`
`
`(propranolol hydrochloride)
`
`Tablets
`
`
`
`
` Rx only
`
`This product's label may have been revised after this insert was used in
`production. For further product information and current package insert,
`please visit www.wyeth.com or call our medical communications department
`toll-free at 1-888-383-1733
`
`
`
`DESCRIPTION
`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 is available as 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg tablets for oral administration.
`
`The inactive ingredients contained in Inderal Tablets are: lactose, magnesium stearate,
`microcrystalline cellulose, and stearic acid. In addition, Inderal 10 mg and 80 mg Tablets contain
`FD&C Yellow No. 6 and D&C Yellow No. 10; Inderal 20 mg Tablets contain FD&C Blue
`No. 1; Inderal 40 mg Tablets contain FD&C Blue No. 1, FD&C Yellow No. 6, and D&C Yellow
`No. 10; Inderal 60 mg Tablets contain D&C Red No. 30.
`
`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.
`
`
`Reference ID: 2919389
`
`1
`
`
`Lower Drug Prices for Consumers v. Forest Labs. Holdings Ltd., IPR2016-00379
`Patent Owner Forest Labs - Ex. 2006, p. 1
`
`
`
`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 is 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 alpha1
`
`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.
`
`
`Reference ID: 2919389
`
`2
`
`
`Lower Drug Prices for Consumers v. Forest Labs. Holdings Ltd., IPR2016-00379
`Patent Owner Forest Labs - Ex. 2006, p. 2
`
`
`
`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 naphthyloxyactic 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 naphthoxylactic acid (NLA-side chain oxidation). No correlation was found
`between age and the partial metabolic clearance to propranolol glucuronide (PPLG-conjugation).
`
`
`Reference ID: 2919389
`
`3
`
`
`Lower Drug Prices for Consumers v. Forest Labs. Holdings Ltd., IPR2016-00379
`Patent Owner Forest Labs - Ex. 2006, p. 3
`
`
`
`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
`
`alpha1 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 (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.
`
`
`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).
`
`
`
`Reference ID: 2919389
`
`4
`
`
`Lower Drug Prices for Consumers v. Forest Labs. Holdings Ltd., IPR2016-00379
`Patent Owner Forest Labs - Ex. 2006, p. 4
`
`
`
`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).
`
`
`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 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.
`
`
`Reference ID: 2919389
`
`5
`
`
`Lower Drug Prices for Consumers v. Forest Labs. Holdings Ltd., IPR2016-00379
`Patent Owner Forest Labs - Ex. 2006, p. 5
`
`
`
`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%.
`
`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.
`
`Alcohol
`Concomitant use of alcohol may increase plasma levels of propranolol.
`
`
`Reference ID: 2919389
`
`6
`
`
`Lower Drug Prices for Consumers v. Forest Labs. Holdings Ltd., IPR2016-00379
`Patent Owner Forest Labs - Ex. 2006, p. 6
`
`
`
`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
`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.
`
`
`Reference ID: 2919389
`
`7
`
`
`Lower Drug Prices for Consumers v. Forest Labs. Holdings Ltd., IPR2016-00379
`Patent Owner Forest Labs - Ex. 2006, p. 7
`
`
`
`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
`
`Hypertension
`
`Inderal is indicated in the management of hypertension. It may be used alone or used in
`combination with other antihypertensive agents, particularly a thiazide diuretic. Inderal is not
`indicated in the management of hypertensive emergencies.
`
`Angina Pectoris Due to Coronary Atherosclerosis
`Inderal is indicated to decrease angina frequency and increase exercise tolerance in patients with
`angina pectoris.
`
`Atrial Fibrillation
`Inderal is indicated to control ventricular rate in patients with atrial fibrillation and a rapid
`ventricular response.
`
`Myocardial Infarction
`Inderal is indicated to reduce cardiovascular mortality in patients who have survived the acute
`phase of myocardial infarction and are clinically stable.
`
`Migraine
`Inderal is indicated for the prophylaxis of common migraine headache. The efficacy of
`propranolol in the treatment of a migraine attack that has started has not been established, and
`propranolol is not indicated for such use.
`
`Essential Tremor
`Inderal is indicated in the management of familial or hereditary essential tremor. Familial or
`essential tremor consists of involuntary, rhythmic, oscillatory movements, usually limited to the
`upper limbs. It is absent at rest, but occurs when the limb is held in a fixed posture or position
`against gravity and during active movement. Inderal causes a reduction in the tremor amplitude,
`but not in the tremor frequency. Inderal is not indicated for the treatment of tremor associated
`with Parkinsonism.
`
`
`Reference ID: 2919389
`
`8
`
`
`Lower Drug Prices for Consumers v. Forest Labs. Holdings Ltd., IPR2016-00379
`Patent Owner Forest Labs - Ex. 2006, p. 8
`
`
`
`Hypertrophic Subaortic Stenosis
`Inderal improves NYHA functional class in symptomatic patients with hypertrophic subaortic
`stenosis.
`
`Pheochromocytoma
`Inderal is 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.
`
`
`Reference ID: 2919389
`
`9
`
`
`Lower Drug Prices for Consumers v. Forest Labs. Holdings Ltd., IPR2016-00379
`Patent Owner Forest Labs - Ex. 2006, p. 9
`
`
`
`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.
`
`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 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.
`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.
`
`
`Reference ID: 2919389
`
`10
`
`
`Lower Drug Prices for Consumers v. Forest Labs. Holdings Ltd., IPR2016-00379
`Patent Owner Forest Labs - Ex. 2006, p. 10
`
`
`
`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).
`
`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 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.
`
`
`Reference ID: 2919389
`
`11
`
`
`Lower Drug Prices for Consumers v. Forest Labs. Holdings Ltd., IPR2016-00379
`Patent Owner Forest Labs - Ex. 2006, p. 11
`
`
`
`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.
`
`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 bloc