Inderal

Inderal® (propranolol hydrochloride) is a synthetic beta-adrenergic receptor blocking agent chemically described as 2-Propanol, 1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-, hydrochloride,(±)-. Its molecular and structural formulae are:

Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water and ethanol. Its molecular weight is 295.80.

Inderal (propranolol) is available as 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg tablets for oral administration.

The inactive ingredients contained in Inderal (propranolol) Tablets are: lactose, magnesium stearate, microcrystalline cellulose, and stearic acid. In addition, Inderal (propranolol) 10 mg and 80 mg Tablets contain FD&C Yellow No. 6 and D&C Yellow No. 10; Inderal (propranolol) 20 mg Tablets contain FD&C Blue No. 1; Inderal (propranolol) 40 mg Tablets contain FD&C Blue No. 1, FD&C Yellow No. 6, and D&C Yellow No. 10; Inderal (propranolol) 60 mg Tablets contain D&C Red No. 30.

General

Propranolol is a nonselective beta-adrenergic receptor blocking agent possessing no other autonomic nervous system activity. It specifically competes with beta-adrenergic receptor agonist agents for available receptor sites. When access to beta-receptor sites is blocked by propranolol, the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased proportionately. At dosages greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action, which affects the cardiac action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain.

Mechanism of Action

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

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'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 Inderal (propranolol) is of benefit in exaggerated physiological and essential (familial) tremor.

Pharmacokinetics And Drug Metabolism

Propranolol is highly lipophilic and almost completely absorbed after oral administration. However, it undergoes high first-pass metabolism by the liver and on average, only about 25% of propranolol reaches the systemic circulation. Peak plasma concentrations occur about 1 to 4 hours after an oral dose.

Administration of protein-rich foods increase the bioavailability of propranolol by about 50% with no change in time to peak concentration, plasma binding, half-life, or the amount of unchanged drug in the urine.

Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alphai acid glycoprotein). The binding is enantiomer-selective. The S(-)-enantiomer is preferentially bound to alpha1 glycoprotein and the R(+)-enantiomer preferentially bound to albumin. The volume of distribution of propranolol is approximately 4 liters/kg.

Propranolol crosses the blood-brain barrier and the placenta, and is distributed into breast milk.

Propranolol is extensively metabolized with most metabolites appearing in the urine. Propranolol is metabolized through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation), N-dealkylation followed by further side-chain oxidation, and direct glucuronidation. It has been estimated that the percentage contributions of these routes to total metabolism are 42%, 41% and 17%, respectively, but with considerable variability between individuals. The four major metabolites are propranolol glucuronide, naphthyloxylactic acid and glucuronic acid, and sulfate conjugates of 4-hydroxy propranolol.

In vitro studies have indicated that the aromatic hydroxylation of propranolol is catalyzed mainly by polymorphic CYP2D6. Side-chain oxidation is mediated mainly by CYP1A2 and to some extent by CYP2D6. 4-hydroxy propranolol is a weak inhibitor of CYP2D6.

Propranolol is also a substrate of CYP2C19 and a substrate for the intestinal efflux transporter, p-glycoprotein (p-gp). Studies suggest however that p-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 of 4-hydroxy propranolol was significantly higher and of naphthyloxyactic acid significantly lower in EMs than PMs.

The plasma half-life of propranolol is from 3 to 6 hours.

Propranolol is a racemic mixture of two enantiomers, R(+) and S(-). The S(-)-enantiomer is approximately 100 times as potent as the R(+)-enantiomer in blocking 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. Clearance of the pharmacologically active S(-)-propranolol is lower than R(+)-propranolol after intravenous and oral doses.

Special Populations

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 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).

In a study of 9 healthy women and 12 healthy men, neither the administration of testosterone nor the regular course of the menstrual cycle affected the plasma binding of the propranolol enantiomers. In contrast, there was a 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 confirmed the stimulatory role of this hormone on propranolol metabolism and concluded that the clearance of 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.

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.

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 alpha1 acid glycoprotein.

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.

