PROPRANOLOL HYDROCHLORIDE- propranolol hydrochloride tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
PROPRANOLOL HYDROCHLORIDE (UNII: F8A3652H1V) (PROPRANOLOL - UNII:9Y8NXQ24VQ)
Available from:
Aphena Pharma Solutions - Tennessee, LLC
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Propranolol hydrochloride tablets are indicated in the management of hypertension. It may be used alone or used in combination with other antihypertensive agents, particularly a thiazide diuretic. Propranolol hydrochloride tablets are not indicated in the management of hypertensive emergencies. Propranolol hydrochloride tablets are indicated to decrease angina frequency and increase exercise tolerance in patients with angina pectoris. Propranolol hydrochloride tablets are indicated to control ventricular rate in patients with atrial fibrillation and a rapid ventricular response. Propranolol hydrochloride tablets are indicated to reduce cardiovascular mortality in patients who have survived the acute phase of myocardial infarction and are clinically stable. Propranolol hydrochloride tablets 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. Prop
Product summary:
Propranolol Hydrochloride Tablets, USP are available containing 10 mg, 20 mg, 40 mg, 60 mg or 80 mg of propranolol hydrochloride, USP. The 10 mg tablets are orange, round, scored tablets debossed with MYLAN above the score and 182 below the score on one side of the tablet and 10 on the other side. They are available as follows: NDC 51407-235-01 bottles of 100 tablets NDC 51407-235-10 bottles of 1000 tablets The 20 mg tablets are blue, round, scored tablets debossed with MYLAN above the score and 183 below the score on one side of the tablet and 20 on the other side. They are available as follows: NDC 51407-236-01 bottles of 100 tablets NDC 51407-236-10 bottles of 1000 tablets The 40 mg tablets are green, round, scored tablets debossed with MYLAN above the score and 184 below the score on one side of the tablet and 40 on the other side. They are available as follows: NDC 51407-237-01 bottles of 100 tablets NDC 51407-237-10 bottles of 1000 tablets The 60 mg tablets are light purple, round, scored tablets debossed with MYLAN above the score and PR60 below the score on one side of the tablet and 60 on the other side. They are available as follows: NDC 51407-239-01 bottles of 100 tablets The 80 mg tablets are yellow, round, scored tablets debossed with MYLAN above the score and 185 below the score on one side of the tablet and 80 on the other side. They are available as follows: NDC 51407-238-01 bottles of 100 tablets NDC 51407-238-05 bottles of 500 tablets Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Marketed/Packaged by: GSMS, Inc. Camarillo, CA 93012 USA Revised: 11/2017 PRAN:R28
Authorization status:
Abbreviated New Drug Application
Authorization number:
71610-339-60

PROPRANOLOL HYDROCHLORIDE- propranolol hydrochloride tablet

Aphena Pharma Solutions - Tennessee, LLC

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Propranolol Hydrochloride

DESCRIPTION

Propranolol hydrochloride is a synthetic beta-adrenergic receptor blocking agent chemically described

as (±)-1-(Isopropylamino)-3-(1-naphthyloxy)-2-propanolol hydrochloride. Its molecular and structural

formulae are:

HCI

Propranolol hydrochloride, USP is a stable, white to off-white, crystalline powder which is readily

soluble in water and ethanol. Its molecular weight is 295.80.

Propranolol hydrochloride tablets, USP are available as 10 mg, 20 mg, 40 mg, 60 mg, or 80 mg tablets

for oral administration.

The inactive ingredients contained in propranolol hydrochloride tablets are: colloidal silicon dioxide,

croscarmellose sodium, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn)

and sodium lauryl sulfate.

The 10 mg tablets also contain FD&C Yellow No. 6 Aluminum Lake, the 20 mg tablets also contain

FD&C Blue No. 1 Aluminum Lake, the 40 mg tablets also contain FD&C Blue No. 1 Aluminum Lake,

FD&C Yellow No. 6 Aluminum Lake and D&C Yellow No. 10 Aluminum Lake, the 60 mg tablets also

contain FD&C Blue No. 1 Aluminum Lake and FD&C Red No. 40 Aluminum Lake and the 80 mg tablets

also contain FD&C Yellow No. 6 Aluminum Lake and D&C Yellow No. 10 Aluminum Lake.

CLINICAL PHARMACOLOGY

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

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 propranolol hydrochloride tablets are of benefit in exaggerated physiological and

essential (familial) tremor.

Pharmacokinetics and Drug Metabolism

Absorption

Propranolol is highly lipophilic and almost completely absorbed after oral administration. However, it

undergoes high first-pass metabolism by the liver and on average, only about 25% of propranolol

reaches the systemic circulation. Peak plasma concentrations occur about 1 to 4 hours after an oral

dose.

