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Inderal® LA
Inderal LA
(propranolol hydrochloride)
Long-Acting Capsules
(propranolol hydrochloride)
levels are fairly constant for about twelve (12) hours, then decline exponentially. The apparent plasma half-life is Long-Acting Capsules
about 10 hours.
Enantiomers
DESCRIPTION
Propranolol is a racemic mixture of two enantiomers, R(+) and S(–). The S(–)-enantiomer is approximately 100 Inderal® (propranolol hydrochloride) is a synthetic beta-adrenergic receptor-blocking agent chemically described times as potent as the R(+)-enantiomer in blocking beta-adrenergic receptors. In normal subjects receiving oral as 2-Propanol, 1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-, hydrochloride,(±)-. Its molecular and structural doses of racemic propranolol, S(–)-enantiomer concentrations exceeded those of the R(+)-enantiomer by 40-90% as a result of stereoselective hepatic metabolism. Clearance of the pharmacologically active S(–)-propranolol is lower than R(+)-propranolol after intravenous and oral doses.
Special Population
The pharmacokinetics of Inderal LA 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 were prolonged in the elderly compared with the young (11 hours vs. 5 hours).
Clearance of propranolol is reduced with aging due to decline in oxidation capacity (ring oxidation and side chain oxidation). Conjugation capacity remains unchanged. In a study of 32 patients age 30 to 84 years given a single 20-mg dose of propranolol, an inverse correlation was found between age and the partial metabolic clearances to Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water and ethanol. Its 4-hydroxypropranolol (40HP ring oxidation) and to naphthoxylactic acid (NLA-side chain oxidation). No correlation was found between age and the partial metabolic clearance to propranolol glucuronide (PPLG conjugation).
Inderal LA is formulated to provide a sustained release of propranolol hydrochloride. Inderal LA is available as 60 mg, 80 mg, 120 mg, and 160 mg capsules for oral administration.
The inactive ingredients contained in Inderal LA capsules are: cellulose, ethylcellulose, gelatin capsules, In a study of 9 healthy women and 12 healthy men, neither the administration of testosterone nor the regular hypromellose, and titanium dioxide. In addition, Inderal LA 60 mg, 80 mg, and 120 mg capsules contain course of the menstrual cycle affected the plasma binding of the propranolol enantiomers. In contrast, there was a D&C Red No. 28 and FD&C Blue No. 1; Inderal LA 160 mg capsules contain FD&C Blue No. 1.
significant, although non-enantioselective diminution of the binding of propranolol after treatment with ethinyl estradiol. These findings are inconsistent with another study, in which administration of testosterone cypionate These capsules comply with USP Dissolution Test 1.
confirmed the stimulatory role of this hormone on propranolol metabolism and concluded that the clearance of CLINICAL PHARMACOLOGY
propranolol in men is dependent on circulating concentrations of testosterone. In women, none of the metabolic clearances for propranolol showed any significant association with either estradiol or testosterone.
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 A study conducted in 12 Caucasian and 13 African-American male subjects taking propranolol, showed that at sites. When access to beta-receptor sites is blocked by propranolol, the chronotropic, inotropic, and vasodilator steady state, the clearance of R(+)- and S(–)-propranolol were about 76% and 53% higher in African-Americans 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.
Chinese subjects had a greater proportion (18% to 45% higher) of unbound propranolol in plasma compared to Caucasians, which was associated with a lower plasma concentration of alpha-1-acid glycoprotein.
Inderal LA should not be considered a simple mg-for-mg substitute for conventional propranolol and the blood levels achieved do not match (are lower than) those of two to four times daily dosing with the same dose (see DOSAGE AND ADMINISTRATION). When changing to Inderal LA from conventional propranolol, a possible need for
The pharmacokinetics of Inderal LA have not been investigated in patients with renal insufficiency.
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 In a study conducted in 5 patients with chronic renal failure, 6 patients on regular dialysis, and 5 healthy subjects, levels and clinical effect, Inderal LA has been therapeutically equivalent to the same mg dose of conventional Inderal who received a single oral dose of 40 mg of propranolol, the peak plasma concentrations (Cmax) of propranolol in as assessed by 24-hour effects on blood pressure and on 24-hour exercise responses of heart rate, systolic the chronic renal failure group were 2 to 3-fold higher (161±41 ng/mL) than those observed in the dialysis patients pressure, and rate pressure product.
(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.
