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Verapamil

Pronunciation

Pronunciation

(ver AP a mil)

Index Terms

  • Iproveratril Hydrochloride
  • Verapamil HCl
  • Verapamil Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule Extended Release 24 Hour, Oral, as hydrochloride:

Verelan: 120 mg, 180 mg [contains fd&c red #40, methylparaben, propylparaben]

Verelan: 240 mg, 360 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40, methylparaben, propylparaben]

Verelan PM: 100 mg, 200 mg, 300 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]

Generic: 100 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg

Solution, Intravenous, as hydrochloride:

Generic: 2.5 mg/mL (2 mL, 4 mL)

Tablet, Oral, as hydrochloride:

Calan: 80 mg, 120 mg [scored]

Generic: 40 mg, 80 mg, 120 mg

Tablet Extended Release, Oral, as hydrochloride:

Calan SR: 120 mg

Calan SR: 180 mg [scored]

Calan SR: 240 mg [scored; contains fd&c blue #2 aluminum lake, fd&c yellow #10 aluminum lake]

Isoptin SR: 120 mg [DSC], 180 mg [DSC]

Isoptin SR: 240 mg [DSC] [contains fd&c blue #2 aluminum lake, fd&c yellow #10 aluminum lake]

Generic: 120 mg, 180 mg, 240 mg

Brand Names: U.S.

  • Calan
  • Calan SR
  • Isoptin SR [DSC]
  • Verelan
  • Verelan PM

Pharmacologic Category

  • Antianginal Agent
  • Antiarrhythmic Agent, Class IV
  • Antihypertensive
  • Calcium Channel Blocker
  • Calcium Channel Blocker, Nondihydropyridine

Pharmacology

Inhibits calcium ion from entering the “slow channels” or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization; produces relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina; slows automaticity and conduction of AV node.

Absorption

Oral: Well absorbed (>90%)

Distribution

Vd: 3.89 L/kg (Storstein 1984)

Metabolism

Hepatic (extensive first-pass effect) via multiple CYP isoenzymes; primary metabolite is norverapamil (~20% pharmacologic activity of verapamil)

Excretion

Urine (~70% as metabolites, 3% to 4% as unchanged drug); feces (≥16%)

Onset of Action

Oral (immediate release tablets): Peak effect: Oral: Immediate release: 1 to 2 hours (Singh 1978); IV bolus: 3 to 5 minutes

Time to Peak

Serum: Oral:

Immediate release: 1 to 2 hours

Extended release:

Calan SR: 5.21 hours

Verelan: 7 to 9 hours

Verelan PM: ~11 hours; Drug release delayed ~4 to 5 hours

Duration of Action

Oral: Immediate release tablets: 6 to 8 hours; IV: 10 to 20 minutes (Singh 1978)

Half-Life Elimination

Injection: Terminal: 2 to 5 hours.

Oral:

Immediate release: Single dose: 2.8 to 7.4 hours; Multiple doses: 4.5 to 12 hours

Extended release: ~12 hours

Severe hepatic impairment: 14 to 16 hours

Protein Binding

~90%

Special Populations: Hepatic Function Impairment

Metabolism is delayed, half-life is prolonged, volume of distribution is increased, and plasma clearance is reduced to ~30% of normal.

Special Populations: Elderly

Elimination half-life may be prolonged and bioavailability higher in the elderly.

Special Populations: Gender

Conflicting data suggest that verapamil clearance decreased with age in women to a greater degree than in men.

Use: Labeled Indications

Angina: Immediate-release tablet: Treatment of angina at rest, including vasospastic (Prinzmetal variant) angina and unstable (crescendo, preinfarction) angina; treatment of chronic stable angina (classic effort-associated angina).

Atrial fibrillation (rate control):

Immediate-release tablet: To control ventricular rate at rest and during stress in chronic atrial flutter and/or fibrillation.

IV: Temporary control of rapid ventricular rate in atrial flutter and/or atrial fibrillation (except when the atrial flutter and/or atrial fibrillation are associated with accessory bypass tracts [Wolff-Parkinson-White and Lown-Ganong-Levine syndromes]).

Hypertension: Immediate release tablet/ER capsule and tablet: Management of hypertension.

Paroxysmal supraventricular tachycardia prophylaxis: Immediate-release tablet: Prophylaxis of repetitive paroxysmal supraventricular tachycardia (PSVT).

Supraventricular tachycardias: IV: Rapid conversion to sinus rhythm of PSVT, including those associated with accessory bypass tracts (Wolff-Parkinson-White and Lown-Ganong-Levine syndromes).

Guideline recommendations:

Acute coronary syndrome (ACS): The AHA/ACC guidelines for the management of non-ST-elevation ACS recommend a nondihydropyridine calcium channel blocker (eg, verapamil) to treat ongoing ischemia if beta-blocker therapy is ineffective or contraindicated and in the absence of left ventricular dysfunction, increased risk for cardiogenic shock, PR interval >0.24 seconds, or second- or third-degree AV block (without a pacemaker) (ACC/AHA [Amsterdam 2014]).