Studies have reported a delayed absorption rate and a reduced half-life of propranolol in patients with renal failure of varying severity. Despite this shorter plasma half-life, propranolol peak plasma levels were 3-4 times higher and total plasma levels of metabolites were up to 3 times higher in these patients than in subjects with normal renal function.

Chronic renal failure has been associated with a decrease in drug metabolism via downregulation of hepatic cytochrome P450 activity resulting in a lower "first-pass" clearance.

Propranolol is not significantly dialyzable.

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), co-administration with drugs that are metabolized by, or effect the activity (induction or inhibition) of one or more of these pathways may lead to clinically relevant drug interactions (see DRUG INTERACTIONS under PRECAUTIONS).

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 were observed with either ranitidine or lansoprazole.

Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP1A2, such as imipramine, cimetidine, ciprofloxacin, fluvoxamine, isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan.

Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2C19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, tenioposide, and tolbutamide. No interaction was observed with omeprazole.

Blood levels of propranolol may be decreased by co-administration with inducers such as rifampin, ethanol, phenytoin, and phenobarbital. Cigarette smoking also induces hepatic metabolism and has been shown to increase up to 77% the clearance of propranolol, resulting in decreased plasma concentrations.

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-three fold increased blood concentration and greater degrees of clinical beta-blockade.

The metabolism of lidocaine is inhibited by co-administration of propranolol, resulting in a 25% increase in lidocaine concentrations.

The mean Cmax and AUC of propranolol are increased, respectively, by 50% and 30% by co-administration of nisoldipine and by 80% and 47%, by co-administration of nicardipine.

The mean Cmax and AUC of nifedipine are increased by 64% and 79%, respectively, by co-administration of propranolol.

Propranolol does not affect the pharmacokinetics of verapamil and norverapamil. Verapamil does not affect the pharmacokinetics of propranolol.

Administration of zolmitriptan or rizatriptan with propranolol resulted in increased concentrations of zolmitriptan (AUC increased by 56% and Cmax by 37%) or rizatriptan (the AUC and Cmax were increased by 67% and 75%, respectively).

Co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%.

Propranolol can inhibit the metabolism of diazepam, resulting in increased concentrations of diazepam and its metabolites. Diazepam does not alter the pharmacokinetics of propranolol.

The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by co-administration of propranolol.

Co-administration of long-acting propranolol at doses greater than or equal to 160 mg/day resulted in increased thioridazine plasma concentrations ranging from 55% to 369% and increased thioridazine metabolite (mesoridazine) concentrations ranging from 33% to 209%.

Co-administration of chlorpromazine with propranolol resulted in a 70% increase in propranolol plasma level.

Co-administration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased propranolol AUC and Cmax by 46% and 35%, respectively. Co-administration with aluminum hydroxide gel (1200 mg) may result in a decrease in propranolol concentrations.

Co-administration of metoclopramide with the long-acting propranolol did not have a significant effect on propranolol's pharmacokinetics.

Co-administration of cholestyramine or colestipol with propranolol resulted in up to 50% decrease in propranolol concentrations.

Co-administration of propranolol with lovastatin or pravastatin, decreased 18% to 23% the AUC of both, but did not alter their pharmacodynamics. Propranolol did not have an effect on the pharmacokinetics of fluvastatin.

Concomitant administration of propranolol and warfarin has been shown to increase warfarin bioavailability and increase prothrombin time.

Concomitant use of alcohol may increase plasma levels of propranolol.

Pharmacodynamics And Clinical Effects

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 antihypertensive agent. Propranolol contributed to control of diastolic blood pressure, but the magnitude of the effect of propranolol on blood pressure cannot be ascertained.

In a double-blind, placebo-controlled study of 32 patients of both sexes, aged 32 to 69 years, with stable angina, propranolol 100 mg t.i.d. was administered for 4 weeks and shown to be more effective than placebo in reducing the rate of angina episodes and in prolonging total exercise time.

In a report examining the long-term (5-22 months) efficacy of propranolol, 10 patients, aged 27 to 80, with atrial fibrillation and ventricular rate >120 beats per minute despite digitalis, received propranolol up to 30 mg t.i.d. Seven patients (70%) achieved ventricular rate reduction to <100 beats per minute.

