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Propranolol

Pronunciation

Pronunciation

(proe PRAN oh lole)

Index Terms

  • Hemangeol
  • Inderal
  • Propranolol HCl
  • Propranolol Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule Extended Release 24 Hour, Oral, as hydrochloride:

Inderal LA: 60 mg, 80 mg, 120 mg, 160 mg [contains brilliant blue fcf (fd&c blue #1)]

Inderal XL: 80 mg, 120 mg

InnoPran XL: 80 mg, 120 mg

Generic: 60 mg, 80 mg, 120 mg, 160 mg

Solution, Intravenous, as hydrochloride:

Generic: 1 mg/mL (1 mL)

Solution, Oral, as hydrochloride:

Hemangeol: 4.28 mg/mL (120 mL) [alcohol free, paraben free, sugar free; contains saccharin sodium]

Generic: 20 mg/5 mL (500 mL); 40 mg/5 mL (500 mL)

Tablet, Oral, as hydrochloride:

Generic: 10 mg, 20 mg, 40 mg, 60 mg, 80 mg

Brand Names: U.S.

  • Hemangeol
  • Inderal LA
  • Inderal XL
  • InnoPran XL

Pharmacologic Category

  • Antianginal Agent
  • Antiarrhythmic Agent, Class II
  • Antihypertensive
  • Beta-Adrenergic Blocker, Nonselective

Pharmacology

Nonselective beta-adrenergic blocker (class II antiarrhythmic); competitively blocks response to beta1- and beta2-adrenergic stimulation which results in decreases in heart rate, myocardial contractility, blood pressure, and myocardial oxygen demand. Nonselective beta-adrenergic blockers (propranolol, nadolol) reduce portal pressure by producing splanchnic vasoconstriction (beta2 effect) thereby reducing portal blood flow.

Absorption

Oral: Rapid and complete

Distribution

Vd: 4 L/kg in adults; crosses the blood-brain barrier

Metabolism

Extensive first-pass effect, hepatically metabolized to active and inactive compounds; the 3 main metabolic pathways include: Aromatic hydroxylation (primarily 4-hydroxylation), N-dealkylation followed by further side-chain oxidation and direct glucuronidation; the 4 primary metabolites include: Propranolol glucuronide, naphthyloxylactic acid, and sulfate and glucuronic acid conjugates of 4-hydroxy propranolol; Note: Aromatic hydroxylation is catalyzed primarily by isoenzyme CYP2D6; side chain oxidation is mainly via CYP1A2, but also CYP2D6; 4-hydroxypropranolol possesses beta-adrenergic receptor blocking activity and is a weak inhibitor of CYP2D6.

Excretion

Metabolites are excreted primarily in urine (96% to 99%); <1% excreted in urine as unchanged drug

Onset of Action

Beta-blockade: Oral: 1 to 2 hours; Peak effect: Hypertension: A few days to several weeks

Time to Peak

Immediate release: Adults: 1 to 4 hours; Infants: ≤2 hours (Hemangeol); Extended release capsule (Inderal XL, InnoPran XL): 12 to 14 hours; Long acting capsule (Inderal LA): 6 hours

Duration of Action

Immediate release: 6 to 12 hours; Extended-release formulations: ~24 to 27 hours

Half-Life Elimination

Neonates: Possible increased half-life; Infants: 35 to 150 days: Median 3.5 hours; Children: 3.9 to 6.4 hours; Adults: Immediate release formulation: 3 to 6 hours; Extended-release formulations: 8 to 10 hours

Protein Binding

Newborns: 68%; Adults: ~90% (S-isomer primarily to alpha1-acid glycoprotein; R-isomer primarily to albumin)

Use: Labeled Indications

Management of hypertension; angina pectoris; pheochromocytoma; essential tremor; supraventricular arrhythmias (such as atrial fibrillation and flutter, AV nodal re-entrant tachycardias), ventricular tachycardias (catecholamine-induced arrhythmias, digoxin toxicity); prevention of myocardial infarction; migraine headache prophylaxis; symptomatic treatment of obstructive hypertrophic cardiomyopathy (formerly known as hypertrophic subaortic stenosis); treatment of proliferating infantile hemangioma requiring systemic therapy (Hemangeol only)

Guideline recommendations:

Hypertension: The 2014 guideline for the management of high blood pressure in adults (JNC 8) recommends initiation of pharmacologic treatment to lower blood pressure for the following patients (JNC8 [James 2013]):

• Patients ≥60 years of age, with systolic blood pressure (SBP) ≥150 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg. Goal of therapy is SBP <150 mm Hg and DBP <90 mm Hg.