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 (JNC 8 [James 2013]):

• Patients ≥60 years 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 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 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 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.

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 coronary artery disease (CAD) recommends that a non-dihydropyridine CCB (verapamil, diltiazem) may be used as a substitute for a beta blocker in patients who have an intolerance or contraindication to beta blockers with ongoing ischemia, hypertension and chronic stable angina, or if angina or hypertension continues to be uncontrolled while receiving standard therapies (eg, beta blocker). However, a non-dihydropyridine CCB (eg, verapamil, diltiazem) should be avoided in patients with LV dysfunction or heart failure (with reduced ejection fraction). 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]).

Supraventricular tachycardia: The American College of Cardiology, American Heart Association, and Heart Rhythm Society (ACC/AHA/HRS) supraventricular tachycardia (SVT) guidelines recommends IV verapamil for the acute treatment (ie, conversion) of a variety of SVTs (atrioventricular nodal reentrant tachycardia [AVNRT], atrioventricular reentrant tachycardia [AVRT], focal atrial tachycardia [AT], multifocal atrial tachycardia [MAT]) in hemodynamically stable patients. Oral verapamil is effective and recommended for the ongoing management of hemodynamically stable patients with symptomatic supraventricular tachycardia (AVNRT, AVRT, focal AT, MAT) without pre-excitation in patients who are not candidates for, or prefer not to undergo, catheter ablation. Oral verapamil may also be useful for acute rate control in hemodynamically-stable patients with atrial flutter (ACC/AHA/HRS [Page 2015])

Use: Unlabeled

Hypertrophic cardiomyopathy

Contraindications

Oral: Hypersensitivity to verapamil or any component of the formulation; severe left ventricular dysfunction; hypotension (systolic pressure <90 mm Hg) or cardiogenic shock; sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker); second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker); atrial flutter or fibrillation and an accessory bypass tract (Wolff-Parkinson-White [WPW] syndrome, Lown-Ganong-Levine syndrome)

Canadian labeling: Additional contraindications: Complicated myocardial infarction (ventricular failure manifested by pulmonary congestion); marked bradycardia

IV: Hypersensitivity to verapamil or any component of the formulation; severe heart failure (unless secondary to a supraventricular tachycardia amenable to verapamil); severe hypotension or cardiogenic shock; sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker); second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker); concurrent use of IV beta blocking agents; atrial flutter or fibrillation and an accessory bypass tract (WPW syndrome, Lown-Ganong-Levine syndrome); ventricular tachycardia.

Dosing: Adult

Angina: Oral: Note: When switching from immediate-release to extended-release formulations, the total daily dose remains the same unless formulation strength does not allow for equal conversion.

Immediate release:

Manufacturer’s labeling: 80 to 120 mg 3 times daily; in patients with increased response to verapamil (eg, small stature): 40 mg 3 times daily; may titrate at daily (patients with unstable angina) or weekly intervals based on patient response; maximum: 480 mg/day

Alternate recommendations: Usual dose range (ACC/AHA [Gibbons 2003]): 80 to 160 mg 3 times daily

Atrial fibrillation (rate control):

IV: Initial bolus: 0.075 to 0.15 mg/kg (usual dose: 5 to 10 mg) over at least 2 minutes; if no response, may give an additional 10 mg bolus after 15 to 30 minutes; if patient responds to the initial or repeat bolus dose, then may begin a continuous infusion (AHA/ACC/HRS [January 2014]; Phillips 1997)

Continuous infusion: Initial: 5 mg/hour; titrate to goal heart rate (Barbarash, 1986; Phillips, 1997)

Oral:

Extended release (off-label use): Usual maintenance dose: 180 to 480 mg once daily (AHA/ACC/HRS [January 2014])

Immediate release: 240 to 480 mg daily in 3 to 4 divided doses (maximum: 480 mg/day)

Hypertension: Oral: Note: When switching from immediate-release to extended-release formulations, the total daily dose remains the same unless formulation strength does not allow for equal conversion.

Immediate release: Initial: 80 mg 3 times daily; in patients with increased response to verapamil (eg, small stature): 40 mg 3 times daily; maximum: 480 mg/day; usual dose range (ASH/ISH [Weber 2014]): 240 to 480 mg daily

Extended release: Usual dose range (ASH/ISH [Weber 2014]): 240 to 480 mg daily; Note: There is no evidence of additional benefit with doses >360 mg daily.

Calan SR, Isoptin SR (Canadian product): Initial: 180 mg once daily in the morning; in patients with increased response to verapamil (eg, small stature): 120 mg once daily; if inadequate response to 180 mg once daily, may increase dose at weekly intervals to 240 mg once daily, then 180 mg twice daily (or 240 mg in the morning followed by 120 mg in the evening), up to 240 mg twice daily; maximum: 480 mg/day.