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 U.S. centers (plus one in Canada) in 3,837 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 t.i.d. based on blood levels achieved during an initial trial of 40 mg t.i.d. Therapy with Inderal (propranolol) , begun 5 to 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 Inderal (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 q.i.d. gave overall results which support the findings in the BHAT.

Although the clinical trials used either t.i.d. or q.i.d. dosing, clinical, pharmacologic, and pharmacokinetic data provide a reasonable basis for concluding that b.i.d. dosing with propranolol should be adequate in the treatment of postinfarction patients.

In a 34-week, placebo-controlled, 4-period, dose-finding crossover study with a double-blind randomized treatment sequence, 62 patients with migraine received propranolol 20 to 80 mg 3 or 4 times daily. The headache unit index, a composite of the number of days with headache and the associated severity of the headache, was significantly reduced for patients receiving propranolol as compared to those on placebo.

In a 2 week, double-blind, parallel, placebo-controlled study of 9 patients with essential or familial tremor, propranolol, at a dose titrated as needed from 40-80 mg t.i.d. reduced tremor severity compared to placebo.

In an uncontrolled series of 13 patients with New York Heart Association (NYHA) class 2 or 3 symptoms and 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 class for most patients.

In an uncontrolled series of 3 patients with norepinephrine-secreting pheochromocytoma who were pretreated with an alpha adrenergic blocker (prazosin), perioperative use of propranolol at doses of 40-80 mg t.i.d. resulted in symptomatic blood pressure control.

Inderal is a prescription medication used to treat high blood pressure, irregular heart rhythms, angina (chest pain), pheochromocytoma, and certain types of tremor. It is also used to prevent migraine headaches and to improve survival after a heart attack.

Inderal belongs to a group of drugs called beta blockers. It works to decrease blood pressure, heart rate, and the workload of the heart by blocking beta receptors. The exact way it works for migraine prevention and tremor is unknown.

This medication comes in an extended-release capsule and is usually taken once daily. Inderal can be taken with or without food.

Common side effects include nausea, tiredness, and dizziness or lightheadedness. Do not drive or operate heavy machinery until you know how it affects you.

*Brand name Inderal tablets are no longer available. Generic versions are made available by several manufacturers.

• Akrimax Pharmaceuticals, LLC

• Wyeth Pharmaceuticals, Inc.

Avoid drinking alcohol. It may increase your blood levels of propranolol.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

This section provides information on the proper use of a number of products that contain propranolol. It may not be specific to Inderal. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. Your dose may need to be changed several times in order to find out what works best for you.

This medicine should come with a Medication Guide and patient directions. Read and follow these instructions carefully. Ask your doctor if you have any questions.

In addition to the use of this medicine, treatment for your high blood pressure may include weight control and changes in the types of foods you eat, especially foods high in sodium (salt). Your doctor will tell you which of these are most important for you. You should check with your doctor before changing your diet.

Many patients who have high blood pressure will not notice any signs of the problem. In fact, many may feel normal. It is very important that you take your medicine exactly as directed and that you keep your appointments with your doctor even if you feel well.

Remember that this medicine will not cure your high blood pressure, but it does help control it. You must continue to take it as directed if you expect to lower your blood pressure and keep it down. You may have to take high blood pressure medicine for the rest of your life. If high blood pressure is not treated, it can cause serious problems such as heart failure, blood vessel disease, stroke, or kidney disease.

Swallow the long-acting oral capsules whole. Do not chew, crush, or open them.

Propranolol extended-release capsules should be taken at bedtime (10 p.m.). This medicine may be taken with or without food. However, you should take it the same way each time.

Measure the concentrated oral solution, Intensol™ with the dropper that comes with the package. You may mix the concentrated solution with water, juice, soda, applesauce, or pudding to make it easier to swallow, then take the mixture right away.

