interval. In most clinical settings, however, such as hypertension or angina where there is little correlation between plasma levels and clinical effect, Inderal LA has been therapeutically equivalent to the same mg dose of conventional Inderal as assessed by 24 hour effects on blood pressure and on 24 hour excercise responses of heart rate, systollic pressure, and rate pressure product. Inderal LA can provide effective beta blockade for a 24 hour period.
InnoPran XL Capsules
A single-dose, food-effect study in 36 healthy subjects showed that a high fat meal administered with propanol HCl extended-release at 10:00 PM, increased the lag time from 3-5 hours and the time to reach the maximum concentration from 11.5-15.4 hours, under fed conditions, with no effect on the AUC. (See DOSAGE AND ADMINISTRATION.)
Following multiple-dose administration of propanol HCl extended-release at 10:00 PM 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 propanol HCl XL.
At steady state, the bioavailability of 160 mg dose of propanol HCl extended-release and propranolol HCl LA 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 L.
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 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.
Enantiomers
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.
Special Populations
Pediatric
The pharmacokinetics of propanol HCl extended-release have not been investigated in patients under 18 years of age.
Geriatric
The pharmacokinetics of propanol HCl extended-release have not been investigated in patients over 65 years of age. In a study of 12 elderly (62-79 years old) and 12 young (25-33 years old) healthy subjects, the clearance of S-enantiomer of propranolol was decreased in the elderly. Additionally, the half-life of both the R- and S-propranolol was prolonged in the elderly compared with the young (11 vs 5 hours).
Gender
In a dose-proportionality study, the pharmacokinetics of propanol HCl extended-release were evaluated in 22 male and 14 female healthy volunteers. Following single doses under fasting conditions, the mean AUC and Cmax were about 49% and 16% higher for females across the dosage range. The mean elimination half-life was longer in females than in males (11 vs 7.5 hours).
Race
A study conducted in 12 Caucasian and 13 African-American male subjects taking propranolol, showed that at steady state, the clearance of R- and S-propranolol were about 76% and 53% higher in African-Americans than in Caucasians, respectively.
Renal Insufficiency
The pharmacokinetics of propanol HCl extended-release have not been evaluated in patients with renal insufficiency. In a study conducted in 5 patients with chronic renal failure, 6 patients on regular dialysis, and 5 healthy subjects, who received a single oral dose of 40 mg of propranolol, the peak plasma concentrations (Cmax) of propranolol in the chronic renal failure group were 2- to 3-fold higher (161 ± 41 ng/ml) than those observed in the dialysis patients (47 ± 9 ng/ml) and in the healthy subjects (26 ± 1 ng/ml). Propranolol plasma clearance was also reduced in the patients with chronic renal failure.
Chronic renal failure has been associated with a decrease in drug metabolism via down regulation of hepatic cytochrome P450 activity.
Hepatic Insufficiency
The pharmacokinetics of propanol HCl extended-release have not been evaluated in patients with hepatic impairment. However, propranolol is extensively metabolized by the liver. In a study conducted in 7 patients with cirrhosis and 9 healthy subjects receiving 80 mg oral propranolol every 8 hours for 7 doses, the steady-state unbound propranolol concentration in patients with cirrhosis was increased 3-fold in comparison to controls. In cirrhosis, the half-life increased to 11 hours compared to 4 hours (see PRECAUTIONS).
Drug Interactions
Interactions With Substrates, Inhibitors or Inducers of Cytochrome P-450 Enzymes
Because propranolol's metabolism involves multiple pathways in the cytochrome P-450 system (CYP2D6, 1A2, 2C19), administration of propanol HCl extended-release with drugs that are metabolized by, or affect the activity (induction or inhibition) of one or more of these pathways may lead to clinically relevant drug interactions (see DRUG INTERACTIONS).
The Beta-Blocker Heart Attack Trial (BHAT) was a National Heart, Lung and Blood Institute-sponsored multicenter, randomized, double-blind, placebo-controlled trial conducted in 31 US centers (plus 1 in Canada) in 3837 persons without history of severe congestive heart failure or presence of recent heart failure; certain conduction defects; angina since infarction, who had survived the acute phase of myocardial infarction. Propranolol was administered at either 60 or 80 mg tid based on blood levels achieved during an initial trial of 40 mg tid. Therapy with propranolol HCl, begun 5-21 days following infarction, was shown to reduce overall mortality up to 39 months, the longest period of follow-up. This was primarily attributable to a reduction in cardiovascular mortality. The protective effect of propranolol was consistent regardless of age, sex, or site of infarction. Compared with placebo, total mortality was reduced 39% at 12 months and 26% over an average follow-up period of 25 months. The Norwegian Multicenter Trial in which propranolol was administered at 40 mg qid gave overall results which support the findings in the BHAT.