Mechanism of Action
Studies have reported a delayed absorption rate and a reduced half-life of propranolol in patients with renal failure The mechanism of the antihypertensive effect of propranolol has not been established. Among the factors that may of varying severity. Despite this shorter plasma half-life, propranolol peak plasma levels were 3-4 times higher and be involved in contributing to the antihypertensive action include: (1) decreased cardiac output, (2) inhibition of total plasma levels of metabolites were up to 3 times higher in these patients than in subjects with normal renal 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.
Chronic renal failure has been associated with a decrease in drug metabolism via down regulation of hepatic cytochrome P450 activity resulting in a lower “first-pass” clearance.
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 Propranolol is not significantly dialyzable.
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 The pharmacokinetics of Inderal LA have not been investigated in patients with hepatic insufficiency.
advantageous and is manifested during exercise by delayed onset of pain and increased work capacity.
Propranolol is extensively metabolized by the liver. In a study conducted in 6 patients with cirrhosis and 7 healthy Propranolol exerts its antiarrhythmic effects in concentrations associated with beta-adrenergic blockade, and this subjects receiving 160 mg of a long-acting preparation of propranolol once a day for 7 days, the steady-state appears to be its principal antiarrhythmic mechanism of action. In dosages greater than required for beta blockade, propranolol concentration in patients with cirrhosis was increased 2.5-fold in comparison to controls. In the propranolol also exerts a quinidine-like or anesthetic-like membrane action which affects the cardiac action patients with cirrhosis, the half-life obtained after a single intravenous dose of 10 mg propranolol increased to potential. The significance of the membrane action in the treatment of arrhythmias is uncertain.
7.2 hours compared to 2.9 hours in control (see PRECAUTIONS).
The mechanism of the anti-migraine effect of propranolol has not been established. Beta-adrenergic receptors have Drug Interactions
been demonstrated in the pial vessels of the brain.
All drug interaction studies were conducted with propranolol. There are no data on drug interactions with PHARMACOKINETICS AND DRUG METABOLISM
Absorption
Interactions with Substrates, Inhibitors or Inducers of Cytochrome P-450 Enzymes 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 Because propranolol’s metabolism involves multiple pathways in the Cytochrome P-450 system (CYP2D6, 1A2, circulation. Inderal LA Capsules (60, 80, 120, and 160 mg) release propranolol HCl at a controlled and predictable 2C19), co-administration with drugs that are metabolized by, or affect the activity (induction or inhibition) of one or rate. Peak blood levels following dosing with Inderal LA occur at about 6 hours.
more of these pathways may lead to clinically relevant drug interactions (see Drug Interactions under PRECAUTIONS).
The effect of food on Inderal LA bioavailability has not been investigated.
Distribution
Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2D6, such as amiodarone, cimetidine, delavudin, fluoxetine, paroxetine, quinidine, and ritonavir. No interactions Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha-1-acid glycoprotein).
were observed with either ranitidine or lansoprazole.
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 Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of Propranolol crosses the blood-brain barrier and the placenta, and is distributed into breast milk.
CYP1A2, such as imipramine, cimetidine, ciprofloxacin, fluvoxamine, isoniazid, ritonavir, theophylline, zileuton, Metabolism and Elimination
Propranolol is extensively metabolized with most metabolites appearing in the urine. Propranolol is metabolized Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation), N-dealkylation followed by further CYP2C19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, tenioposide, and tolbutamide. No interaction 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.
Blood levels of propranolol may be decreased by co-administration with inducers such as rifampin, ethanol, In-vitro studies have indicated that the aromatic hydroxylation of propranolol is catalyzed mainly by polymorphic phenytoin, and phenobarbital. Cigarette smoking also induces hepatic metabolism and has been shown to increase CYP2D6. Side-chain oxidation is mediated mainly by CYP1A2 and to some extent by CYP2D6. 4-hydroxy up to 77% the clearance of propranolol, resulting in decreased plasma concentrations.
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-gp is not dose-limiting for intestinal absorption of propranolol in the usual The AUC of propafenone is increased by more than 200% by co-administration of propranolol.
The metabolism of propranolol is reduced by co-administration of quinidine, leading to a two to three fold increased In healthy subjects, no difference was observed between CYP2D6 extensive metabolizers (EMs) and poor blood concentration and greater degrees of clinical beta-blockade.
metabolizers (PMs) with respect to oral clearance or elimination half-life. Partial clearance of 4-hydroxy propranolol was significantly higher and naphthyloxyactic acid was significantly lower in EMs than PMs.