Verelan: Usual dosage: 240 mg once daily in the morning; in patients with increased response to verapamil (eg, small stature): 120 mg once daily; if inadequate response to 120 mg once daily, may increase dose at weekly intervals in the following manner: 180 mg once daily; 240 mg once daily; 360 mg once daily; 480 mg once daily; maximum: 480 mg/day

Verelan PM: Usual dosage: 200 mg once daily at bedtime; in patients with increased response to verapamil (eg, small stature): 100 mg once daily; if inadequate response to 200 mg once daily, may increase to 300 mg once daily, then 400 mg once daily; maximum dose: 400 mg daily

PSVT prophylaxis: Oral: Note: When switching from immediate-release to extended release formulations, the total daily dose remains the same unless formulation strength does not allow for equal conversion.

Manufacturer’s labeling: Immediate release: 240 to 480 mg daily in 3 to 4 divided doses (maximum: 480 mg/day)

Alternate recommendations: Supraventricular tachycardia (ongoing management): Initial: 120 mg daily in divided doses (immediate release) or once daily (extended release); maximum maintenance dose: 480 mg/day in divided doses (immediate release) or once daily (extended release) (ACC/AHA/HRS [Page 2015])

Supraventricular tachycardia (SVT), acute treatment (off-label dose): IV:

ACLS guidelines: 2.5 to 5 mg over 2 minutes (over 3 minutes in older patients); second dose of 5 to 10 mg (~0.15 mg/kg) may be given 15 to 30 minutes after the initial dose if patient tolerates, but does not respond to initial dose; maximum total dose: 20 to 30 mg (ACLS [Neumar 2010])

ACC/AHA/HRS SVT guidelines: 5 to 10 mg (0.075 to 0.15 mg/kg) over 2 minutes; if no response, a second dose of 10 mg (0.15 mg/kg) may be given 30 minutes after the initial dose; followed by an infusion at 0.005 mg/kg/minute (ACC/AHA/HRS [Page 2015])

Dosing: Geriatric

Hypertension: Oral: Note: When switching from immediate-release to extended-release formulations, the total daily dose remains the same unless formulation strength does not allow for equal conversion.

Manufacturer's labeling:

Immediate release: Initial: 40 mg 3 times daily

Extended release: Initial: 120 mg once daily in the morning (Calan SR, Isoptin SR [Canadian product] Verelan) or 100 mg once daily at bedtime (Verelan PM)

Alternate recommendations: Consider lower initial doses and titrating to response (ACCF/AHA [Aronow 2011])

Other indications: Refer to adult dosing.

Dosing: Pediatric

SVT: Note: Verapamil is not included in the Pediatric Advanced Life Support (PALS) tachyarrhythmia algorithm. Optimal interval for subsequent doses is unknown and must be individualized for each specific patient.

Children and Adolescents 1 to 15 years: IV, Intraosseous: 0.1 to 0.3 mg/kg/dose over 2 minutes; maximum: 5 mg/dose, may repeat dose in 15 to 30 minutes if inadequate response; maximum for second dose: 10 mg (Kliegman 2016; PALS [Kleinman 2010]; Park 2014)

Adolescents >15 years: IV:

Initial:

Manufacturer labeling: 5 to 10 mg (0.075 to 0.15 mg/kg)

PALS guidelines: 0.1 to 0.3 mg/kg/dose; maximum dose: 5 mg/dose (PALS [Kleinman 2010]; Park 2014)

Repeat dose: May repeat dose in 15 to 30 minutes if adequate response not achieved; maximum for second dose: 10 mg/dose (Kliegman 2015; PALS [Kleinman 2010]; Park 2014)

Dosing: Renal Impairment

Manufacturer's labeling:

Oral: Verelan PM: Initial: 100 mg once daily at bedtime. There are no dosage adjustments provided in the manufacturer’s labeling for the other products; however, use with caution and consider additional ECG monitoring.

Injection: There are no dosage adjustments provided in the manufacturer’s labeling; however, repeated injections in patients with renal failure may lead to accumulation and excessive pharmacologic effects and should be avoided. If repeated injections are essential, monitor blood pressure and PR interval closely and use smaller repeat doses.

Alternate recommendations: A multiple dose study in adults suggests reduced renal clearance of verapamil and its metabolite (norverapamil) with advanced renal failure (Storstein 1984). Additionally, several clinical papers report adverse effects of verapamil in patients with chronic renal failure receiving recommended doses of verapamil (Pritza 1991; Váquez 1996). In contrast, a number of single dose studies show no difference in verapamil (or norverapamil metabolite) disposition between chronic renal failure and control patients (Beyerlein 1990; Hanyok 1988; Mooy 1985; Zachariah 1991).

Dialysis: Not removed by hemodialysis (Mooy 1985); supplemental dose is not necessary.

Dosing: Hepatic Impairment

Oral: In cirrhosis, reduce dose to 20% of normal and monitor ECG (Somogyi 1981).

Calan, Calan SR, Verelan: Administer 30% of the normal dose in severe hepatic impairment.

Verelan PM: Initial: 100 mg once daily at bedtime.

Injection: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution and consider additional ECG monitoring in severe impairment. In cirrhosis, reduce dose to 50% of normal and monitor ECG (Somogyi, 1981). Repeated injections in patients with hepatic failure may lead to accumulation and excessive pharmacologic effects and should be avoided. If repeated injections are essential, monitor blood pressure and PR interval closely and use smaller repeat doses.