Measure the oral liquid with the dosing syringe that comes with the package. It should be given directly into the child's mouth, during or right after eating or breastfeeding. It may also be mixed with a small amount of milk or fruit juice and given with a baby's bottle. Do not shake before use.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For acute heart attack:
  • For oral dosage form (solution):
    • Adults—180 to 240 milligrams (mg) per day, given in divided doses.
    • Children—Dose is based on body weight and must be determined by your doctor.
  • For oral dosage form (tablets):
    • Adults—At first, 40 milligrams (mg) three times a day. Your doctor may increase your dose if needed.
    • Children—Use and dose must be determined by your doctor.
• For adrenal gland tumor (pheochromocytoma):
  • For oral dosage form (solution):
    • Adults—60 milligrams (mg) per day, given in divided doses for 3 days before having surgery. In patients who cannot have surgery, the usual dose is 30 mg per day, given in divided doses.
    • Children—Dose is based on body weight and must be determined by your doctor.
  • For oral dosage form (tablets):
    • Adults—60 milligrams (mg) per day, given in divided doses for 3 days before having surgery. In patients who cannot have surgery, the usual dose is 30 mg per day, given in divided doses.
    • Children—Use and dose must be determined by your doctor.
• For chest pain (angina):
  • For oral dosage form (long-acting oral capsules):
    • Adults—At first, 80 milligrams (mg) once a day. Your doctor may increase your dose if needed.
    • Children—Use and dose must be determined by your doctor.
  • For oral dosage form (solution):
    • Adults—80 to 320 milligrams (mg) per day, given in divided doses.
    • Children—Dose is based on body weight and must be determined by your doctor.
  • For oral dosage form (tablets):
    • Adults—80 to 320 milligrams (mg) per day, given in divided doses.
    • Children—Use and dose must be determined by your doctor.
• For high blood pressure (hypertension):
  • For oral dosage form (extended-release capsules):
    • Adults—At first, 80 milligrams (mg) once a day, given at bedtime. Your doctor may increase your dose if needed. However, the dose is usually not more than 120 mg per day.
    • Children—Use and dose must be determined by your doctor.
  • For oral dosage form (long-acting oral capsules):
    • Adults—At first, 80 milligrams (mg) once a day. Your doctor may increase your dose if needed.
    • Children—Use and dose must be determined by your doctor.
  • For oral dosage form (solution):
    • Adults—At first, 40 milligrams (mg) two times a day. Your doctor may increase your dose if needed.
    • Children—Dose is based on body weight and must be determined by your doctor.
  • For oral dosage form (tablets):
    • Adults—At first, 40 milligrams (mg) two times a day. Your doctor may increase your dose if needed.
    • Children—Use and dose must be determined by your doctor.
• For hypertrophic subaortic stenosis (thickened heart muscle):
  • For oral dosage form (long-acting oral capsules):
    • Adults—80 to 160 milligrams (mg) once a day.
    • Children—Use and dose must be determined by your doctor.
  • For oral dosage form (solution):
    • Adults—20 to 40 milligrams (mg) three or four times a day, given before meals and at bedtime.
    • Children—Dose is based on body weight and must be determined by your doctor.
  • For oral dosage form (tablets):
    • Adults—20 to 40 milligrams (mg) three or four times a day, given before meals and at bedtime.
    • Children—Use and dose must be determined by your doctor.
• For irregular heartbeats:
  • For oral dosage form (solution):
    • Adults—10 to 30 milligrams (mg) three or four times a day, given before meals and at bedtime.
    • Children—Dose is based on body weight and must be determined by your doctor.
  • For oral dosage form (tablets):
    • Adults—10 to 30 milligrams (mg) three or four times a day, given before meals and at bedtime.
    • Children—Use and dose must be determined by your doctor.
• For migraine headaches:
  • For oral dosage form (long-acting oral capsules):
    • Adults—At first, 80 milligrams (mg) once a day. Your doctor may increase your dose if needed.
    • Children—Use and dose must be determined by your doctor.
  • For oral dosage form (solution):
    • Adults—At first, 80 milligrams (mg) per day, given in divided doses. Your doctor may increase your dose if needed.
    • Children—Dose is based on body weight and must be determined by your doctor.
  • For oral dosage form (tablets):
    • Adults—At first, 80 milligrams (mg) per day, given in divided doses. Your doctor may increase your dose if needed.
    • Children—Use and dose must be determined by your doctor.
• For proliferating infantile hemangioma:
  • For oral dosage form (solution):
    • Children 5 weeks to 5 months of age—Dose is based on your child's body weight and must be determined by the doctor. The starting dose is usually 0.6 milligram (mg) per kilogram (kg) of your child's body weight two times a day, taken at least 9 hours apart. Give the dose during or immediately after a feeding. Do not administer the dose if the infant is vomiting or not eating. After 1 week, the doctor will increase the dose to 1.1 mg per kg of body weight two times a day. After 2 weeks, the doctor will increase the dose to 1.7 mg per kg of body weight two times a day, taken for 6 months.
    • Children under 5 weeks of age—Use is not recommended.
• For tremors:
  • For oral dosage form (solution):
    • Adults—At first, 40 milligrams (mg) two times a day. Your doctor may increase your dose if needed.
    • Children—Dose is based on body weight and must be determined by your doctor.
  • For oral dosage form (tablets):
    • Adults—At first, 40 milligrams (mg) two times a day. Your doctor may increase your dose if needed.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Throw away any unused Hemangeol™ after 2 months.

