Propranolol hydrochloride extended-release capsules
`
`Rx only
`
`
`DESCRIPTION
`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:
`
`C16H21NO2 · HCl
`
`
`
`Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water
`and ethanol. Its molecular weight is 295.80.
`
`Propranolol hydrochloride extended-release capsules are formulated to provide a sustained
`release of propranolol hydrochloride. Propranolol hydrochloride extended-release capsules are
`available as 60 mg, 80 mg, 120 mg, and 160 mg capsules for oral administration.
`
`The inactive ingredients contained in propranolol hydrochloride extended-release capsules are:
`cellulose, ethylcellulose, gelatin capsules, hypromellose, and titanium dioxide. In addition,
`propranolol hydrochloride extended-release capsules 60 mg, 80 mg, and 120 mg capsules contain
`D&C Red No. 28 and FD&C Blue No. 1; propranolol hydrochloride extended-release capsules
`160 mg capsules contain FD&C Blue No. 1.
`
`These capsules comply with USP Dissolution Test 1.
`
`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-
`stimulating 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.
`
`Propranolol hydrochloride extended-release capsules should not be considered a simple mg-for­
`mg substitute for conventional propranolol and the blood levels achieved do not match (are lower
`than) those of two to four times daily dosing with the same dose (see DOSAGE AND
`ADMINISTRATION). When changing to propranolol hydrochloride extended-release capsules
`
`
`Reference ID: 2919382
`
`1
`
`

`

`from conventional propranolol, a possible need for retitration upwards should be considered,
`especially to maintain effectiveness at the end of the dosing interval. In most clinical settings,
`however, such as hypertension or angina where there is little correlation between plasma levels
`and clinical effect, propranolol hydrochloride extended-release capsules have been
`therapeutically equivalent to the same mg dose of conventional propranolol hydrochloride
`extended-release capsules as assessed by 24-hour effects on blood pressure and on 24-hour
`exercise responses of heart rate, systolic pressure, and rate pressure product.
`
`Mechanism of Action
`The mechanism of the antihypertensive effect of propranolol has not been established. Among
`the factors that may be involved in contributing to the antihypertensive action 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 anti-migraine effect of propranolol has not been established.
`Beta-adrenergic receptors have been demonstrated in the pial vessels of the brain.
`
`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. Propranolol hydrochloride extended-release
`capsules (60, 80, 120, and 160 mg) release propranolol HCl at a controlled and predictable rate.
`Peak blood levels following dosing with propranolol hydrochloride extended-release capsules
`occur at about 6 hours.
`
`The effect of food on propranolol hydrochloride extended-release capsules bioavailability has
`not been investigated.
`
`
`Reference ID: 2919382
`
`2
`
`

`

`Distribution
`Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and
`alpha-1-acid glycoprotein). The binding is enantiomer-selective. The S(–)-enantiomer is
`preferentially bound to alpha-1-glycoprotein and the R(+)-enantiomer preferentially bound to
`albumin. The volume of distribution of propranolol is approximately 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 naphthyloxyactic acid was
`significantly lower in EMs than PMs.
`
`When measured at steady state over a 24-hour period the areas under the propranolol plasma
`
`concentration-time curve (AUCs) for the propranolol hydrochloride extended-release capsules
`are approximately 60% to 65% of the AUCs for a comparable divided daily dose of propranolol
`hydrochloride extended-release capsules. The lower AUCs for the propranolol hydrochloride
`extended-release capsules are due to greater hepatic metabolism of propranolol, resulting from
`
`the slower rate of absorption of propranolol. Over a twenty-four (24) hour period, blood levels
`are fairly constant for about twelve (12) hours, then decline exponentially. The apparent plasma
`
`half-life is about 10 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.
`
`
`Reference ID: 2919382
`
`3
`
`