Although the clinical trials used either tid or qid dosing, clinical, pharmacologic, and pharmacokinetic data provide a reasonable basis for concluding that bid dosing with propranolol should be adequate in the treatment of postinfarction patients.
Clinical
In the BHAT, patients on propranolol were prescribed either 180 mg/day (82% of patients) or 240 mg/day (18% of patients). Patients were instructed to take the medication 3 times a day at mealtimes. This dosing schedule would result in an overnight dosing interval of 12-14 hours, which is similar to the dosing interval for a bid regimen. In addition, blood samples were drawn at various times and analyzed for propranolol. When the patients were grouped into tertiles based on the blood levels observed and the mortality in the upper and lower tertiles was compared, there was no evidence that blood levels affected mortality.
Pharmacologic
Studies in normal volunteers have shown that a 90 mg bid regimen maintains beta blockade at, or above, the minimum for 60 mg tid dosing for 24 hours even though differences occurred at 2 time intervals. At 10-12 hours after the first dose of the day, tid dosing gave more beta blockade than bid dosing; at 20-24 hours the trend of the relationship was reversed. These relationships were similar in direction to those observed for plasma propranolol levels. (See Pharmacokinetics.)
Pharmacokinetics
A bioavailability study in normal volunteers showed that the blood levels produced by 180 mg/day given bid are below those provided by the same daily dosage given tid at 10-12 hours after the first dose of the day, but above those of a tid regimen at 20-24 hours. However, the blood levels produced by bid dosing were always equivalent to or above the minimum for tid dosing throughout the 24 hours. In addition, the mean AUC on the fourth day for the bid regimen was about 17% greater than for the tid regimen (1194 vs 1024 ng/ml·h).
In a double-blind, parallel, dose-response study in patients with mild-to-moderate hypertension (n=434), doses of propanol HCl extended-release from 80-640 mg were taken once daily at approximately 10:00 PM. Propanol HCl extended-release 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 propanol HCl extended-release (160, 640 mg) had no additional blood pressure lowering effect when compared with 120 mg. The antihypertensive effects of propanol HCl extended-release were seen in the elderly (≥65 years old) and men and women. There were too few non-caucasian patients to assess the efficacy of propanol HCl extended-release in these patients.
Hypertension
Inderal and Inderal LA are indicated in the management of hypertension. They may be used alone or used in combination with other antihypertensive agents, particularly a thiazide diuretic. Inderal and Inderal LA are not indicated in the management of hypertensive emergencies.
InnoPran XL is indicated in the management of hypertension; it may be used alone or in combination with other antihypertensive agents.
Angina Pectoris Due to Coronary Atherosclerosisa
Inderal and Inderal LA are indicated for the long-term management of patients with angina pectoris.
Cardiac Arrhythmias
Supraventricular Arrhythmias:
Ventricular Tachycardias:
Myocardial Infarction
Inderal is indicated to reduce cardiovascular mortality in patients who have survived the acute phase of myocardial infarction and are clinically stable.
Migraine
Inderal and Inderal LA are indicated for the prophylaxis of common migraine headache. The efficacy of propranolol in the treatment of a migraine attack that has started has not been established, and propranolol is not indicated for such use.
Essential Tremor
Inderal is indicated in the management of familial or hereditary essential tremor. Familial or essential tremor consists of involuntary, rhythmic, oscillatory movements, usually limited to the upper limbs. It is absent at rest but occurs when the limb is held in a fixed posture or position against gravity and during active movement. Propranolol causes a reduction in the tremor amplitude but not in the tremor frequency. Propranolol is not indicated for the treatment of tremor associated with Parkinsonism.
Hypertrophic Subaortic Stenosis
Inderal and Inderal LA are useful in the management of hypertrophic subaortic stenosis, especially for treatment of exertional or other stress-induced angina, palpitations, and syncope. Inderal and Inderal LA also improves exercise performance. The effectiveness of propranolol hydrochloride in this disease appears to be due to a reduction of the elevated outflow pressure gradient, which is exacerbated by beta-receptor stimulation. Clinical improvement may be temporary.