Hypertension

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 antihypertensive agent. Propranolol contributed to control of diastolic blood pressure, but the magnitude of the effect of propranolol on blood pressure cannot be ascertained.

Angina Pectoris

In a double-blind, placebo-controlled study of 32 patients of both sexes, aged 32 to 69 years, with stable angina, propranolol 100 mg t.i.d. was administered for 4 weeks and shown to be more effective than placebo in reducing the rate of angina episodes and in prolonging total exercise time.

Atrial Fibrillation

In a report examining the long-term (5-22 months) efficacy of propranolol, 10 patients, aged 27 to 80, with atrial fibrillation and ventricular rate >120 beats per minute despite digitalis, received propranolol up to 30 mg t.i.d. Seven patients (70%) achieved ventricular rate reduction to <100 beats per minute.

Myocardial Infarction

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 U.S. centers (plus one in Canada) in 3,837 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 t.i.d. based on blood levels achieved during an initial trial of 40 mg t.i.d. Therapy with Inderal, begun 5 to 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 Inderal 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 q.i.d. gave overall results which support the findings in the BHAT.

Although the clinical trials used either t.i.d. or q.i.d. dosing, clinical, pharmacologic, and pharmacokinetic data provide a reasonable basis for concluding that b.i.d. dosing with propranolol should be adequate in the treatment of postinfarction patients.

Migraine

In a 34-week, placebo-controlled, 4-period, dose-finding crossover study with a double-blind randomized treatment sequence, 62 patients with migraine received propranolol 20 to 80 mg 3 or 4 times daily. The headache unit index, a composite of the number of days with headache and the associated severity of the headache, was significantly reduced for patients receiving propranolol as compared to those on placebo.

Essential Tremor

In a 2 week, double-blind, parallel, placebo-controlled study of 9 patients with essential or familial tremor, propranolol, at a dose titrated as needed from 40-80 mg t.i.d. reduced tremor severity compared to placebo.

Hypertrophic Subaortic Stenosis

In an uncontrolled series of 13 patients with New York Heart Association (NYHA) class 2 or 3 symptoms and 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 class for most patients.

Pheochromocytoma

In an uncontrolled series of 3 patients with norepinephrine-secreting pheochromocytoma who were pretreated with an alpha adrenergic blocker (prazosin), perioperative use of propranolol at doses of 40-80 mg t.i.d. resulted in symptomatic blood pressure control.

General

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

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

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

Clinical Laboratory Tests

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

Drug Interactions

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

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 Inderal 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.

Co-administration 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. Inderal 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.

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: 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. Inderal 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 Inderal 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 Inderal 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.

You should not use Inderal if you have asthma, very slow heart beats, or a serious heart condition such as "sick sinus syndrome" or "AV block" (unless you have a pacemaker).