• Patients <60 years of age, with SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

• Patients ≥18 years of age with diabetes, with SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

• Patients ≥18 years of age with chronic kidney disease (CKD), with SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

Chronic kidney disease (CKD) and hypertension: Regardless of race or diabetes status, the use of an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) as initial therapy is recommended to improve kidney outcomes. In the general nonblack population (without CKD) including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic, calcium channel blocker, ACEI, or ARB. In the general black population (without CKD) including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic or a calcium channel blocker instead of an ACEI or ARB. Beta-blockers are no longer recommended as first-line therapy in the general patient population.

Coronary artery disease (CAD) and hypertension: The American Heart Association, American College of Cardiology, and American Society of Hypertension (AHA/ACC/ASH) 2015 scientific statement for the treatment of hypertension in patients with CAD recommends the use of a beta blocker as part of a regimen in patients with hypertension and chronic stable angina with a history of prior MI. A BP target of <140/90 mm Hg is reasonable for the secondary prevention of cardiovascular events. A lower target BP (<130/80 mm Hg) may be appropriate in some individuals with CAD, previous MI, stroke or transient ischemic attack, or CAD risk equivalents (AHA/ACC/ASH [Rosendorff 2015]).

Use: Unlabeled

Tremor due to Parkinson's disease; tremor due to lithium; performance anxiety, antipsychotic-induced akathisia; primary and secondary prophylaxis of variceal hemorrhage; thyroid storm; thyrotoxicosis; tetralogy of Fallot (TOF) hypercyanotic spells

Contraindications

Hypersensitivity to propranolol, beta-blockers, or any component of the formulation; uncompensated congestive heart failure (unless the failure is due to tachyarrhythmias being treated with propranolol), cardiogenic shock; severe sinus bradycardia, sick sinus syndrome, or heart block greater than first-degree (except in patients with a functioning artificial pacemaker); bronchial asthma

Hemangeol (additional contraindications): Premature infants with corrected age <5 weeks; infants weighing <2 kg; heart rate <80 bpm; blood pressure <50/30 mm Hg; pheochromocytoma; history of bronchospasm

Dosing: Adult

Essential tremor: Oral: Immediate-release formulations: 40 mg twice daily initially; maintenance doses: Usually 120 to 320 mg/day

Hypertension: Oral:

Immediate-release formulations: 40 mg twice daily; increase dosage every 3 to 7 days; usual dose: 120 to 240 mg divided in 2 to 3 doses/day; maximum daily dose: 640 mg; usual dosage range (ASH/ISH [Weber 2014]): 40 to 160 mg twice daily

Extended-release formulations:

Inderal LA: Initial: 80 mg once daily; usual maintenance: 120 to 160 mg once daily; maximum daily dose: 640 mg

Inderal XL, InnoPran XL: Initial: 80 mg once daily at bedtime; if initial response is inadequate, may be increased at 2 to 3 week intervals to a maximum daily dose of 120 mg

Migraine headache prophylaxis: Oral:

Immediate-release formulations: Initial: 80 mg/day divided every 6 to 8 hours; increase by 20 to 40 mg/dose every 3 to 4 weeks to a maximum of 160 to 240 mg/day given in divided doses every 6 to 8 hours; if satisfactory response not achieved within 6 weeks of starting therapy, drug should be withdrawn gradually over several weeks

Inderal LA: Initial: 80 mg once daily; effective dose range: 160 to 240 mg once daily

Obstructive hypertrophic cardiomyopathy: Oral:

Immediate-release formulations: 20 to 40 mg 3 to 4 times/day

Inderal LA: 80 to 160 mg once daily

Pheochromocytoma: Oral: Immediate-release formulations: 30 to 60 mg/day in divided doses

Post-MI mortality reduction: Oral: Immediate-release formulations: Initial: 40 mg 3 times/day; usual dosage range: 180 to 240 mg/day in 3 to 4 divided doses

Stable angina: Oral:

Immediate-release formulations: 80 to 320 mg/day in doses divided 2 to 4 times/day

Inderal LA: Initial: 80 mg once daily; maximum dose: 320 mg once daily

Tachyarrhythmias:

Oral: Immediate-release formulations: 10 to 30 mg/dose every 6 to 8 hours or a usual maintenance dose of 10 to 40 mg three or four times daily for rate control in patients with atrial fibrillation (AHA/ACC/HRS [January 2014]).