Pheochromocytoma
After primary treatment with an alpha-adrenergic blocking agent has been instituted, propranolol may be useful as adjunctive therapy if the control of tachycardia becomes necessary before of during surgery.
It is hazardous to use propranolol unless alpha-adrenergic blocking drugs are already in use, since this would predispose to serious blood pressure elevation. Blocking only the peripheral dilator (beta) action of epinephrine leaves its constrictor (alpha) action unopposed.
In the event of hemorrhage or shock, there is a disadvantage in having both beta and alpha blockade since the combination prevents the increase in heart rate and peripheral vasoconstriction needed to maintain blood pressure.
With inoperable or metastatic pheochromocytoma, propranolol may be useful as an adjunct to the management of symptoms due to excessive beta-receptor stimulation.
Non-FDA Approved Indications
Propranolol is used without FDA approval for the treatment of symptoms of hyperthyroidism, alcohol withdrawal, anxiety, Parkinsonian tremors, and for the prevention of esophageal variceal hemorrhage in patients with a history of esophageal varices.
Propranolol is contraindicated in (1) cardiogenic shock, (2) sinus bradycardia and greater than first degree block, (3) bronchial asthma, (4) congestive heart failure (see WARNINGS) unless the failure is secondary to a tachyarrhythmia treatable with propranolol, and (5) in patients with known hypersensitivity to propranolol HCl.
Cardiac Failure
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, if necessary, they can be used with close follow-up in patients with a history of failure who are well compensated and are receiving digitalis and diuretics. Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle.
In Patients Without a History of Heart Failure
Continued use of beta blockers can, in some cases, lead to cardiac failure. Therefore, at the first sign or symptom of heart failure, the patient should be digitalized and/or treated with diuretics, and the response observed closely, or propranolol should be discontinued (gradually, if possible).
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Nonallergic Bronchospasm (e.g., Chronic Bronchitis, Emphysema)
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD IN GENERAL NOT RECEIVE BETA BLOCKERS. Propranolol should be administered with caution since it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta receptors.
Major Surgery
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 may augment the risks of general anesthesia and surgical procedures.
Propranolol, like other beta blockers, 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. Difficulty in starting and maintaining the heartbeat has also been reported with beta blockers.
Diabetes and Hypoglycemia
Beta-adrenergic blockage may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemica in labile insulin-dependent diabetes. In these patients, it may be more difficult to adjust the dosage of insulin. Hypoglycemic attacks may be accompanied by a precipitous elevation of blood pressure in patients on propranolol.
Propranolol therapy, particularly in infants and children, diabetic or not, has been associated with hypoglycemia especially during fasting as in preparation for surgery. Hypoglycemia also has been found after this type of drug therapy and prolonged physical exertion and has occurred in renal insufficiency, both during dialysis and sporadically, in patients on propranolol.
Acute increases in blood pressure have occurred after insulin-induced hypoglycemia in patients on propranolol.
Thyrotoxicosis
Beta 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 reverse T3 and decreasing T3.
In Patients With Wolf-Parkinson-White Syndrome
Several cases have been reported in which, after propranolol, the tachycardia was replaced by a severe bradycardia requiring a demand pacemaker. In 1 case this resulted after an initial dose of 5 mg propranolol.
General
Propranolol should be used with caution in patients with impaired hepatic or renal function. Propranolol HCl is not indicated for the treatment of hypertensive emergencies.
Beta-adrenoreceptor blockade can cause reduction of intraocular pressure. Patients should be told that propranolol may interfere with the glaucoma screening test. Withdrawal may lead to a return of increased intraocular pressure.
Clinical Laboratory Tests
Elevated blood urea levels in patients with severe heart disease, elevated serum transaminase, alkaline phosphatase, lactate dehydrogenase.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
In dietary administration studies in which mice and rats were treated with propranolol for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis. In a study in which both male and female rats were exposed to propranolol in their diets at concentrations of up to 0.05%, 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 in bacteria (S. typhimurium strain TA 1538).