Avoid drinking alcohol. It may increase your blood levels of Inderal.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Get emergency medical help if you have any signs of an allergic reaction to Inderal: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• slow or uneven heartbeats;

• a light-headed feeling, like you might pass out;

• wheezing or trouble breathing;

• shortness of breath (even with mild exertion), swelling, rapid weight gain;

• sudden weakness, vision problems, or loss of coordination;

• cold feeling in your hands and feet;

• depression, confusion, hallucinations;

• liver problems - nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

• low blood sugar - headache, hunger, weakness, sweating, confusion, irritability, dizziness, fast heart rate, or feeling jittery;

• low blood sugar in a baby - pale skin, blue or purple skin, sweating, fussiness, crying, not wanting to eat, feeling cold, drowsiness, weak or shallow breathing (breathing may stop for short periods), seizure (convulsions), or loss of consciousness; or

• severe skin reaction - fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common Inderal side effects may include:

• nausea, vomiting, diarrhea, constipation, stomach cramps;

• decreased sex drive, impotence, or difficulty having an orgasm;

• sleep problems (insomnia); or

• tired feeling.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with Inderal, especially:

• a blood thinner - warfarin, Coumadin, Jantoven;

• an antidepressant - amitriptyline, clomipramine, desipramine, imipramine, and others;

• drugs to treat high blood pressure or a prostate disorder - doxazosin, prazosin, terazosin;

• heart or blood pressure medicine - amiodarone, diltiazem, propafenone, quinidine, verapamil, and others;

• NSAIDs (nonsteroidal anti-inflammatory drugs) - aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others; or

• steroid medicine-prednisone and others.

This list is not complete. Other drugs may interact with propranolol, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Applies to propranolol: intravenous solution, oral capsule extended release, oral concentrate, oral liquid, oral solution, oral tablet

Cardiovascular

Use of a nonselective beta-blocker like propranolol (the active ingredient contained in Inderal) may at least blunt cardiac output in some patients, especially those with preexisting left ventricular systolic dysfunction and during exertion. Data have shown that cardiac conditioning can delay or attenuate this side effect of propranolol.

Abrupt cessation of propranolol therapy may result in hypertension, myocardial infarction, and angina pectoris in some patients.

Paradoxical hypertension may occur in patients with pheochromocytoma, unless alpha-adrenergic blockade is already instituted.

At least two cases of electrical alternans associated with propranolol are reported from pediatric cases. In one case, electrical alternans was clearly not rate-related (since it occurred during propranolol therapy at a slower rate than the patient's "native" ventricular tachycardia) and was associated with echocardiographically-demonstrated mechanical alternans.[Ref]

Common (1% to 10%): Hypotension, cold extremities, Raynaud's phenomenon
Uncommon (0.1% to 1%): Heart failure, precipitation of heart block
Rare (less than 0.1%): Exacerbation of claudication, postural hypotension (which may be associated with syncope)
Frequency not reported: Bradycardia, congestive heart failure[Ref]

Nervous system

Rare cases of paresthesias and myasthenia gravis have been associated with propranolol (the active ingredient contained in Inderal) [Ref]

Common (1% to 10%): Fatigue and/or lassitude (often transient), sleep disturbances, nightmares, sleep disorder, agitation, somnolence, irritability
Rare (less than 0.1%): Dizziness, paresthesia (especially of the hands)
Very rare (less than 0.01%): Seizure (linked to hypoglycemia)
Frequency not reported: Reduction or loss of libido, lightheadedness, mental depression (manifested by insomnia), weakness, catatonia, hallucinations, an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium[Ref]

Renal

There are reports of patients who experienced reversible renal insufficiency with no decline in systemic blood pressure, but these patients had preexisting renal disease. This may be important in patients with preexisting renal insufficiency. New or worsened renal dysfunction has been reported in patients with underlying renal disease and no decline in systemic blood pressure.[Ref]

Uncommon (0.1% to 1%): Renal insufficiency (related to lowering of systemic blood pressure)[Ref]

Respiratory

Rare (less than 0.1%): Dyspnea, worsening of reactive airways diseases, bronchospasm in patients with bronchial asthma or a history of asthmatic complaints (sometimes fatal)[Ref]

Limited data have shown a mean fall in maximal midexpiratory flow rate (MMFR) during propranolol therapy relative to placebo in nine of ten patients whose lung function was assessed. Interestingly, the fall was not related to smoking or to atopic status, suggestive of resting beta-adrenergic bronchodilator activity in nonasthmatic subjects.