IV: 1 to 3 mg/dose slow IVP; repeat every 2-5 minutes up to a total of 5 mg; titrate initial dose to desired response. Note: Once response achieved or maximum dose administered, additional doses should not be given for at least 4 hours.

or

0.5 to 1 mg over 1 minute; may repeat, if necessary, up to a total maximum dose of 0.1 mg/kg (ACLS guidelines 2010)

or

1 mg over 1 minute; may be repeated every 2 minutes up to 3 doses for rate control in patients with atrial fibrillation (AHA/ACC/HRS [January 2014]).

Akathisia, antipsychotic-induced (off-label use): Oral: Immediate-release formulations: Initial: 10 mg twice daily or 10 mg 3 times daily; adjust dose based on response and tolerability up to 120 mg/day (Adler 1986; Adler 1993; Kane 2009; Kramer 1989). Treatment guidelines recommend doses of 30 to 90 mg/day (APA [Lehman 2004]; WFSBP [Hasan 2013].

Performance anxiety (off-label use): Oral: Immediate-release formulations: 40 mg 60 to 90 minutes prior to anxiety-provoking event (Hartley 1983). Additional data may be necessary to further define the role of propranolol in this condition.

Thyroid storm (off-label use):

Oral: Immediate-release formulations: 60 to 80 mg every 4 hours; may consider the use of an intravenous shorter-acting beta-blocker (ie, esmolol) (Bahn 2011)

IV: 0.5 to 1 mg administered over 10 minutes every 3 hours (Gardner 2011)

Thyrotoxicosis (off-label use): Oral: Immediate-release formulations: 10 to 40 mg/dose every 6 to 8 hours; may also consider administering extended or sustained release formulations (Bahn 2011)

Tremor, lithium-induced (off-label use): Oral: Immediate-release formulations: 30 to 80 mg/day in divided doses; adjust dose based on response and tolerability (Gelenberg 1995; Kirk 1973; Lapierre 1976). Additional data may be necessary to further define the role of propranolol in this condition.

Variceal hemorrhage prophylaxis (off-label use) (AASLD [Garcia-Tsao 2007]): Oral:

Primary prophylaxis: Immediate-release formulations: Initial: 20 mg twice daily; adjust to maximal tolerated dose. Note: Risk factors for hemorrhage include Child-Pugh class B/C or variceal red wale markings on endoscopy.

Secondary prophylaxis: Immediate-release formulations: Initial: 20 mg twice daily; adjust to maximal tolerated dose

Dosing: Geriatric

IV: Use caution; initiate at lower end of the dosing range.

Oral:

Hypertension: Consider lower initial doses and titrate to response (Aronow 2011)

Tachyarrhythmias: Immediate-release formulations: Initial: 10 mg twice daily; increase dosage every 3 to 7 days; usual dose range: 10 to 320 mg/day given in 1 to 2 divided doses.

Refer to adult dosing for additional uses.

Dosing: Pediatric

Proliferating infantile hemangioma (Hemangeol): Infants ≥2 kg: Oral: Note: Initiate treatment at age 5 weeks to 5 months; doses should be administered at least 9 hours apart. Refer to product labeling for detailed weight-based dosing tabulation.

Week 1: 0.15 mL/kg (~0.6 mg/kg) twice daily

Week 2: 0.3 mL/kg (~1.1 mg/kg) twice daily

Week 3 (maintenance): 0.4 mL/kg (~1.7 mg/kg) twice daily; maintain this dose for 6 months. Readjust dose periodically as the child's weight increases. Treatment may be reinitiated if hemangiomas recur.