The metabolism of lidocaine is inhibited by co-administration of propranolol, resulting in a 25% increase in When measured at steady state over a 24-hour period the areas under the propranolol plasma concentration-time curve (AUCs) for the Inderal LA capsules are approximately 60% to 65% of the AUCs for a comparable divided daily dose of Inderal Tablets. The lower AUCs for the Inderal LA capsules are due to greater hepatic metabolism of propranolol, resulting from the slower rate of absorption of propranolol. Over a twenty-four (24) hour period, blood Inderal® LA
Inderal® LA
(propranolol hydrochloride)
(propranolol hydrochloride)
Long-Acting Capsules
Long-Acting Capsules
CONTRAINDICATIONS
The mean Cmax and AUC of propranolol are increased respectively, by 50% and 30% by co-administration of Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than first-degree block; nisoldipine and by 80% and 47%, by co-administration of nicardipine.
3) bronchial asthma; and 4) in patients with known hypersensitivity to propranolol hydrochloride.
The mean Cmax and AUC of nifedipine are increased by 64% and 79%, respectively, by co-administration of WARNINGS
Angina Pectoris
Propranolol does not affect the pharmacokinetics of verapamil and norverapamil. Verapamil does not affect the There have been reports of exacerbation of angina and, in some cases, myocardial infarction, following abrupt
discontinuance of propranolol therapy. Therefore, when discontinuance of propranolol is planned, the dosage
should be gradually reduced over at least a few weeks, and the patient should be cautioned against interruption
or cessation of therapy without the physician’s advice. If propranolol therapy is interrupted and exacerbation of
angina occurs, it usually is advisable to reinstitute propranolol therapy and take other measures appropriate for
Administration of zolmitriptan or rizatriptan with propranolol resulted in increased concentrations of zolmitriptan the management of unstable angina pectoris. Since coronary artery disease may be unrecognized, it may be
(AUC increased by 56% and Cmax by 37%) or rizatriptan (the AUC and Cmax were increased by 67% and 75%, prudent to follow the above advice in patients considered at risk of having occult atherosclerotic heart disease
who are given propranolol for other indications.
Hypersensitivity and Skin Reactions
Co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%.
Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated with the administration of propranolol (see ADVERSE REACTIONS).
Propranolol can inhibit the metabolism of diazepam, resulting in increased concentrations of diazepam and its Cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative dermatitis, metabolites. Diazepam does not alter the pharmacokinetics of propranolol.
erythema multiforme, and urticaria, have been reported with use of propranolol (see ADVERSE REACTIONS).
The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by co-administration 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 Co-administration of long-acting propranolol at doses greater than or equal to 160 mg/day resulted in increased avoided in overt congestive heart failure, some have been shown to be highly beneficial when used with close thioridazine plasma concentrations ranging from 55% to 369% and increased thioridazine metabolite follow-up in patients with a history of failure who are well compensated and are receiving diuretics as needed. (mesoridazine) concentrations ranging from 33% to 209%.
Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle.
Co-administration of chlorpromazine with propranolol resulted in a 70% increase in propranolol plasma level.
In Patients without a History of Heart Failure, continued use of beta-blockers can, in some cases, lead to cardiac
Anti-Ulcer DrugsCo-administration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased propranolol AUC and Nonallergic Bronchospasm (e.g., Chronic Bronchitis, Emphysema)
In general, patients with bronchospastic lung disease should not receive beta-blockers. Propranolol should be max by 46% and 35%, respectively. Co-administration with aluminum hydroxide gel (1200 mg) may result in a decrease in propranolol concentrations.
administered with caution in this setting since it may provoke a bronchial asthmatic attack by blocking bronchodilation Co-administration of metoclopramide with the long-acting propranolol did not have a significant effect on produced by endogenous and exogenous catecholamine stimulation of beta-receptors.
Major Surgery
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however Co-administration of cholestyramine or colestipol with propranolol resulted in up to 50% decrease in propranolol the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia Co-administration of propranolol with lovastatin or pravastatin, decreased 18% to 23% the AUC of both, but did not Diabetes and Hypoglycemia
alter their pharmacodynamics. Propranolol did not have an effect on the pharmacokinetics of fluvastatin.
Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and 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.
Concomitant administration of propranolol and warfarin has been shown to increase warfarin bioavailability and Propranolol therapy, particularly when given to infants and children, diabetic or not, has been associated with hypoglycemia especially during fasting as in preparation for surgery. Hypoglycemia has been reported in patients PHARMACODYNAMICS AND CLINICAL EFFECTS
taking propranolol after prolonged physical exertion and in patients with renal insufficiency.