Extemporaneously Prepared

A 50 mg/mL oral suspension may be made with immediate release tablets and either a 1:1 mixture of Ora-Sweet and Ora-Plus or a 1:1 mixture of Ora-Sweet SF and Ora-Plus or cherry syrup. When using cherry syrup, dilute cherry syrup concentrate 1:4 with simple syrup, NF. Crush seventy-five verapamil hydrochloride 80 mg tablets in a mortar and reduce to a fine powder. Add small portions of chosen vehicle (40 mL total) and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label "shake well", "refrigerate", and "protect from light". Stable for 60 days refrigerated (preferred) or at room temperature (Allen, 1996).

A 50 mg/mL oral suspension may be made with immediate release tablets, a 1:1 preparation of methylcellulose 1% and simple syrup, and purified water. Crush twenty 80 mg verapamil tablets in a mortar and reduce to a fine powder. Add 3 mL purified water USP and mix to a uniform paste; mix while adding the vehicle incremental proportions to almost 32 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 32 mL. Label "shake well" and "refrigerate". Stable for 91 days refrigerated (preferred) or at room temperature (Nahata, 1997).

Allen LV Jr and Erickson MA 3rd, "Stability of Labetalol Hydrochloride, Metoprolol Tartrate, Verapamil Hydrochloride, and Spironolactone With Hydrochlorothiazide in Extemporaneously Compounded Oral Liquids," Am J Health Syst Pharm, 1996, 53(19):304-9.8893069Nahata MC, "Stability of Verapamil in an Extemporaneous Liquid Dosage Form," J Appl Ther Res, 1997,1(3):271-3.

Administration

Oral: Do not crush or chew extended-release products.

Calan SR, Isoptin SR (Canadian product): Administer with food. Isoptin SR 240 mg tablet may be split in half.

Verelan, Verelan PM: Capsules may be opened and the contents sprinkled on 1 tablespoonful of applesauce, swallow immediately (without chewing) and follow with a glass of cool water. Do not subdivide contents of capsules.

IV: Administer over at least 2 minutes; in older patients for the acute treatment of SVT, ACLS guidelines recommend administering over 3 minutes (ACLS [Neumar 2010])

Compatibility

See Trissel’s IV Compatibility Database

Storage

Injection: Store at 15°C to 30°C (59°F to 86°F).

Oral:

Calan, Calan SR: Store at 15°C to 25°C (59°F to 77°F). Protect from light and moisture.

Verelan: Store at 20°C to 25°C (68°F to 77°F). Avoid excessive heat; protect from moisture. Brief temperature >25°C (77°F) should be avoided.

Verelan PM: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59 to 86°F). Protect from moisture.

Drug Interactions

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

Alcohol (Ethyl): Verapamil may increase the serum concentration of Alcohol (Ethyl). Monitor therapy

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

Aliskiren: Verapamil may increase the serum concentration of Aliskiren. Monitor therapy

Alpha1-Blockers: May enhance the hypotensive effect of Calcium Channel Blockers. Monitor therapy

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

Amiodarone: Calcium Channel Blockers (Nondihydropyridine) may enhance the bradycardic effect of Amiodarone. Sinus arrest has been reported. Monitor therapy

AmLODIPine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of AmLODIPine. Monitor therapy

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

Anilidopiperidine Opioids: May enhance the bradycardic effect of Calcium Channel Blockers (Nondihydropyridine). Anilidopiperidine Opioids may enhance the hypotensive effect of Calcium Channel Blockers (Nondihydropyridine). Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May enhance the adverse/toxic effect of Calcium Channel Blockers. Specifically, itraconazole may enhance the negative inotropic effects of verapamil or diltiazem. Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Calcium Channel Blockers. Fluconazole and isavuconazonium likely exert weaker effects than other azoles and are addressed in separate monographs. Management: Concurrent use of felodipine or nisoldipine with itraconazole is specifically contraindicated. Frequent monitoring is warranted with any such combination; calcium channel blocker dose reductions may be required. Exceptions: Fluconazole; Isavuconazonium Sulfate. Consider therapy modification

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

Apixaban: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Apixaban. Monitor therapy

Aprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Aprepitant. Avoid combination

ARIPiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Aspirin: Calcium Channel Blockers (Nondihydropyridine) may enhance the antiplatelet effect of Aspirin. Monitor therapy

Asunaprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Asunaprevir. Avoid combination

AtorvaSTATin: May increase the serum concentration of Verapamil. Verapamil may increase the serum concentration of AtorvaSTATin. Management: Consider using lower atorvastatin doses when used together with verapamil. Consider therapy modification

Atosiban: Calcium Channel Blockers may enhance the adverse/toxic effect of Atosiban. Specifically, there may be an increased risk for pulmonary edema and/or dyspnea. Monitor therapy

Avanafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil. Management: The maximum avanafil adult dose is 50 mg per 24-hour period when used together with a moderate CYP3A4 inhibitor. Patients receiving such a combination should also be monitored more closely for evidence of adverse effects. Consider therapy modification