Hypertension (off-label use): Children and Adolescents: Oral: Immediate-release formulations: Initial: 1 to 2 mg/kg/day divided in 2 to 3 doses/day; titrate dose to effect; maximum dose: 4 mg/kg/day up to 640 mg/day; sustained-release formulation may be dosed once daily (NHBPEP 2004; NHLBI 2011).

Thyrotoxicosis (off-label use): Adolescents: Oral: Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling. However, renal impairment increases systemic exposure to propranolol. Use with caution.

Not dialyzable (0% to 5%); supplemental dose is not necessary.

Peritoneal dialysis effects: Supplemental dose is not necessary.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling. However, hepatic impairment increases systemic exposure to propranolol. Use with caution.

Administration

IV: IV dose is much smaller than oral dose. When administered acutely for cardiac treatment, monitor ECG and blood pressure. May administer by rapid infusion (IV push) at a rate of 1 mg/minute or by slow infusion over ~30 minutes. Necessary monitoring for surgical patients who are unable to take oral beta-blockers (prolonged ileus) has not been defined. Some institutions require monitoring of baseline and postinfusion heart rate and blood pressure when a patient's response to beta-blockade has not been characterized (ie, the patient's initial dose or following a change in dose). Consult individual institutional policies and procedures. Do not crush long-acting oral forms.

Oral: Tablets (immediate release) should be taken on an empty stomach; capsules (extended release) may be taken with or without food, but should always be taken consistently (with food or on an empty stomach). Do not crush long-acting oral forms.

Hemangeol should be administered during or right after a feeding to reduce the risk of hypoglycemia; skip dose if child is not eating or is vomiting. Administer doses at least 9 hours apart. Do not shake Hemangeol before use. Administer Hemangeol directly into the child’s mouth using the supplied oral dosing syringe; if needed, may be diluted with a small quantity of milk or fruit juice and given in a baby’s bottle.

Dietary Considerations

Tablets (immediate release) should be taken on an empty stomach; capsules (extended release) may be taken with or without food, but should always be taken consistently (with food or on an empty stomach). Hemangeol should be administered during or right after a feeding to reduce the risk of hypoglycemia; skip dose if child is not eating or is vomiting.

Compatibility

Stable in D51/2NS, D5NS, D5W, LR, 1/2NS, NS.

Y-site administration: Incompatible with amphotericin B cholesteryl sulfate complex, pantoprazole.

Compatibility in syringe: Incompatible with pantoprazole.

Storage

Injection: Store at 20°C to 25°C (68°F to 77°F); protect from freezing or excessive heat. Once diluted, propranolol is stable for 24 hours at room temperature in D5W or NS. Protect from light. Solution has a maximum stability at pH of 3 and decomposes rapidly in alkaline pH.

Capsule, tablet, oral solution: Store at controlled room temperature; protect from freezing or excessive heat. Protect from light and moisture. Dispense Hemangeol in original container; discard 2 months after first opening.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Acetylcholinesterase Inhibitors: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Ajmaline: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Alcohol (Ethyl): May decrease the serum concentration of Propranolol. Alcohol (Ethyl) may increase the serum concentration of Propranolol. Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Alpha-/Beta-Agonists (Direct-Acting): Beta-Blockers may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Epinephrine used as a local anesthetic for dental procedures will not likely cause clinically relevant problems. Some beta-adrenoceptor mediated effects of Alpha-/Beta-Agonists (Direct-Acting), including anti-anaphylactic effects of epinephrine, may be diminished by Beta-Blockers. Management: Cardioselective beta-blockers and lower doses of epinephrine may confer a more limited risk. Patients who may require acute subcutaneous epinephrine (e.g., bee sting kits) should probably avoid beta blockers. Exceptions: Dipivefrin. Consider therapy modification

Alpha1-Blockers: Beta-Blockers may enhance the orthostatic hypotensive effect of Alpha1-Blockers. The risk associated with ophthalmic products is probably less than systemic products. Monitor therapy

Alpha2-Agonists: May enhance the AV-blocking effect of Beta-Blockers. Sinus node dysfunction may also be enhanced. Beta-Blockers may enhance the rebound hypertensive effect of Alpha2-Agonists. This effect can occur when the Alpha2-Agonist is abruptly withdrawn. Management: Closely monitor heart rate during treatment with a beta blocker and clonidine. Withdraw beta blockers several days before clonidine withdrawal when possible, and monitor blood pressure closely. Recommendations for other alpha2-agonists are unavailable. Exceptions: Apraclonidine. Consider therapy modification