Hypertension
Thyrotoxicosis
In a retrospective, uncontrolled study, 107 patients with diastolic blood pressure 110 to 150 mmHg received propranolol 120 mg t.i.d. for at least 6 months, in addition to diuretics and potassium, but with no other hypertensive Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism. Therefore, abrupt withdrawal of agent. Propranolol contributed to control of diastolic blood pressure, but the magnitude of the effect of propranolol may be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm.
propranolol on blood pressure cannot be ascertained.
Propranolol may change thyroid-function tests, increasing T4 and reverse T3, and decreasing T3.
Four double-blind, randomized, crossover studies were conducted in a total of 74 patients with mild or moderately Wolff-Parkinson-White Syndrome
severe hypertension treated with Inderal LA 160 mg once daily or propranolol 160 mg given either once daily or in Beta-adrenergic blockade in patients with Wolff-Parkinson-White syndrome and tachycardia has been associated two 80 mg doses. Three of these studies were conducted over a 4-week treatment period. One study was assessed with severe bradycardia requiring treatment with a pacemaker. In one case, this result was reported after an initial after a 24-hour period. Inderal LA was as effective as propranolol in controlling hypertension (pulse rate, systolic and diastolic blood pressure) in each of these trials.
PRECAUTIONS
Angina Pectoris
In a double-blind, placebo-controlled study of 32 patients of both sexes, aged 32 to 69 years, with stable angina, Propranolol should be used with caution in patients with impaired hepatic or renal function. Inderal LA is not propranolol 100 mg t.i.d. was administered for 4 weeks and shown to be more effective than placebo in reducing indicated for the treatment of hypertensive emergencies.
the rate of angina episodes and in prolonging total exercise time.
Beta-adrenergic receptor blockade can cause reduction of intraocular pressure. Patients should be told that Inderal LA Twelve male patients with moderately severe angina pectoris were studied in a double-blind, crossover study.
may interfere with the glaucoma screening test. Withdrawal may lead to a return of increased intraocular pressure.
Patients were randomized to either Inderal LA 160 mg daily or conventional propranolol 40 mg four times a day for While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may 2 weeks. Nitroglycerine tablets were allowed during the study. Blood pressure, heart rate and ECG’s were recorded be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be during serial exercise treadmill testing. Inderal LA was as effective as conventional propranolol for exercise heart unresponsive to the usual doses of epinephrine used to treat allergic reaction.
rate, systolic and diastolic blood pressure, duration of anginal pain and ST-segment depression before or after exercise, exercise duration, angina attack rate and nitroglycerine consumption.
Clinical Laboratory Tests
In another double-blind, randomized, crossover trial, the effectiveness of propranolol LA 160 mg daily and In patients with hypertension, use of propranolol has been associated with elevated levels of serum potassium, conventional propranolol 40 mg four times a day were evaluated in 13 patients with angina. ECG’s were recorded serum transaminases, and alkaline phosphatase. In severe heart failure, the use of propranolol has been associated while patients exercised until angina developed. Inderal LA was as effective as conventional propranolol for amount with increases in Blood Urea Nitrogen.
of exercise performed, ST-segment depression, number of anginal attacks, amount of nitroglycerine consumed, Drug Interactions
systolic and diastolic blood pressures and heart rate at rest and after exercise.
Caution should be exercised when Inderal LA is administered with drugs that have an affect on CYP2D6, 1A2, or Migraine
2C19 metabolic pathways. Co-administration of such drugs with propranolol may lead to clinically relevant drug In a 34-week, placebo-controlled, 4-period, dose-finding crossover study with a double-blind randomized treatment interactions and changes on its efficacy and/or toxicity (see Drug Interactions in PHARMACOKINETICS AND DRUG
sequence, 62 patients with migraine received propranolol 20 to 80 mg 3 or 4 times daily. The headache unit index, METABOLISM).
a composite of the number of days with headache and the associated severity of the headache, was significantly Alcohol when used concomitantly with propranolol, may increase plasma levels of propranolol.
reduced for patients receiving propranolol as compared to those on placebo.
Cardiovascular Drugs
Hypertrophic Subaortic Stenosis
In an uncontrolled series of 13 patients with New York Heart Association (NYHA) class 2 or 3 symptoms and Propafenone has negative inotropic and beta-blocking properties that can be additive to those of propranolol.
hypertrophic subaortic stenosis diagnosed at cardiac catheterization, oral propranolol 40-80 mg t.i.d. was administered and patients were followed for up to 17 months. Propranolol was associated with improved NYHA 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 INDICATIONS AND USAGE
with ß-blockers such as propranolol.