Administration of protein-rich foods increase the bioavailability of propranolol by about 50% with no

change in time to peak concentration, plasma binding, half-life, or the amount of unchanged drug in the

urine.

Distribution

Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha

acid

glycoprotein). The binding is enantiomer-selective. The S(-)-enantiomer is preferentially bound to alpha

glycoprotein and the R(+)-enantiomer preferentially bound to albumin. The volume of distribution of

propranolol is approximately 4 liters/kg.

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

Metabolism and Elimination

Propranolol is extensively metabolized with most metabolites appearing in the urine. Propranolol is

metabolized through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation), N-

dealkylation followed by further side-chain oxidation, and direct glucuronidation. It has been estimated

that the percentage contributions of these routes to total metabolism are 42%, 41% and 17%,

respectively, but with considerable variability between individuals. The four major metabolites are

propranolol glucuronide, naphthyloxylactic acid and glucuronic acid, and sulfate conjugates of 4-

hydroxy propranolol.

In vitro studies have indicated that the aromatic hydroxylation of propranolol is catalyzed mainly by

polymorphic CYP2D6. Side-chain oxidation is mediated mainly by CYP1A2 and to some extent by

CYP2D6. 4-hydroxy propranolol is a weak inhibitor of CYP2D6.

Propranolol is also a substrate of CYP2C19 and a substrate for the intestinal efflux transporter, p-

glycoprotein (p-gp). Studies suggest however that p-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 naphthyloxylactic acid significantly lower in EMs

than PMs.

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

Enantiomers

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

Geriatric

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 naphthyloxylactic

acid (NLA-side chain oxidation). No correlation was found between age and the partial metabolic

clearance to propranolol glucuronide (PPLG-conjugation).

Gender

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.

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.

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

acid

glycoprotein.

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 (C

) 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.

Hepatic Insufficiency

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 PRECAUTIONS: Drug Interactions).

Substrates or Inhibitors of CYP2D6

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.

Substrates or Inhibitors of CYP1A2

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.

Substrates or Inhibitors of CYP2C19

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.

Inducers of Hepatic Drug Metabolism

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.

Cardiovascular Drugs

Antiarrhythmics

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.

Calcium Channel Blockers

The mean C

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 C

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.

Non-Cardiovascular Drugs

Migraine Drugs

Administration of zolmitriptan or rizatriptan with propranolol resulted in increased concentrations of

zolmitriptan (AUC increased by 56% and C

by 37%) or rizatriptan (the AUC and C

were

increased by 67% and 75%, respectively).

Theophylline

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

52%.

Benzodiazepines

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.

Neuroleptic Drugs

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.

Anti-Ulcer Drugs

Co-administration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased

propranolol AUC and C

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.

Lipid Lowering Drugs

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.

Warfarin

Concomitant administration of propranolol and warfarin has been shown to increase warfarin

bioavailability and increase prothrombin time.

Alcohol

Concomitant use of alcohol may increase plasma levels of propranolol.

Pharmacodynamics and Clinical Effects

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 propranolol hydrochloride

tablets, 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 propranolol hydrochloride tablets 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.

INDICATIONS AND USAGE

Hypertens ion

Propranolol hydrochloride tablets are indicated in the management of hypertension. It may be used alone

or used in combination with other antihypertensive agents, particularly a thiazide diuretic. Propranolol

hydrochloride tablets are not indicated in the management of hypertensive emergencies.

Angina Pectoris Due to Coronary Atherosclerosis

Propranolol hydrochloride tablets are indicated to decrease angina frequency and increase exercise

tolerance in patients with angina pectoris.

Atrial Fibrillation

Propranolol hydrochloride tablets are indicated to control ventricular rate in patients with atrial

fibrillation and a rapid ventricular response.

Myocardial Infarction

Propranolol hydrochloride tablets are indicated to reduce cardiovascular mortality in patients who have

survived the acute phase of myocardial infarction and are clinically stable.

Migraine

Propranolol hydrochloride tablets 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

Propranolol hydrochloride tablets are 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 hydrochloride tablets cause a

reduction in the tremor amplitude, but not in the tremor frequency. Propranolol hydrochloride tablets are

not indicated for the treatment of tremor associated with Parkinsonism.

Hypertrophic Subaortic Stenosis

Propranolol hydrochloride tablets improve NYHA functional class in symptomatic patients with

hypertrophic subaortic stenosis.