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Aminoquinolines (Antimalarial): May decrease the metabolism of Beta-Blockers. Monitor therapy

Amiodarone: May enhance the bradycardic effect of Beta-Blockers. Possibly to the point of cardiac arrest. Amiodarone may increase the serum concentration of Beta-Blockers. Monitor therapy

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Anilidopiperidine Opioids: May enhance the bradycardic effect of Beta-Blockers. Anilidopiperidine Opioids may enhance the hypotensive effect of Beta-Blockers. Monitor therapy

Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Beta-Blockers. Beta-Blockers may decrease the metabolism of Antipsychotic Agents (Phenothiazines). Antipsychotic Agents (Phenothiazines) may decrease the metabolism of Beta-Blockers. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Consider therapy modification

Barbiturates: May decrease the serum concentration of Beta-Blockers. Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Beta2-Agonists: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Beta2-Agonists. Avoid combination

Bile Acid Sequestrants: May decrease the serum concentration of Propranolol. Monitor therapy

Bosutinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bosutinib. Avoid combination

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bupivacaine: Beta-Blockers may increase the serum concentration of Bupivacaine. Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May enhance the hypotensive effect of Beta-Blockers. Bradycardia and signs of heart failure have also been reported. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Beta-Blockers. Exceptions: Bepridil. Monitor therapy

Cannabis: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Cardiac Glycosides: Beta-Blockers may enhance the bradycardic effect of Cardiac Glycosides. Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination

Cholinergic Agonists: Beta-Blockers may enhance the adverse/toxic effect of Cholinergic Agonists. Of particular concern are the potential for cardiac conduction abnormalities and bronchoconstriction. Management: Administer these agents in combination with caution, and monitor for conduction disturbances. Avoid methacholine with any beta blocker due to the potential for additive bronchoconstriction. Monitor therapy

Cobicistat: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Monitor therapy

CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Consider therapy modification

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Consider therapy modification

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Darunavir: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dipyridamole: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy

Disopyramide: May enhance the bradycardic effect of Beta-Blockers. Beta-Blockers may enhance the negative inotropic effect of Disopyramide. Monitor therapy

Doxofylline: Propranolol may increase the serum concentration of Doxofylline. Monitor therapy

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronedarone: May enhance the bradycardic effect of Beta-Blockers. Dronedarone may increase the serum concentration of Beta-Blockers. This likely applies only to those agents that are metabolized by CYP2D6. Management: Use lower initial beta-blocker doses; adequate tolerance of the combination, based on ECG findings, should be confirmed prior to any increase in beta-blocker dose. Consider therapy modification

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Ergot Derivatives: Beta-Blockers may enhance the vasoconstricting effect of Ergot Derivatives. Exceptions: Nicergoline. Consider therapy modification

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

Fingolimod: Beta-Blockers may enhance the bradycardic effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and beta-blockers if possible. If coadministration is necessary, patients should have overnight continuous ECG monitoring conducted after the first dose of fingolimod. Monitor patients for bradycardia. Consider therapy modification

Floctafenine: May enhance the adverse/toxic effect of Beta-Blockers. Avoid combination

FluvoxaMINE: May increase the serum concentration of Propranolol. Management: Use a lower initial propranolol dose and be cautious with propranolol dose titration. Consider therapy modification

Grass Pollen Allergen Extract (5 Grass Extract): Beta-Blockers may enhance the adverse/toxic effect of Grass Pollen Allergen Extract (5 Grass Extract). More specifically, Beta-Blockers may inhibit the ability to effectively treat severe allergic reactions to Grass Pollen Allergen Extract (5 Grass Extract) with epinephrine. Some other effects of epinephrine may be unaffected or even enhanced (e.g., vasoconstriction) during treatment with Beta-Blockers. Consider therapy modification

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Imatinib: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Insulin: Beta-Blockers may enhance the hypoglycemic effect of Insulin. Monitor therapy