`

`Special Population
`Geriatric
`
`The pharmacokinetics of propranolol hydrochloride extended-release capsules have not been
`
`investigated in patients over 65 years of age.
`
`
`In a study of 12 elderly (62-79 years old) and 12 young (25-33 years old) healthy subjects, the
`
`clearance of S-enantiomer of propranolol was decreased in the elderly. Additionally, the half-life
`
`of both the R- and S-propranolol were prolonged in the elderly compared with the young
`
`(11 hours vs. 5 hours).
`
`
`Clearance of propranolol is reduced with aging due to decline in oxidation capacity (ring
`
`oxidation and side chain oxidation). Conjugation capacity remains unchanged. In a study of 32
`
`patients age 30 to 84 years given a single 20-mg dose of propranolol, an inverse correlation was
`
`
`found between age and the partial metabolic clearances to 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).
`
`
`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-1-acid glycoprotein.
`
`
`Renal Insufficiency
`
`The pharmacokinetics of propranolol hydrochloride extended-release capsules have not been
`
`investigated in patients with renal insufficiency.
`
`
`In a study conducted in 5 patients with chronic renal failure, 6 patients on regular dialysis, and 5
`
`healthy subjects, who received a single oral dose of 40 mg of propranolol, the peak plasma
`
`
`concentrations (Cmax) of propranolol in the chronic renal failure group were 2 to 3-fold higher
`
`(161±41 ng/mL) than those observed in the dialysis patients (47±9 ng/mL) and in the healthy
`
`subjects (26±1 ng/mL). Propranolol plasma clearance was also reduced in the patients with
`
`chronic renal failure.
`
`
`
`Reference ID: 2919382
`
`4
`
`

`

`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 down
`regulation of hepatic cytochrome P450 activity resulting in a lower “first-pass” clearance.
`
`Propranolol is not significantly dialyzable.
`
`Hepatic Insufficiency
`The pharmacokinetics of propranolol hydrochloride extended-release capsules have not been
`investigated in patients with hepatic insufficiency.
`
`Propranolol is extensively metabolized by the liver. In a study conducted in 6 patients with
`cirrhosis and 7 healthy subjects receiving 160 mg of a long-acting preparation of propranolol
`once a day for 7 days, the steady-state propranolol concentration in patients with cirrhosis was
`increased 2.5-fold in comparison to controls. In the patients with cirrhosis, the half-life obtained
`after a single intravenous dose of 10 mg propranolol increased to 7.2 hours compared to
`2.9 hours in control (see PRECAUTIONS).
`
`Drug Interactions
`All drug interaction studies were conducted with propranolol. There are no data on drug
`interactions with propranolol hydrochloride extended-release capsules capsules.
`
`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 affect the
`activity (induction or inhibition) of one or more of these pathways may lead to clinically relevant
`
`drug interactions (see Drug Interactions under PRECAUTIONS).
`
`
`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.
`
`
`
`Reference ID: 2919382
`
`5
`
`

`

` 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 to
`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 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.
`
`
`Non-Cardiovascular Drugs
`
`Migraine Drugs
`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).
`
` 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%.
`
`
`Reference ID: 2919382
`
`6
`
`

`

`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 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.
`
`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.
`
`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 hypertensive agent. Propranolol contributed to control
`of diastolic blood pressure, but the magnitude of the effect of propranolol on blood pressure
`cannot be ascertained.
`
`Four double-blind, randomized, crossover studies were conducted in a total of 74 patients with
`mild or moderately severe hypertension treated with propranolol hydrochloride extended-release
`capsules 160 mg once daily or propranolol 160 mg given either once daily or in two 80 mg
`doses. Three of these studies were conducted over a 4-week treatment period. One study was
`assessed after a 24-hour period. Propranolol hydrochloride extended-release capsules were as
`effective as propranolol in controlling hypertension (pulse rate, systolic and diastolic blood
`pressure) in each of these trials.
`
`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.
`
`Twelve male patients with moderately severe angina pectoris were studied in a double-blind,
`crossover study. Patients were randomized to either Propranolol hydrochloride extended-release
`capsules 160 mg daily or conventional propranolol 40 mg four times a day for 2 weeks.
`
`
`Reference ID: 2919382
`
`7
`
`