Pheochromocytoma

Propranolol hydrochloride tablets are indicated as an adjunct to alpha-adrenergic blockade to control

blood pressure and reduce symptoms of catecholamine-secreting tumors.

CONTRAINDICATIONS

Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than first

degree block; 3) bronchial asthma; and 4) in patients with known hypersensitivity to propranolol

hydrochloride.

WARNINGS

Angina Pectoris

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 the

management of angina pectoris. Since coronary artery disease may be unrecognized, it may be

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

Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated with

the administration of propranolol (see ADVERSE REACTIONS).

Cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative

dermatitis, erythema multiforme, and urticaria, have been reported with use of propranolol (see

ADVERSE REACTIONS).

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, some have been shown to

be highly beneficial when used with close follow-up in patients with a history of failure who are well

compensated and are receiving additional therapies, including diuretics as needed. 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.

Nonallergic Bronchospasm (e.g., Chronic Bronchitis, Emphysema)

In general, patients with bronchospastic lung disease should not receive beta blockers. Propranolol

should be administered with caution in this setting since it may provoke a bronchial asthmatic attack by

blocking bronchodilation 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 the impaired ability of the heart to respond to reflex adrenergic stimuli may augment

the risks of general anesthesia and surgical procedures.

Diabetes and Hypoglycemia

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.

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 taking propranolol after prolonged physical exertion and in patients with renal

insufficiency.

Thyrotoxicos is

Beta-adrenergic 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 T

and reverse T

and decreasing T

Wolff-Parkinson-White Syndrome

Beta-adrenergic blockade in patients with Wolf-Parkinson-White Syndrome and tachycardia has been

associated with severe bradycardia requiring treatment with a pacemaker. In one case, this result was

reported after an initial dose of 5 mg propranolol.

Pheochromocytoma

Blocking only the peripheral dilator (beta) action of epinephrine with propranolol 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.

PRECAUTIONS

General

Propranolol should be used with caution in patients with impaired hepatic or renal function. Propranolol

hydrochloride tablets are not indicated for the treatment of hypertensive emergencies.

Beta-adrenergic receptor blockade can cause reduction of intraocular pressure. Patients should be told

that propranolol hydrochloride tablets 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 propranolol hydrochloride tablets are 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 CLINICAL PHARMACOLOGY: Drug Interactions).

Cardiovascular Drugs

Antiarrhythmics

Propafenone has negative inotropic and beta-blocking properties that can be additive to those of

propranolol.

Quinidine increases the concentration of propranolol and produces greater degrees of clinical beta-

blockade and may cause postural hypotension.

Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to

those seen with β-blockers such as propranolol.

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

reported following coadministration with propranolol.

Caution should be exercised when administering propranolol hydrochloride tablets with drugs that slow

A-V nodal conduction, e.g., digitalis, lidocaine and calcium channel blockers.

Digitalis Glycosides

Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate.

Concomitant use can increase the risk of bradycardia.

Calcium Channel Blockers

Caution should be exercised when patients receiving a beta blocker are administered a calcium-channel-

blocking drug with negative inotropic and/or chronotropic effects. Both agents may depress myocardial

contractility or atrioventricular conduction.

There have been reports of significant bradycardia, heart failure, and cardiovascular collapse with

concurrent use of verapamil and beta-blockers.

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. Propranolol

hydrochloride tablets should be administered cautiously to patients withdrawing from clonidine.

Alpha Blockers

Prazosin has been associated with prolongation of first dose hypotension in the presence of beta-

blockers.

Postural hypotension has been reported in patients taking both beta-blockers and terazosin or doxazosin.

Reserpine

Patients receiving catecholamine-depleting drugs, such as reserpine, should be closely observed for

excessive reduction of resting sympathetic nervous activity, which may result in hypotension, marked

bradycardia, vertigo, syncopal attacks, or orthostatic hypotension.

Inotropic Agents

Patients on long-term therapy with propranolol may experience uncontrolled hypertension if

administered epinephrine as a consequence of unopposed alpha-receptor stimulation. Epinephrine is

therefore not indicated in the treatment of propranolol overdose (see OVERDOSAGE).

Isoproterenol and Dobutamine

Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by

administration of such agents, e.g., dobutamine or isoproterenol. Also, propranolol may reduce

sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial

ischemia.

Non-Cardiovascular Drugs

Nonsteroidal Anti-Inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDS) have been reported to blunt the antihypertensive effect

of beta-adrenoreceptor blocking agents.

Administration of indomethacin with propranolol may reduce the efficacy of propranolol in reducing

blood pressure and heart rate.

Antidepressants

The hypotensive effects of MAO inhibitors or tricyclic antidepressants may be exacerbated when

administered with beta-blockers by interfering with the beta blocking activity of propranolol.