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy

Lacidipine: May enhance the hypotensive effect of Propranolol. Lacidipine may increase the serum concentration of Propranolol. Propranolol may decrease the serum concentration of Lacidipine. Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lidocaine (Systemic): Beta-Blockers may increase the serum concentration of Lidocaine (Systemic). Monitor therapy

Lidocaine (Topical): Beta-Blockers may increase the serum concentration of Lidocaine (Topical). Monitor therapy

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Mepivacaine: Beta-Blockers may increase the serum concentration of Mepivacaine. Monitor therapy

Methacholine: Beta-Blockers may enhance the adverse/toxic effect of Methacholine. Avoid combination

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Midodrine: Beta-Blockers may enhance the bradycardic effect of Midodrine. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

NIFEdipine: May enhance the hypotensive effect of Beta-Blockers. NIFEdipine may enhance the negative inotropic effect of Beta-Blockers. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May diminish the antihypertensive effect of Beta-Blockers. Monitor therapy

Obeticholic Acid: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Panobinostat: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Consider therapy modification

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Peginterferon Alfa-2b: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Perhexiline: CYP2D6 Substrates may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Propafenone: May increase the serum concentration of Propranolol. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

QuiNIDine: May increase the serum concentration of Propranolol. Monitor therapy

QuiNINE: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

Regorafenib: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy

Reserpine: May enhance the hypotensive effect of Beta-Blockers. Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of Beta-Blockers. Exceptions: Rifabutin. Monitor therapy

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Rivastigmine: May enhance the bradycardic effect of Beta-Blockers. Avoid combination

Rizatriptan: Propranolol may increase the serum concentration of Rizatriptan. Management: Rizatriptan adult dose should be reduced to 5 mg in patients who are also being treated with propranolol. Consider therapy modification

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May increase the serum concentration of Beta-Blockers. Exceptions: Citalopram; Escitalopram; FluvoxaMINE. Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Sulfonylureas: Beta-Blockers may enhance the hypoglycemic effect of Sulfonylureas. Cardioselective beta-blockers (eg, acebutolol, atenolol, metoprolol, and penbutolol) may be safer than nonselective beta-blockers. All beta-blockers appear to mask tachycardia as an initial symptom of hypoglycemia. Ophthalmic beta-blockers are probably associated with lower risk than systemic agents. Monitor therapy

Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Theophylline Derivatives: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Theophylline Derivatives. Consider therapy modification

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Vemurafenib: May increase the serum concentration of CYP1A2 Substrates. Management: Consider alternatives to such combinations whenever possible, particularly if the CYP1A2 substrate has a relatively narrow therapeutic index. Consider therapy modification

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Zileuton: May increase the serum concentration of Propranolol. Monitor therapy

ZOLMitriptan: Propranolol may increase the serum concentration of ZOLMitriptan. Monitor therapy

Adverse Reactions

Frequency not always defined.

Cardiovascular: Cold extremities (infants: 7% to 8%), angina pectoris, atrioventricular conduction disturbance, bradycardia, cardiogenic shock, congestive heart failure, hypotension, ineffective myocardial contractions, syncope

Central nervous system: Sleep disorder (infants: 16% to 18%), agitation (infants: 5% to 9%), fatigue (5% to 7%), dizziness (4% to 7%), nightmares (infants: 2% to 6%), irritability (infants: 1% to 6%), drowsiness (infants: 1% to 5%), amnesia, carpal tunnel syndrome (rare), catatonia, cognitive dysfunction, confusion, hypersomnia, lethargy, paresthesia, psychosis, vertigo

Dermatologic: Changes in nails, contact dermatitis, dermal ulcer, eczematous rash, erosive lichen planus, hyperkeratosis, pruritus, skin rash

Endocrine & metabolic: Hyperglycemia, hyperkalemia, hyperlipidemia, hypoglycemia

Gastrointestinal: Diarrhea (infants: 5% to 6%), abdominal pain (infants: ≤4%), decreased appetite (infants: 3% to 4%), constipation (1% to 3%), anorexia, stomach discomfort

Genitourinary: Oliguria (rare), proteinuria (rare)

Hematologic & oncologic: Immune thrombocytopenia, thrombocytopenia

Hepatic: Increased serum alkaline phosphatase, increased serum transaminases

Neuromuscular & skeletal: Arthropathy, oculomucocutaneous syndrome, polyarthritis