Hypertension
Inderal LA is indicated in the management of hypertension. It may be used alone or used in combination with
The clearance of lidocaine is reduced with administration of propranolol. Lidocaine toxicity has been reported other antihypertensive agents, particularly a thiazide diuretic. Inderal LA is not indicated in the management of following co-administration with propranolol.
Caution should be exercised when administering Inderal LA with drugs that slow A-V nodal conduction, e.g., lidocaine and calcium channel blockers.
Angina Pectoris Due to Coronary Atherosclerosis
Inderal LA is indicated to decrease angina frequency and increase exercise tolerance in patients with angina pectoris.
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant Migraine
use can increase the risk of bradycardia.
Inderal LA is 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 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 Hypertrophic Subaortic Stenosis
Inderal LA improves NYHA functional class in symptomatic patients with hypertrophic subaortic stenosis.
Inderal® LA
Inderal® LA
(propranolol hydrochloride)
(propranolol hydrochloride)
Long-Acting Capsules
Long-Acting Capsules
There have been reports of significant bradycardia, heart failure, and cardiovascular collapse with concurrent use of Gastrointestinal: Nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, constipation, mesenteric
arterial thrombosis, ischemic colitis.
Co-administration of propranolol and diltiazem in patients with cardiac disease has been associated with bradycardia, Allergic: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions; pharyngitis and agranulocytosis;
hypotension, high degree heart block, and heart failure.
erythematous rash; fever combined with aching and sore throat; laryngospasm; respiratory distress.
Respiratory: Bronchospasm.
When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the setting of acute Hematologic: Agranulocytosis, nonthrombocytopenic purpura, and thrombocytopenic purpura.
Autoimmune: Systemic lupus erythematosus (SLE).
The antihypertensive effects of clonidine may be antagonized by beta-blockers. Inderal LA should be administered Skin and mucous membranes: Stevens-Johnson Syndrome, toxic epidermal necrolysis, dry eyes, exfoliative
cautiously to patients withdrawing from clonidine.
dermatitis, erythema multiforme, urticaria, alopecia, SLE-like reactions, and psoriasisiform rashes. Oculomucocutaneous syndrome involving the skin, serous membranes, and conjunctivae reported for Prazosin has been associated with prolongation of first dose hypotension in the presence of beta-blockers.
a beta-blocker (practolol) have not been associated with propranolol.
Postural hypotension has been reported in patients taking both beta-blockers and terazosin or doxazosin.
Genitourinary: Male impotence; Peyronie’s disease.
OVERDOSAGE
Patients receiving catecholamine-depleting drugs, such as reserpine should be closely observed for excessive Propranolol is not significantly dialyzable. In the event of overdosage or exaggerated response, the following reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension.
General: If ingestion is or may have been recent, evacuate gastric contents, taking care to prevent pulmonary
Patients on long-term therapy with propranolol may experience uncontrolled hypertension if administered Supportive Therapy: Hypotension and bradycardia have been reported following propranolol overdose and should
epinephrine as a consequence of unopposed alpha-receptor stimulation. Epinephrine is therefore not indicated be treated appropriately. Glucagon can exert potent inotropic and chronotropic effects and may be particularly in the treatment of propranolol overdose (see OVERDOSAGE).
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, Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of however, may provoke uncontrolled hypertension. Bradycardia can be treated with atropine or isoproterenol.
such agents, e.g., dobutamine or isoproterenol. Also, propranolol may reduce sensitivity to dobutamine stress Serious bradycardia may require temporary cardiac pacing.
echocardiography in patients undergoing evaluation for myocardial ischemia.
The electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output balance must be Non-Cardiovascular Drugs
monitored. Isoproterenol and aminophylline may be used for bronchospasm.
DOSAGE AND ADMINISTRATION
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to blunt the antihypertensive effect of beta-adrenoreceptor blocking agents.
Inderal® LA provides propranolol hydrochloride in a sustained-release capsule for administration once daily. If Administration of indomethacin with propranolol may reduce the efficacy of propranolol in reducing blood pressure 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.
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.
Hypertension
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 Methoxyflurane and trichloroethylene may depress myocardial contractility when administered with propranolol.
dosage is 120 to 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.