Anesthetic Agents

Methoxyflurane and trichloroethylene may depress myocardial contractility when administered with

propranolol.

Warfarin

Propranolol when administered with warfarin increases the concentration of warfarin. Prothrombin time,

therefore, should be monitored.

Neuroleptic Drugs

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

haloperidol.

Thyroxine

Thyroxine may result in a lower than expected T

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. Propranolol hydrochloride tablets should be used during

pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Propranolol is excreted in human milk. Caution should be exercised when propranolol hydrochloride

tablets are administered to a nursing woman.

Pediatric Use

Safety and effectiveness of propranolol in pediatric patients have not been established.

Bronchospasm and congestive heart failure have been reported coincident with the administration of

propranolol therapy in pediatric patients.

Geriatric Use

Clinical studies of propranolol hydrochloride tablets did not include sufficient numbers of subjects

aged 65 and over to determine whether they respond differently from younger subjects. Other reported

clinical experience has not identified differences in responses between the elderly and younger

patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low

end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac

function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

The following adverse events were observed and have been reported in patients using propranolol.

Cardiovascular: Bradycardia; congestive heart failure; intensification of AV block; hypotension;

paresthesia of hands; thrombocytopenic purpura; arterial insufficiency, usually of the Raynaud type.

Central Nervous System: Light-headedness, mental depression manifested by insomnia, lassitude,

weakness, fatigue; catatonia; visual disturbances; hallucinations; vivid dreams; an acute reversible

syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability,

slightly clouded sensorium, and decreased performance on neuropsychometrics. For immediate-release

formulations, fatigue, lethargy, and vivid dreams appear dose-related.

Gastrointestinal: Nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, constipation,

mesenteric arterial thrombosis, ischemic colitis.

Allergic: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, pharyngitis and

agranulocytosis; erythematous rash, fever combined with aching and sore throat; laryngospasm, and

respiratory distress.

Respiratory: Bronchospasm.

Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.

Autoimmune: Systemic lupus erythematosus (SLE).

Skin and Mucous Membranes: Stevens-Johnson Syndrome, toxic epidermal necrolysis, dry eyes,

exfoliative dermatitis, erythema multiforme, urticaria, alopecia, SLE-like reactions, and psoriasiform

rashes. Oculomucocutaneous syndrome involving the skin, serous membranes and conjunctivae reported

for a beta blocker (practolol) have not been associated with propranolol.

Genitourinary: Male impotence; Peyronie’s disease.

OVERDOSAGE

Propranolol is not significantly dialyzable. In the event of overdosage or exaggerated response, the

following measures should be employed:

General

If ingestion is or may have been recent, evacuate gastric contents, taking care to prevent pulmonary

aspiration.

Supportive Therapy

Hypotension and bradycardia have been reported following propranolol overdose and should be treated

appropriately. Glucagon can exert potent inotropic and chronotropic effects and may be particularly

useful for the treatment of hypotension or depressed myocardial function after a propranolol overdose.

Glucagon should be administered as 50-150 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, however, may provoke uncontrolled hypertension. Bradycardia can be

treated with atropine or isoproterenol. Serious bradycardia may require temporary cardiac pacing.

The electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output balance

must be monitored. Isoproterenol and aminophylline may be used for bronchospasm.

DOSAGE AND ADMINISTRATION

General

Because of the variable bioavailability of propranolol, the dose should be individualized based on

response.

Hypertens ion

The usual initial dosage is 40 mg propranolol hydrochloride tablets 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 mg to 240 mg per day. In some instances a dosage of

640 mg a 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

Total daily doses of 80 mg to 320 mg propranolol hydrochloride tablets, when administered orally,

twice a day, three times a day, or four times a 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).

Atrial Fibrillation

The recommended dose is 10 mg to 30 mg propranolol hydrochloride tablets three or four times daily

before meals and at bedtime.

Myocardial Infarction

In the Beta-Blocker Heart Attack Trial (BHAT), the initial dose was 40 mg t.i.d., with titration after 1

month to 60 mg to 80 mg t.i.d. as tolerated. The recommended daily dosage is 180 mg to 240 mg

propranolol hydrochloride tablets per day in divided doses. Although a t.i.d. regimen was used in the

BHAT and a q.i.d. regimen in the Norwegian Multicenter Trial, there is a reasonable basis for the use

of either a t.i.d. or b.i.d. regimen (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Clinical

Effects). 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 above).