Pregnancy Category C
In a series of reproduction and developmental toxicology studies, propranolol was given to rats by gavage or in the diet throughout pregnancy and through lactation. At doses of 150 mg/kg/day (>10 times the maximum recommended human daily dose of propranolol on a body weight basis), but not at doses of 80 mg/kg/day, treatment was associated with embryotoxicity (reduced litter size and increased resorption sites) as well as neonatal toxicity (deaths). Propranolol also was administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (>15 times the maximum recommended daily human dose). No evidence of embryo or neonatal toxicity was noted.
There are no adequate and well-controlled studies in pregnant women. Intertwine growth retardation has been reported in neonates whose mothers received propranolol during pregnancy. Neonates whose mothers are receiving propranolol at parturition have exhibited bradycardia, hypoglycemia and respiratory depression. Adequate facilities for monitoring these infants at birth should be available. Propranolol 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 is administered to a nursing woman.
Pediatric Use
High serum propranolol levels have been noted in patients with Down's syndrome (trisomy 21), suggesting that the bioavailability of propranolol may be increased in patients with this condition.
Evaluation of the effects of propranolol in children, relative to the drug's efficacy and safety, has not been as systematically performed as in adults. Information is available in the medical literature to allow fair estimates, and specific dosing information has been reasonably studied.
Cardiovascular diseases that are common to adults and children are generally as responsive to propranolol intervention in children as they are in adults.
Adverse reactions are also similar, for example, bronchospasm and congestive heart failure related to propranolol therapy have been reported in children and occur through the same mechanisms as previously described in adults.
The normal echocardiogram evolves through a series of changes as the heart matures during growth and development in children. Should echocardiography be used to monitor propranolol therapy in children, the age-related changes in the echocardiogram need to be borne in mind.
Geriatric Use
Clinical studies of propranolol did not include sufficient numbers of subjects aged 65 and over to determine whether thay respond differently from younger subjects. Other reported clinical experience has not identified differences in reponses 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 the decreased hepatic, renal or cardiac function, and concomitant disease or other drug therapy.
Cardiovascular Drugs
ACE Inhibitors
When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the setting of acute myocardial infarction.
Certain ACE inhibitors have been reported to increase bronchial hyperreactivity when administered with propranolol.
The antihypertensive effects of clonidine may be antagonized by beta-blockers. Propanolol 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.
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.
Disopyramide is a Type 1 antiarrhythmic drug with potent negative inotropic and chronotropic effects and has been associated with severe bradycardia, asystole and heart failure when administered with propranolol.
Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with 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 with drugs that slow A-V nodal conduction, e.g., digitalis, lidocaine and calcium channel blockers.
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.
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.
Reserpine
Patients receiving catecholamine-depleting drugs, such as reserpine and propanol, 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. Administration of reserpine with propranolol may also potentiate depression.
Non-Cardiovascular Drugs
Anesthetic Agents
Methoxyflurane and trichloroethylene may depress myocardial contractility when administered with propranolol.
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.
Neuroleptic Drugs
Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol.
Non-Steroidal 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.
Thyroxine
Thyroxine may result in a lower than expected T3 concentration when used concomitantly with propranolol.
Warfarin
Propranolol when administered with warfarin increases the concentration of warfarin. Prothrombin time, therefore, should be monitored.
Most adverse effects have been mild and transient and have rarely required the withdrawal of therapy.
The following adverse events were observed and have been reported with use of formulations of sustained- or immediate-release propranolol:
Adverse events occurring at a rate of ≥3%, excluding those reported more commonly in placebo encountered in the propanol HCl extended-release placebo-controlled hypertension trials and are plausibly related to treatment, are shown in TABLE 1.
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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.
Bradycardia: ADMINISTER ATROPINE (0.25-1.0 mg); IF THERE IS NO RESPONSE TO VAGAL BLOCKADE, ADMINISTER ISOPROTERENOL CAUTIOUSLY.
Cardiac Failure: DIGITALIZATION AND DIURETICS.
Hypotension: VASOPRESSORS, [e.g., NOREPINEPHRINE OR EPINEPHRINE (THERE IS EVIDENCE THAT EPINEPHRINE IS THE DRUG OF CHOICE)].
Bronchospasm: ADMINISTER ISOPROTERENOL AND AMINOPHYLLINE.
Oral
The dosage range for propranolol is different for each indication.
Hypertension
Dosage must be individualized. The usual initial dosage is 40 mg propranolol twice daily, whether used alone or added to a diuretic. Dosage may be increased gradually until adequate blood pressure control is achieved. The usual maintenance dosage is 120-240 mg/day. In some instances a dosage of 640 mg/day may be required. The time needed for full antihypertensive response to a given dosage is variable and may range from a few days to several weeks.