`

`Nitroglycerine tablets were allowed during the study. Blood pressure, heart rate and ECG's were
`recorded during serial exercise treadmill testing. Propranolol hydrochloride extended-release
`capsules were as effective as conventional propranolol for exercise heart rate, systolic and
`diastolic blood pressure, duration of anginal pain and ST-segment depression before or after
`exercise, exercise duration, angina attack rate and nitroglycerine consumption.
`
`In another double-blind, randomized, crossover trial, the effectiveness of propranolol
`hydrochloride extended-release capsules 160 mg daily and conventional propranolol 40 mg four
`times a day were evaluated in 13 patients with angina. ECG's were recorded while patients
`exercised until angina developed. Propranolol hydrochloride extended-release capsules were as
`effective as conventional propranolol for amount of exercise performed, ST-segment depression,
`
`number of anginal attacks, amount of nitroglycerine consumed, systolic and diastolic blood
`pressures and heart rate at rest and after exercise.
`
`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.
`
`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.
`
`INDICATIONS AND USAGE
`Hypertension
`Propranolol hydrochloride extended-release capsules 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 extended-release capsules is not
`indicated in the management of hypertensive emergencies.
`
`Angina Pectoris Due to Coronary Atherosclerosis
`Propranolol hydrochloride extended-release capsules are indicated to decrease angina frequency
`and increase exercise tolerance in patients with angina pectoris.
`
`Migraine
`Propranolol hydrochloride extended-release capsules 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.
`
`Hypertrophic Subaortic Stenosis
`Propranolol hydrochloride extended-release capsules improve NYHA functional class in
`symptomatic patients with hypertrophic subaortic stenosis.
`
`
`Reference ID: 2919382
`
`8
`
`

`

`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 unstable 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 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.
`
`
`Reference ID: 2919382
`
`9
`
`

`

`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.
`
`Thyrotoxicosis
`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 T4 and
`reverse T3, and decreasing T3.
`
`Wolff-Parkinson-White Syndrome
`Beta-adrenergic blockade in patients with Wolff-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.
`
`PRECAUTIONS
`General
`Propranolol should be used with caution in patients with impaired hepatic or renal function.
`Propranolol hydrochloride extended-release capsules 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 extended-release capsules 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 extended-release capsules are
`administered with drugs that have an affect 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).
`
`
`Reference ID: 2919382
`
`10
`
`

`

`Alcohol when used concomitantly with propranolol, may increase plasma levels of propranolol.
`
`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 co-administration with propranolol.
`
`Caution should be exercised when administering propranolol hydrochloride extended-release
`capsules with drugs that slow A-V nodal conduction, e.g., 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 extended-release capsules 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.
`
`
`Reference ID: 2919382
`
`11
`
`

`

`Postural hypotension has been reported in patients taking both beta-blockers and terazosin or
`
`doxazosin.
`
`
`Reserpine
`
`
`Patients receiving catecholamine-depleting drugs, such as reserpine should be closely observed
`
`for excessive reduction of resting sympathetic nervous activity, which may result in hypotension,
`
`marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension.
`
`
`Inotropic Agents
`
`Patients on long-term therapy with propranolol may experience uncontrolled hypertension if
`administered epinephrine as a consequence of unopposed alpha-receptor stimulation.
`Epinephrine is therefore not indicated in the treatment of propranolol overdose (see
`OVERDOSAGE).
`
`Isoproterenol and Dobutamine
`
`Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by
`administration of such agents, e.g., dobutamine or isoproterenol. Also, propranolol may reduce
`sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for
`myocardial ischemia.
`
`Non-Cardiovascular Drugs
`Nonsteroidal Anti-Inflammatory Drugs
`
`Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to blunt the
`antihypertensive effect of beta-adrenoreceptor blocking agents.
`
`Administration of indomethacin with propranolol may reduce the efficacy of propranolol in
`reducing blood pressure and heart rate.
`
`Antidepressants
`
`The hypotensive effects of MAO inhibitors or tricyclic antidepressants may be exacerbated when
`administered with beta-blockers by interfering with the beta blocking activity of propranolol.
`
`
`Anesthetic Agents
`Methoxyflurane and trichloroethylene may depress myocardial contractility when administered
`with propranolol.
`
`
`Warfarin
`
`Propranolol when administered with warfarin increases the concentration of warfarin.
`
`Prothrombin time, therefore, should be monitored.
`
`
`Neuroleptic Drugs
`
`Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and
`haloperidol.
`
`Thyroxine
`
`Thyroxine may result in a lower than expected T3 concentration when used co