Migraine

The initial dose is 80 mg propranolol hydrochloride tablets daily in divided doses. The usual effective

dose range is 160 mg to 240 mg per day. The dosage may be increased gradually to achieve optimum

migraine prophylaxis. If a satisfactory response is not obtained within four to six weeks after reaching

the maximum dose, propranolol hydrochloride tablets therapy should be discontinued. It may be

advisable to withdraw the drug gradually over a period of several weeks.

Essential Tremor

The initial dosage is 40 mg propranolol hydrochloride tablets twice daily. Optimum reduction of

essential tremor is usually achieved with a dose of 120 mg per day. Occasionally, it may be necessary

to administer 240 mg to 320 mg per day.

Hypertrophic Subaortic Stenosis

The usual dosage is 20 mg to 40 mg propranolol hydrochloride tablets three or four times daily before

meals and at bedtime.

Pheochromocytoma

The usual dosage is 60 mg propranolol hydrochloride tablets daily in divided doses for three days

prior to surgery as adjunctive therapy to alpha-adrenergic blockade. For the management of inoperable

tumors, the usual dosage is 30 mg daily in divided doses as adjunctive therapy to alpha-adrenergic

blockade.

HOW SUPPLIED

Propranolol Hydrochloride Tablets, USP are available containing 10 mg, 20 mg, 40 mg, 60 mg or 80

mg of propranolol hydrochloride, USP.

The 10 mg tablets are orange, round, scored tablets debossed with MYLAN above the score and 182

below the score on one side of the tablet and 10 on the other side. They are available as follows:

NDC 51407-235-01

bottles of 100 tablets

NDC 51407-235-10

bottles of 1000 tablets

The 20 mg tablets are blue, round, scored tablets debossed with MYLAN above the score and 183

below the score on one side of the tablet and 20 on the other side. They are available as follows:

NDC 51407-236-01

bottles of 100 tablets

NDC 51407-236-10

bottles of 1000 tablets

The 40 mg tablets are green, round, scored tablets debossed with MYLAN above the score and 184

below the score on one side of the tablet and 40 on the other side. They are available as follows:

NDC 51407-237-01

bottles of 100 tablets

NDC 51407-237-10

bottles of 1000 tablets

The 60 mg tablets are light purple, round, scored tablets debossed with MYLAN above the score and

PR60 below the score on one side of the tablet and 60 on the other side. They are available as follows:

NDC 51407-239-01

bottles of 100 tablets

The 80 mg tablets are yellow, round, scored tablets debossed with MYLAN above the score and 185

below the score on one side of the tablet and 80 on the other side. They are available as follows:

NDC 51407-238-01

bottles of 100 tablets

NDC 51407-238-05

bottles of 500 tablets

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Marketed/Packaged by:

GSMS, Inc.

Camarillo, CA 93012 USA

Revised: 11/2017

PRAN:R28

Repackaging Information

Please reference the How Supplied section listed above for a description of individual tablets. This

drug product has been received by Aphena Pharma - TN in a manufacturer or distributor packaged

configuration and repackaged in full compliance with all applicable cGMP regulations. The package

configurations available from Aphena are listed below:

Count

20 mg

71610-339-60

Store between 20°-25°C (68°-77°F). See USP Controlled Room Temperature. Dispense in a tight light-

resistant container as defined by USP. Keep this and all drugs out of the reach of children.

Repackaged by:

Cookeville, TN 38506

20190828JH

PRINCIPAL DISPLAY PANEL - 20 mg

NDC 71610-339 - Propranolol HCl, USP 20 mg Tablets - Rx Only

PROPRANOLOL HYDROCHLORIDE

propranolol hydrochloride tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:716 10 -339 (NDC:5140 7-236 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

PRO PRANO LO L HYDRO CHLO RIDE (UNII: F8 A36 52H1V) (PROPRANOLOL -

UNII:9 Y8 NXQ24VQ)

PROPRANOLOL

HYDROCHLORIDE

20 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

STARCH, CO RN (UNII: O8 232NY3SJ)

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

FD&C BLUE NO . 1 (UNII: H3R47K3TBD)

Product Characteristics

Color

blue

S core

2 pieces

S hap e

ROUND

S iz e

Flavor

Imprint Code

MYLAN;18 3;20

Contains

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:716 10 -339 -

9 0 in 1 BOTTLE, PLASTIC; Type 0 : No t a Co mbinatio n

Pro duc t

0 8 /20 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 70 213

11/19 /19 8 5

Labeler -

Aphena Pharma Solutions - T ennessee, LLC (128385585)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Aphena Pharma Solutions - Tennessee, LLC

Aphena Pharma So lutio ns - Tennessee, LLC

128 38 558 5

REPACK(716 10 -339 )

Revised: 8/2019

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