While twice-daily dosing is effective and can maintain a reduction in blood pressure throughout the day, some patients, especially when lower doses are used, may experience a modest rise in blood pressure toward the end of the 12 hour dosing interval. This can be evaluated by measuring blood pressure near the end of the dosing interval to determine whether satisfactory control is being maintained throughout the day. If control is not adequate, a larger dose, or 3 times daily therapy may achieve better control.
Angina Pectoris
Dosage must be individualized. Total daily doses of 80-320 mg, when administered orally, twice a day, 3 times/day, or 4 times/day, have been shown to increase exercise tolerance and to reduce ischemic changes in the ECG. If treatment is to be discontinued, reduce dosage gradually over a period of several weeks. (See WARNINGS.)
Arrhythmias
10-30 mg 3 or 4 times daily, before meals and at bedtime.
Myocardial Infarction
The recommended daily dosage is 180-240 mg/day in divided doses. Although a tid regimen was used in the Beta-Blocker Heart Attack Trial and a qid regimen in the Norwegian Multicenter Trial, there is a reasonable basis for the use of either a tid or bid regimen (see CLINICAL PHARMACOLOGY). The effectiveness and safety of daily dosages greater than 240 mg for prevention of cardiac mortality have not been established. However, higher dosages may be needed to effectively treat coexisting diseases such as angina or hypertension. (See DOSAGE AND ADMINISTRATION.)
Migraine
Dosage must be individualized. The initial oral dose is 80 mg propranolol daily in divided doses. The usual effective dose range is 160-240 mg/day. The dosage may be increased gradually to achieve optimum migraine prophylaxis. If a satisfactory response is not obtained within 4-6 weeks after reaching the maximum dose, propranolol therapy should be discontinued. It may be advisable to withdraw the drug gradually over a period of several weeks.
Essential Tremor
Dosage must be individualized. The initial dosage is 40 mg propranolol twice daily. Optimum reduction of essential tremor is usually achieved with a dose of 120 mg/day. Occasionally, it may be necessary to administer 240-320 mg/day.
Hypertrophic Subaortic Stenosis
20-40 mg 3 or 4 times daily, before meals and at bedtime.
Pheochromocytoma
Preoperatively — 60 mg daily in divided doses for 3 days prior to surgery, concomitantly with an alpha-adrenergic blocking agent.
Management of Inoperable Tumor
30 mg daily in divided doses.
Use in Children
Intravenous administration of propranolol is not recommended in children. Oral dosage for treating hypertension requires individual titration, beginning with a 1.0 mg/kg (body weight)/day dosage regimen (i.e., 0.5 mg/kg bid).
The usual pediatric dosage range is 2-4 mg/kg/day in 2 equally divided doses (i.e., 1.0-2.0 mg/kg bid). Pediatric dosage calculated by weight (recommended) generally produces propranolol plasma levels in a therapeutic range similar to that in adults. On the other hand, pediatric doses calculated on the basis of body surface area (not recommended) usually result in plasma levels above the mean adult therapeutic range. Doses above 16 mg/kg/day should not be used in children. If treatment with propranolol is to be discontinued, a gradually decreasing dose titration over a 7-14 day period is necessary.
Intravenous
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Intravenous administration is reserved for life-threatening arrhythmias or those occurring under anesthesia. The usual dose is from 1-3 mg administered under careful monitoring, (e.g., electrocardiographic, central venous pressure). The rate of administration should not exceed 1 mg (1 ml)/ to diminish the possibility of lowering blood pressure and causing cardiac standstill. Sufficient time should be allowed for the drug to reach the site of action even when a slow circulation is present. If necessary, a second dose may be given after 2 minutes. Thereafter, additional drug should not be given in less than 4 hours. Additional propranolol should not be given when the desired alteration in rate and/or rhythm is achieved.
Transference to oral therapy should be made as soon as possible.
The IV administration of propranolol has not been evaluated adequately in the management of hypertensive emergencies.
Inderal LA Capsules
Inderal LA provides propanalol HCl in a sustained-release capsule for administration once daily. If patients are switched from Inderal tablets to Inderal LA capsules, care should be taken to assure that the desired therapeutic effect is maintained. Inderal LA should not be considered a simple mg-for-mg substitute for Inderal. Inderal LA has different kinetics and produces lower blood levels. Retitration may be necessary, especially to maintain effectiveness at the end of the 24 hour dosing interval.