Barbiturates: May increase the metabolism of Calcium Channel Blockers. Management: Monitor for decreased therapeutic effects of calcium channel blockers with concomitant barbiturate therapy. Calcium channel blocker dose adjustments may be necessary. Nimodipine Canadian labeling contraindicates concomitant use with phenobarbital. Monitor therapy

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

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

Beta-Blockers: 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: Levobunolol; Metipranolol. Monitor therapy

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. Consider therapy modification

Blonanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Blonanserin. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosentan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Bosutinib: CYP3A4 Inhibitors (Moderate) 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

Brexpiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: The brexpiprazole dose should be reduced to 25% of usual if used together with both a moderate CYP3A4 inhibitor and a strong or moderate CYP2D6 inhibitor, or if a moderate CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Monitor therapy

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

Bromocriptine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bromocriptine. Management: The bromocriptine dose should not exceed 1.6 mg daily with use of a moderate CYP3A4 inhibitor. The Cycloset brand specifically recommends this dose limitation, but other bromocriptine products do not make such specific recommendations. Consider therapy modification

Budesonide (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic). Avoid combination

Budesonide (Topical): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification

BusPIRone: Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of BusPIRone. Consider therapy modification

Calcium Channel Blockers (Dihydropyridine): May enhance the hypotensive effect of Calcium Channel Blockers (Nondihydropyridine). Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Calcium Channel Blockers (Dihydropyridine). Monitor therapy

Calcium Salts: May diminish the therapeutic effect of Calcium Channel Blockers. Monitor therapy

Cannabis: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy

CarBAMazepine: Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Calcium Channel Blockers (Nondihydropyridine). Management: Consider empiric reductions in carbamazepine dose with initiation of nondihydropyridine calcium channel blockers. Monitor for increased toxic effects of carbamazepine and reduced therapeutic effects of the calcium channel blocker. Consider therapy modification

Cardiac Glycosides: Calcium Channel Blockers (Nondihydropyridine) may enhance the AV-blocking effect of Cardiac Glycosides. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration 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

Cilostazol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving moderate inhibitors of CYP3A4. Consider therapy modification

Cimetidine: May increase the serum concentration of Calcium Channel Blockers. Management: Consider alternatives to cimetidine. If no suitable alternative exists, monitor for increased effects of calcium channel blockers following cimetidine initiation/dose increase, and decreased effects following cimetidine discontinuation/dose decrease. Consider therapy modification

CloNIDine: May enhance the AV-blocking effect of Calcium Channel Blockers (Nondihydropyridine). Sinus node dysfunction may also be enhanced. Monitor therapy

Clopidogrel: Calcium Channel Blockers may diminish the therapeutic effect of Clopidogrel. Monitor therapy

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Monitor therapy

Cobimetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib. Management: Avoid the concomitant use of cobimetinib and moderate CYP3A4 inhibitors. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose to 20 mg daily. Avoid combination

Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. Use extra caution in patients with impaired renal and/or hepatic function. Consider therapy modification

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

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CycloSPORINE (Systemic): Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may decrease the metabolism of Calcium Channel Blockers (Nondihydropyridine). Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

CYP3A4 Substrates: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates. Exceptions: Alitretinoin (Systemic); Praziquantel; Vinorelbine. Monitor therapy

Dabigatran Etexilate: Verapamil may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Consider giving dabigatran 2 hrs before oral verapamil; other dose reductions may be needed. Specific recommendations vary by US vs Canadian labeling, renal function, and indication for dabigatran. Refer to full monograph or dabigatran labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dantrolene: May enhance the hyperkalemic effect of Calcium Channel Blockers (Nondihydropyridine). Dantrolene may enhance the negative inotropic effect of Calcium Channel Blockers (Nondihydropyridine). Management: This interaction has only been described with intravenous dantrolene administration. Avoid combination

Dapoxetine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dapoxetine. Management: The dose of dapoxetine should be limited to 30 mg/day when used together with a moderate inhibitor of CYP3A4. Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deflazacort: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Deflazacort. Management: Administer one third of the recommended deflazacort dose when used together with a strong or moderate CYP3A4 inhibitor. Consider therapy modification

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

Disopyramide: Verapamil may enhance the adverse/toxic effect of Disopyramide. Of particular concern is the potential for profound depression of myocardial contractility. Avoid combination

Dofetilide: Verapamil may increase the serum concentration of Dofetilide. Avoid combination

Domperidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Domperidone. Avoid combination

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

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

Dronabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Dronedarone: Calcium Channel Blockers (Nondihydropyridine) may enhance the AV-blocking effect of Dronedarone. Other electrophysiologic effects of Dronedarone may also be increased. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Dronedarone. Dronedarone may increase the serum concentration of Calcium Channel Blockers (Nondihydropyridine). Management: Use lower starting doses of the nondihydropyridine calcium channel blockers (i.e., verapamil, diltiazem), and only consider increasing calcium channel blocker dose after obtaining ECG-based evidence that the combination is being well-tolerated. 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

Efavirenz: May decrease the serum concentration of Calcium Channel Blockers. Monitor therapy

Eletriptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eletriptan. Management: The use of eletriptan within 72 hours of a moderate CYP3A4 inhibitor should be avoided. Consider therapy modification

Eliglustat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: When used concomitantly with moderate inhibitors of CYP3A4, eplerenone dosing recommendations vary by indication and international labeling. See full drug interaction monograph for details. Consider therapy modification

Esmolol: Calcium Channel Blockers (Nondihydropyridine) may enhance the bradycardic effect of Esmolol. Management: Administration of IV verapamil or diltiazem together with esmolol is contraindicated if one agent is given while the effects of the other are still present. Canadian esmolol labeling specifies that use within 24 hours is contraindicated. Consider therapy modification

Everolimus: CYP3A4 Inhibitors (Moderate) 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

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

FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary. Consider therapy modification

Fexofenadine: Verapamil may increase the bioavailability of Fexofenadine. Monitor therapy

Fingolimod: Verapamil may enhance the bradycardic effect of Fingolimod. Monitor therapy

Flecainide: Verapamil may enhance the adverse/toxic effect of Flecainide. In particular, this combination may significantly impair myocardial contractility and AV nodal conduction. Monitor therapy

Flibanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin. Avoid combination

Fluconazole: May increase the serum concentration of Calcium Channel Blockers. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fosphenytoin: Calcium Channel Blockers may increase the serum concentration of Fosphenytoin. Management: Monitor for phenytoin toxicity with concomitant use of a calcium channel blocker (CCB) or decreased phenytoin effects with CCB discontinuation. Monitor for decreased CCB therapeutic effects. Nimodipine Canadian labeling contraindicates use with phenytoin. Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Grapefruit Juice: May increase the serum concentration of Verapamil. Monitor therapy

GuanFACINE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination. Consider therapy modification

Halofantrine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine. 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

HYDROcodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of HYDROcodone. Monitor therapy

HydrOXYzine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of HydrOXYzine. Management: This combination is specifically contraindicated in some non-U.S. labeling. Consider therapy modification

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

Ibrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib. Management: If a moderate CYP3A inhibitor must be used, consider reducing the dose of ibrutinib to 140mg daily and monitor closely for signs of toxicity. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ifosfamide: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Imatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Imatinib. Monitor therapy

Ivabradine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivabradine. Avoid combination

Ivabradine: Calcium Channel Blockers (Nondihydropyridine) may enhance the bradycardic effect of Ivabradine. Ivabradine may enhance the QTc-prolonging effect of Calcium Channel Blockers (Nondihydropyridine). Specifically, the QTc prolonging effects of bepridil may be enhanced. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Ivabradine. Specifically, verapamil or diltiazem may increase serum ivabradine concentrations. Avoid combination

Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult full monograph content for specific age- and weight-based recommendations. No dose adjustment is needed when using ivacaftor/lumefantrine with a moderate CYP3A4 inhibitor. Consider therapy modification

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

Lithium: Calcium Channel Blockers (Nondihydropyridine) may enhance the neurotoxic effect of Lithium. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Lithium. Decreased or unaltered lithium concentrations have also been reported with this combination. Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lomitapide. Avoid combination

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

Lovastatin: Verapamil may increase the serum concentration of Lovastatin. Management: Initiate lovastatin at a maximum adult dose of 10 mg/day, and do not exceed 20 mg/day, in patients receiving verapamil. Monitor closely for signs of HMG-CoA reductase inhibitor toxicity (e.g., myositis, rhabdomyolysis). Consider therapy modification

Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Management: Lurasidone US labeling recommends reducing lurasidone dose by half with a moderate CYP3A4 inhibitor. Some non-US labeling recommends initiating lurasidone at 20 mg/day and limiting dose to 40 mg/day; avoid concurrent use of grapefruit products. Consider therapy modification

Macrolide Antibiotics: May decrease the metabolism of Calcium Channel Blockers. Management: Consider using a noninteracting macrolide. Felodipine Canadian labeling specifically recommends avoiding its use in combination with clarithromycin. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin; Spiramycin. Consider therapy modification

Magnesium Salts: Calcium Channel Blockers may enhance the adverse/toxic effect of Magnesium Salts. Magnesium Salts may enhance the hypotensive effect of Calcium Channel Blockers. Monitor therapy

Manidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Manidipine. Monitor therapy

MetFORMIN: Verapamil may diminish the therapeutic effect of MetFORMIN. Monitor therapy

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

Midodrine: Calcium Channel Blockers (Nondihydropyridine) may enhance the bradycardic effect of Midodrine. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mirodenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mirodenafil. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

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: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Neuromuscular-Blocking Agents (Nondepolarizing): Calcium Channel Blockers may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). 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

NiMODipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NiMODipine. Monitor therapy

Nintedanib: Combined Inhibitors of CYP3A4 and P-glycoprotein may increase the serum concentration of Nintedanib. Monitor therapy

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

Olaparib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib. Management: Avoid use of moderate CYP3A4 inhibitors in patients being treated with olaparib. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 200 mg twice daily. Avoid combination

OxyCODONE: CYP3A4 Inhibitors (Moderate) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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