Non-selective beta-blockers, such as propranolol, are used with caution in patients with asthma and chronic obstructive pulmonary disease due to inhibition of bronchodilation.[Ref]

Endocrine

Beta-blockers, such as propranolol (the active ingredient contained in Inderal) are used with caution in patients with diabetes due to masking of the catecholamine response to hypoglycemia. Propranolol may also mask the signs of hyperthyroidism by the same mechanism.

Propranolol has been associated with significant increases in serum triglycerides, fasting blood glucose, and LDL and VLDL cholesterol, and significant decreases in HDL cholesterol.[Ref]

Very rare (less than 0.01%): Hypoglycemia (particularly in neonates, infants, children, elderly patients, patients on hemodialysis, patients on concomitant antidiabetic therapy, patients with prolonged fasting and patients with chronic liver disease), hypertriglyceridemia[Ref]

Gastrointestinal

Uncommon (0.1% to 1%): Anorexia, nausea, vomiting, diarrhea, abdominal pain, flatulence, decreased appetite[Ref]

Psychiatric

One study of 34 hypertensive patients who were taking propranolol (the active ingredient contained in Inderal) found the incidence of depressive symptoms in this population to be 50% to 74% (depending on the criteria used). Propranolol-induced depression may be more likely in patients with a personal or family history of depression. Of the 34 patients, 12 had a history of depression and 8 had a history of substance abuse, alcoholism, or a family history of psychiatric disorders. Since none of the 12 patients with a history of depression were clinically depressed at the start of propranolol therapy and were comparable by age, diagnosis, and propranolol dosage to the other 22 patients, a comparison was made. Patients with a personal or family history of depression had significantly higher scores on depression scales than those without such histories.

A 72-year-old retired college professor with no history of affective disorders developed progressive sadness, tearfulness, hopelessness, decreased energy, social withdrawal, anhedonia, insomnia, and decreased memory and concentration within two weeks after beginning propranolol monotherapy for hypertension. The signs and symptoms of depression resolved upon substitution with a thiazide diuretic. Interestingly, the patient later was treated for recurrent depression while not receiving propranolol.

Rare cases of psychoses associated with propranolol have been reported.[Ref]

Rare (less than 0.1%): Depression (dose dependent), hallucinations, psychoses, mood changes, confusion, memory loss[Ref]

Hypersensitivity

Rare (less than 0.1%): Anaphylaxis, contact dermatitis[Ref]

Hematologic

Uncommon (0.1% to 1%): Reduction of platelet adhesiveness, thrombocytopenic purpura, nonthrombocytopenic purpura, agranulocytosis, eosinophilia[Ref]

Dermatologic

Rare (less than 0.1%): Psoriatic flares
Frequency not reported: Stevens - Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, urticaria, purpura, alopecia, skin rashes, SLE-like reactions[Ref]

Immunologic

Postmarketing reports: Enhanced immune system[Ref]

Propranolol can enhance the immune system by causing an increase in the number of circulating T cells, increased interleukin-2 (IL-2) secretion, increased expression of IL-2 receptors, and increased lymphocyte production in response to the T cell mitogen Con A. Interestingly, NK (natural killer) cell activity may be decreased during propranolol therapy, although the number of circulating NK cells may remain unchanged. These results are consistent with previous data showing decreased immunologic function during periods of elevated sympathetic activity, such as congestive heart failure, uremia, or life-threatening events.[Ref]

Genitourinary

Frequency not reported: Male impotence, Peyronie's disease[Ref]

Metabolic

Frequency not reported: Weight gain[Ref]

The mechanism by which propranolol induces weight gain is unknown. Some investigators have reported a 4% to 9% reduction in total energy expenditure and a 25% reduction in thermogenic response to food during beta-blocker treatment.[Ref]

Musculoskeletal

Very rare (less than 0.01%): Myasthenia gravis like syndrome or exacerbation of myasthenia gravis
Frequency not reported: Myopathy, myotonia[Ref]

Hepatic

Very rare (less than 0.01%): Elevated liver function tests[Ref]

Ocular

Rare (less than 0.1%): Dry eyes, visual disturbances[Ref]

Some side effects of Inderal may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.