Ophthalmic: Conjunctival hyperemia, decreased visual acuity, mydriasis

Renal: Increased blood urea nitrogen, interstitial nephritis (rare)

Respiratory: Bronchitis (infants: 8% to 13%; associated with cough, fever, diarrhea, and vomiting), bronchiolitis (infants; associated with cough, fever, diarrhea, and vomiting), bronchospasm, dyspnea, pulmonary edema, wheezing

Miscellaneous: Ulcer

<1% (Limited to important or life-threatening): Agranulocytosis, alopecia, arterial insufficiency, arterial mesenteric thrombosis, decreased heart rate (infants), decreased serum glucose (infants), depression, emotional lability, epigastric distress, erythema multiforme, fever combined with generalized ache, sore throat, laryngospasm, and respiratory distress), hallucination, hypersensitivity reaction (including anaphylaxis, anaphylactoid reaction), impotence, insomnia, ischemic colitis, lupus-like syndrome, myotonia, myopathy, nonthrombocytopenic purpura, peripheral arterial disease (exacerbation), Peyronie's disease, pharyngitis, psoriasiform eruption, purpura, Raynaud's phenomenon, second degree atrioventricular block (infants; in a patient with an underlying conduction disorder), slightly clouded sensorium, Stevens-Johnson syndrome, systemic lupus erythematosus, temporary amnesia, tingling of extremities (hands), toxic epidermal necrolysis, urticaria, visual disturbance, weakness, xerophthalmia

ALERT: U.S. Boxed Warning

Cardiac ischemia after abrupt discontinuation (Inderal LA, Inderal XL, Innopran XL):

Following abrupt discontinuation of therapy with beta-blockers, exacerbations of angina pectoris and myocardial infarction (MI) have occurred.

When discontinuing long-term administration of propranolol, particularly in patients with ischemic heart disease, gradually reduce the dose over a period of 1 to 2 weeks and monitor the patient. If angina markedly worsens or acute coronary insufficiency develops, promptly resume therapy, at least temporarily, and take other measures appropriate for the management of unstable angina. Warn patients against interruption or discontinuation of therapy without health care provider's advice.

Because coronary artery disease is common and may be unrecognized, avoid abrupt discontinuation of propranolol therapy, even in patients treated only for hypertension.

Warnings/Precautions

Concerns related to adverse events:

• Anaphylactic reactions: Use caution with history of severe anaphylaxis to allergens; patients taking beta-blockers may become more sensitive to repeated challenges. Treatment of anaphylaxis (eg, epinephrine) in patients taking beta-blockers may be ineffective or promote undesirable effects.

Disease-related concerns:

• Bronchospastic disease: In general, patients with bronchospastic disease should not receive beta-blockers; if used at all, should be used cautiously with close monitoring.

• Conduction abnormality: Consider pre-existing conditions such as sick sinus syndrome before initiating.

• Diabetes: Use with caution in patients with diabetes mellitus; may potentiate hypoglycemia and/or mask signs and symptoms.

• Heart failure (HF): Use with caution in patients with compensated HF and monitor for a worsening of the condition (efficacy of propranolol in HF has not been demonstrated).

• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustment may be required.

• Myasthenia gravis: Use with caution in patients with myasthenia gravis.

• Peripheral vascular disease (PVD) and Raynaud's disease: Can precipitate or aggravate symptoms of arterial insufficiency in patients with PVD and Raynaud's disease. Use with caution and monitor for progression of arterial obstruction.

• Pheochromocytoma (untreated): Adequate alpha-blockade is required prior to use of any beta-blocker.

• Prinzmetal variant angina: Beta-blockers without alpha1-adrenergic receptor blocking activity should be avoided in patients with Prinzmetal variant angina since unopposed alpha1-adrenergic receptors mediate coronary vasoconstriction and can worsen anginal symptoms (Mayer 1998).

• Psoriasis: Beta-blocker use has been associated with induction or exacerbation of psoriasis, but cause and effect have not been firmly established.

• Psychiatric disease: Use with caution in patients with a history of psychiatric illness; may cause or exacerbate CNS depression.

• Renal impairment: Use with caution in patients with renal impairment; may have increased side effects.