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

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

Phenytoin: Calcium Channel Blockers may increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Calcium Channel Blockers. Management: Avoid use of nimodipine or nifedipine with phenytoin. Monitor for phenytoin toxicity and/or decreased calcium channel blocker effects with any concurrent use. Consider therapy modification

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

Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Monitor therapy

Pimozide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pimozide. Avoid combination

Propafenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Propafenone. Monitor therapy

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

Protease Inhibitors: May decrease the metabolism of Calcium Channel Blockers (Nondihydropyridine). Increased serum concentrations of the calcium channel blocker may increase risk of AV nodal blockade. Management: Avoid concurrent use when possible. If used, monitor for CCB toxicity. The manufacturer of atazanavir recommends a 50% dose reduction for diltiazem be considered. Saquinavir, tipranavir, and darunavir/cobicistat use with bepridil is contraindicated. Consider therapy modification

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 enhance the hypotensive effect of Verapamil. Verapamil may increase the serum concentration of QuiNIDine. Monitor therapy

Ranolazine: Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Ranolazine. Management: Limit ranolazine dose to a maximum of 500 mg twice daily when used with diltiazem or verapamil. Consider therapy modification

Ranolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine. Management: Limit the ranolazine adult dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.). Consider therapy modification

Red Yeast Rice: Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Red Yeast Rice. Specifically, concentrations of lovastatin (and possibly other related compounds) may be increased. Monitor therapy

Regorafenib: May enhance the bradycardic effect of Calcium Channel Blockers (Nondihydropyridine). Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of Calcium Channel Blockers. This primarily affects oral forms of calcium channel blockers. Management: The labeling for some US and Canadian calcium channel blockers contraindicate use with rifampin, however recommendations vary. Consult appropriate labeling. Consider therapy modification

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

RisperiDONE: Verapamil may increase the serum concentration of RisperiDONE. Monitor therapy

Rivaroxaban: Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Rivaroxaban. Management: No action is needed in patients with normal renal function. US labeling recommends avoidance in patients with estimated creatinine clearance 15 to 80 mL/min unless prospective benefits outweigh the risks. See monograph for details of Canadian labeling. Consider therapy modification

Rupatadine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rupatadine. Monitor therapy

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

Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Monitor therapy

SAXagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of SAXagliptin. Monitor therapy

Sildenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sildenafil. Monitor therapy

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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simeprevir. Avoid combination

Simvastatin: Verapamil may increase the serum concentration of Simvastatin. Management: Avoid concurrent use of verapamil with simvastatin when possible. If used together, limit adult maximum simvastatin dose to 10 mg/day, and avoid Simcor (simvastatin/niacin) because fixed simvastatin doses in the product exceed this maximum. Consider therapy modification

Sonidegib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sonidegib. Management: Avoid concomitant use of sonidegib and moderate CYP3A4 inhibitors when possible. When concomitant use cannot be avoided, limit CYP3A4 inhibitor use to less than 14 days and monitor for sonidegib toxicity (particularly musculoskeletal adverse reactions). Consider therapy modification

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Suvorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Suvorexant. Consider therapy modification

Tacrolimus (Systemic): Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Tacrolimus (Systemic). Monitor therapy

Tacrolimus (Topical): Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Tacrolimus (Topical). Monitor therapy

Telithromycin: May enhance the bradycardic effect of Verapamil. Telithromycin may enhance the hypotensive effect of Verapamil. Consider therapy modification

Tetrahydrocannabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Ticagrelor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ticagrelor. Monitor therapy

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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Avoid combination

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

Trabectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin. Avoid combination

Udenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Udenafil. Monitor therapy

Ulipristal: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combination should be monitored for ulipristal toxicity. Avoid combination

Venetoclax: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. 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

Vilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone. Monitor therapy

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

Vindesine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vindesine. Monitor therapy

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

Zopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zopiclone. Management: The starting adult dose of zopiclone should not exceed 3.75 mg if combined with a moderate CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification

Zuclopenthixol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zuclopenthixol. Monitor therapy

Test Interactions

May interfere with urine detection of methadone (false-positive) (Lichtenwalner 1998).

Adverse Reactions

>10%:

Central nervous system: Headache (1% to 12%)

Gastrointestinal: Gingival hyperplasia (≤19%), constipation (7% to 12%)

1% to 10%:

Cardiovascular: Peripheral edema (1% to 4%), hypotension (3%), cardiac failure (≤2%), atrioventricular block (1% to 2%), bradycardia (heart rate <50 bpm: 1%), flushing (1%), angina pectoris (oral: ≤1%), atrioventricular dissociation (oral: ≤1%), cerebrovascular accident (oral: ≤1%), chest pain (oral: ≤1%), claudication (oral: ≤1%), ECG abnormality (oral: ≤1%), myocardial infarction (oral: ≤1%), palpitations (oral: ≤1%), syncope (oral: ≤1%)

Central nervous system: Fatigue (2% to 5%), dizziness (1% to 5%), lethargy (3%), pain (2%), paresthesia (1%), sleep disorder (1%), confusion (oral: ≤1%), drowsiness (oral: ≤1%; IV: <1%), equilibrium disturbance (oral: ≤1%), extrapyramidal reaction (oral: ≤1%), insomnia (oral: ≤1%), psychosis (oral: ≤1%), shakiness (oral: ≤1%)