Propranolol when administered with warfarin increases the concentration of warfarin. Prothrombin time, therefore, Angina Pectoris
Starting with 80 mg Inderal LA once daily, dosage should be gradually increased at three- to seven-day intervals until optimal response is obtained. Although individual patients may respond at any dosage level, the average Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol.
optimal dosage appears to be 160 mg once daily. In angina pectoris, the value and safety of dosage exceeding 320 mg per day have not been established.
Thyroxine may result in a lower than expected T If treatment is to be discontinued, reduce dosage gradually over a period of a few weeks (see “WARNINGS”).
3 concentration when used concomitantly with propranolol.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Migraine
In dietary administration studies in which mice and rats were treated with propranolol hydrochloride for up to The initial oral dose is 80 mg Inderal LA once daily. The usual effective dose range is 160 to 240 mg once daily. 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis. On a body The dosage may be increased gradually to achieve optimal migraine prophylaxis. If a satisfactory response is not surface area basis, this dose in the mouse and rat is, respectively, about equal to and about twice the maximum obtained within four to six weeks after reaching the maximal dose, Inderal LA therapy should be discontinued. It recommended human oral daily dose (MRHD) of 640 mg propranolol hydrochloride. In a study in which both male may be advisable to withdraw the drug gradually over a period of several weeks depending on the patient’s age, and female rats were exposed to propranolol hydrochloride in their diets at concentrations of up to 0.05% (about comorbidity, and dose of Inderal LA.
50 mg/kg body weight and less than the MRHD), from 60 days prior to mating and throughout pregnancy and Hypertrophic Subaortic Stenosis
lactation for two generations, there were no effects on fertility. Based on differing results from Ames Tests performed The usual dosage is 80 to 160 mg Inderal LA once daily.
by different laboratories, there is equivocal evidence for a genotoxic effect of propranolol in bacteria (S. typhimurium HOW SUPPLIED
Pregnancy: Pregnancy Category C
Inderal® LA Capsules (propranolol hydrochloride) In a series of reproductive and developmental toxicology studies, propranolol was given to rats by gavage or in the Each white/light-blue capsule, identified by 3 narrow bands, 1 wide band, and “INDERAL LA 60,” contains 60 mg of diet throughout pregnancy and lactation. At doses of 150 mg/kg/day, but not at doses of 80 mg/kg/day (equivalent propranolol hydrochloride in bottles of 100 (NDC 24090-470-88).
to the MRHD on a body surface area basis), treatment was associated with embryotoxicity (reduced litter size and Each light-blue capsule, identified by 3 narrow bands, 1 wide band, and “INDERAL LA 80,” contains 80 mg of increased resorption rates) as well as neonatal toxicity (deaths). Propranolol hydrochloride also was administered propranolol hydrochloride in bottles of 100 (NDC 24090-471-88).
(in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (about 5 times the Each light-blue/dark-blue capsule, identified by 3 narrow bands, 1 wide band, and “INDERAL LA 120,” contains maximum recommended human oral daily dose). No evidence of embryo or neonatal toxicity was noted.
120 mg of propranolol hydrochloride in bottles of 100 (NDC 24090-473-88).
There are no adequate and well-controlled studies in pregnant women. Intrauterine growth retardation, small Each dark-blue capsule, identified by 3 narrow bands, 1 wide band, and “INDERAL LA 160,” contains 160 mg of placentas, and congenital abnormalities have been reported in neonates whose mothers received propranolol during propranolol hydrochloride in bottles of 100 (NDC 24090-479-88).
pregnancy. Neonates whose mothers are receiving propranolol at parturition have exhibited bradycardia, hypoglycemia and/or respiratory depression. Adequate facilities for monitoring such infants at birth should be available. Inderal Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled
LA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Room Temperature]
Nursing Mothers
Protect from light, moisture, freezing, and excessive heat.
Propranolol is excreted in human milk. Caution should be exercised when Inderal LA is administered to a Dispense in a tight, light-resistant container as defined in the USP.
nursing woman.
Pediatric Use
This product’s label may have been updated. For current package insert and further product information, Safety and effectiveness of propranolol in pediatric patients have not been established.
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Bronchospasm and congestive heart failure have been reported coincident with the administration of propranolol therapy in pediatric patients.
Geriatric Use
Clinical studies of Inderal LA 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 Manufactured for Akrimax Pharmaceuticals, LLC cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of the decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
By Wyeth Pharmaceuticals, Inc., a subsidiary of Pfizer, Inc. 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

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