• Thyroid disease: May mask signs of hyperthyroidism (eg, tachycardia). If thyrotoxicosis is suspected, carefully manage and monitor; abrupt withdrawal may exacerbate symptoms of hyperthyroidism or precipitate thyroid storm. Alterations in thyroid function tests may be observed.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Infants and children: Considerations when treating infantile hemangioma:

- Cardiovascular concerns: Bradycardia and/or hypotension may occur or be worsened; monitor heart rate and blood pressure after propranolol initiation or increase in dose; discontinue treatment if severe (<80 bpm) or symptomatic bradycardia or hypotension (systolic blood pressure <50 mm Hg) occurs. Infants with large facial infantile hemangioma should be investigated for potential arteriopathy associated with PHACE syndrome prior to propranolol therapy; decreases in blood pressure caused by propranolol may increase risk of stroke in PHACE syndrome patients with cerebrovascular anomalies.

- Hypoglycemia: May potentiate hypoglycemia and/or mask signs and symptoms. Withhold the dose in infants or children who are not feeding regularly or who are vomiting; discontinue therapy and seek immediate treatment if hypoglycemia occurs.

- Respiratory concerns: May cause bronchospasm. Interrupt therapy in infants or children with lower respiratory tract infection associated with dyspnea or wheezing.

• Elderly: Bradycardia may be observed more frequently in elderly patients (>65 years of age); dosage reductions may be necessary.

Smokers: Cigarette smoking may decrease plasma levels of propranolol by increasing metabolism. Patients should be advised to avoid smoking.

Other warnings/precautions:

• Abrupt withdrawal: [US Boxed Warning]: Beta-blocker therapy should not be withdrawn abruptly (particularly in patients with CAD), but gradually tapered to avoid acute tachycardia, hypertension, and/or ischemia. Severe exacerbation of angina, ventricular arrhythmias, and myocardial infarction (MI) have been reported following abrupt withdrawal of beta-blocker therapy. Temporary but prompt resumption of beta-blocker therapy may be indicated with worsening of angina or acute coronary insufficiency.

• Major surgery: Chronic beta-blocker therapy should not be routinely withdrawn prior to major surgery.

Monitoring Parameters

Acute cardiac treatment: Monitor ECG, heart rate, and blood pressure with IV administration; heart rate and blood pressure with oral administration

Consult individual institutional policies and procedures.

Hemangeol: Monitor heart rate and blood pressure for 2 hours after initiation or dose increases.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Propranolol crosses the placenta and is measurable in the newborn serum following maternal use during pregnancy (Taylor 1981). According to the manufacturer, congenital abnormalities have been reported following maternal use of propranolol. Bradycardia, hypoglycemia, and/or respiratory depression have been observed in neonates following in utero exposure to propranolol at parturition. Reduced birth weight has also been observed following in utero exposure to beta-blockers as a class. Adequate facilities for monitoring infants at birth should be available.

Untreated chronic maternal hypertension and preeclampsia are also associated with adverse events in the fetus, infant, and mother (ACOG 2015; Magee 2014). When treatment of hypertension in pregnancy is indicated, beta-blockers may be used. Specific recommendations vary by guideline. Although other agents are preferred (ACOG 2013), use of propranolol may be considered (Magee 2014). Use of propranolol may be considered for some arrhythmias, including SVT, when use of a beta-blocker is needed during pregnancy (ACC/AHA/HRS [Page 2015]; ESC [Regitz-Zagrosek 2011]). Propranolol is recommended for use in controlling hypermetabolic symptoms of thyrotoxicosis in pregnancy (Stagnaro-Green 2011). Propranolol may be used if prophylaxis of migraine is needed in pregnant women; it should be discontinued 2 to 3 days prior to delivery to decrease the risk of adverse events to the fetus/neonate and potential reductions in uterine contraction (Pringsheim 2012).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience constipation, diarrhea, fatigue, loss of strength and energy, nausea, vomiting, or insomnia. Have patient report immediately to prescriber severe dizziness, passing out, angina, confusion, hallucinations, memory impairment, mood changes, burning or numbness feeling, vision changes, shortness of breath, excessive weight gain, swelling of arms or legs, bruising, bleeding, bradycardia, abnormal heartbeat, sensation of cold, signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, tachycardia, confusion, hunger, or sweating), or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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