Hypertension
Dosage must be individualized. The usual initial dosage is 80 mg Inderal LA once daily, whether used alone or added to a diuretic. The dosage may be increased to 120 mg once daily or higher until adequate blood pressure control is achieved. The usual maintenance dosage is 120-160 mg once daily. In some instances a dosage of 640 mg may be required. The time needed for full hypertensive response to a given dosage is variable and may range from a few days to several weeks.
Angina Pectoris
Dosage must be individualized. Starting 80 mg Inderal LA once daily, dosage should be gradually increased at 3-7 day intervals until optimal response is obtained. Although individual patients may repond at any dosage level, the average optimal dosage appears to be 160 mg once daily. In angina pectoris, the value and safety of dosage exceeding 320 mg/day have not been established.
If treatment is to be discontinued, reduce dosage gradually over a period of a few weeks (see WARNINGS).
Migrane
Dosage must be individualized. The initial oral dose is 80 mg Inderal LA once daily. The usual effective dose range is 160-240 mg once daily. The dosage may be increased gradually to achieve optimal migrane prophylaxis. If a satisfactory response is not obtained within 4-6 weeks after reaching the maximal dose, Inderal LA therapy should be discontinued. It may be advisable to withdraw the drug gradually over a period of several weeks.
Hypertrophic Subaortic Stenosis
80-160 mg Inderal LA once daily.
Pediatric Dosage
At this time the data on the use of the drug in this age group are too limited to permit adequate directions for use.
InnoPran XL Capsules
InnoPran XL capsules should be administered once daily at bedtime (approximately 10:00 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 CLINICAL STUDIES). The time needed for full antihypertensive response is variable, but is usually achieved within 2-3 weeks.
Inderal Tablets
Inderal tablets are available containing 10, 20, 40, 60 and 80 mg of propranolol hydrochloride.
10 mg Tablets: Orange, hexagonal-shaped, scored tablets embossed with "I" on one side and imprinted with "INDERAL 10" on the other.
20 mg Tablets: Blue, hexagonal-shaped, scored tablets embossed with "I" on one side and imprinted with "INDERAL 20" on the other.
40 mg Tablets: Green, hexagonal-shaped, scored tablets embossed with "I" on one side and imprinted with "INDERAL 40" on the other.
60 mg Tablets: Pink, hexagonal-shaped, scored tablets embossed with "I" on one side and imprinted with "INDERAL 60" on the other.
80 mg Tablets: Yellow, hexagonal-shaped, scored tablets embossed with "I" on one side and imprinted with "INDERAL 80" on the other.
Storage
Store at controlled room temperature 20-25°C (68-77°F).
Dispense in a well-closed container.
Inderal Injectable
Each 1 ml ampul contains 1 mg of propranolol HCl in water for injection. The pH is adjusted with citric acid.
Storage
Protect from freezing or excessive heat.
Inderal LA (long-acting) Capsules
Inderal LA capsules are available containing 60, 80, 120 and 160 mg of propranolol HCl.
60 mg Capsules: White/light-blue capsules identified by 3 narrow bands, 1 wide band and imprinted with "INDERAL LA 60".
80 mg Capsules: Light-blue capsules identified by 3 narrow bands, 1 wide band and imprinted with "INDERAL LA 80".
120 mg Capsules: Light-blue/dark-blue capsules identified by 3 narrow bands, 1 wide band and imprinted with "INDERAL LA 120".
160 mg Capsules: Dark-blue capsules identified by 3 narrow bands, 1 wide band, and imprinted with "INDERAL LA 160".
Storage
Store at controlled room temperature 20-25°C (68-77°F).
Protect from light, moisure, freezing, and excessive heat.
Dispense in a tight, light-resistant container as defined in the USP.
InnoPran XL (Extended-Release) Capsules
InnoPran XL capsules are available containing 80 mg or 120 mg of propranolol HCl.
80 mg Capsules: Gray/white capsule identified by 2 segmented bands, imprinted with "80", "RD201", and Reliant logo.
120 mg Capsules: Each gray/off-white capsule identified by 3 segmented bands, imprinted with "120", "RD201", and Reliant logo.
Storage
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) in a tightly closed container. The unit dose packaging should be stored in the carton.
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