Dermatologic: Skin rash (1% to 2%), alopecia (oral: ≤1%), diaphoresis (oral: ≤1%), erythema multiforme (oral: ≤1%), hyperkeratosis (oral: ≤1%), macular eruption (oral: ≤1%), Stevens-Johnson syndrome (oral: ≤1%), urticaria (oral: ≤1%)

Endocrine & metabolic: Galactorrhea (oral: ≤1%), gynecomastia (oral: ≤1%), hyperprolactinemia (oral: ≤1%), spotty menstruation (oral: ≤1%)

Gastrointestinal: Dyspepsia (3%), nausea (1% to 3%), diarrhea (2%), abdominal distress (oral: ≤1%), gastrointestinal distress (oral: ≤1%), xerostomia (oral: ≤1%)

Genitourinary: Impotence (oral: ≤1%)

Hematologic & oncologic: Bruise (oral: ≤1%), purpuric vasculitis (oral: ≤1%)

Hepatic: Increased liver enzymes (1%)

Neuromuscular & skeletal: Myalgia (1%), arthralgia (oral: ≤1%), muscle cramps (oral: ≤1%), weakness (oral: ≤1%)

Ophthalmic: Blurred vision (oral: ≤1%)

Otic: Tinnitus (oral: ≤1%)

Renal: Polyuria (oral: ≤1%)

Respiratory: Flu-like symptoms (4%), pulmonary edema (≤2%), dyspnea (1%)

<1% (Limited to important or life-threatening): Asystole, bronchospasm (IV administration), depression (IV administration), diaphoresis (IV administration), drowsiness (IV administration), electromechanical dissociation, eosinophilia, exfoliative dermatitis, gastrointestinal obstruction, hair discoloration, laryngospasm (IV administration), muscle fatigue (IV administration), paralytic ileus, Parkinsonian-like syndrome, pruritus (IV administration), respiratory failure (IV administration), rotary nystagmus (IV administration), seizure (IV administration), shock, urticaria (IV administration), vertigo (IV administration), ventricular fibrillation

Warnings/Precautions

Concerns related to adverse effects:

• Conduction abnormalities: May cause first-degree AV block or sinus bradycardia. Higher degrees of AV block may also occur (rare) and in extreme cases, asystole; more likely to occur in patients with a sick sinus syndrome. If marked first degree block, progressive development to second- or third-degree AV block, or unifascicular, bifascicular, or trifascicular bundle branch block occurs, consider a dosage reduction or discontinue therapy.

• Hepatic effects: Elevations of hepatic transaminases, alkaline phosphatase, and bilirubin have been reported; hepatocellular injury has been proven by rechallenge. Periodically monitor liver function. Some elevations have been transient and disappeared with continued therapy.

• Hypotension/syncope: Symptomatic hypotension with or without syncope may occur; blood pressure must be lowered at a rate appropriate for the patient's clinical condition.

Disease-related concerns:

• Arrhythmia: Considered contraindicated in patients with wide complex tachycardias unless known to be supraventricular in origin; severe hypotension likely to occur upon administration (ACLS 2010).

• Attenuated neuromuscular transmission: Decreased neuromuscular transmission has been reported; use with caution in patients with attenuated neuromuscular transmission (Duchenne muscular dystrophy, myasthenia gravis); dosage reduction may be required.

• Heart failure: The ACCF/AHA heart failure guidelines recommend to avoid use in patients with heart failure due to lack of benefit and/or worse outcomes with calcium channel blockers in general (Yancy 2013).

• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage reduction may be required; monitor hemodynamics and possibly ECG in severe impairment. Avoid repeated injections of IV verapamil in patients with significant hepatic failure.

• Hypertrophic cardiomyopathy (HCM): Use with caution in patients with HCM with outflow tract obstruction (especially those with high gradients, advanced heart failure, or sinus bradycardia); may be used in patients who cannot tolerate beta-blockade. Verapamil should not be used in those with systemic hypotension or severe dyspnea at rest (Gersh 2011; Nishimura 2004).

• Increased intracranial pressure: IV verapamil has increased intracranial pressure in patients with supratentorial tumors at the time of anesthesia induction; use with caution in these patients.

• Renal impairment: Use with caution in patients with renal impairment; monitor hemodynamics and possibly ECG in severe impairment, particularly if concomitant hepatic impairment. Avoid repeated injections of IV verapamil in patients with significant renal failure.

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:

• Pediatric: In neonates and young infants, avoid IV use for SVT due to severe apnea, bradycardia, hypotensive reactions, and cardiac arrest; in older children, use IV with caution as myocardial depression and hypotension may occur (PALS [Kleinman 2010]).

Monitoring Parameters

Monitor blood pressure and heart rate; periodic liver function tests; ECG, especially with renal and/or hepatic impairment

Consult individual institutional policies and procedures.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies in doses, which also caused maternal toxicity. Verapamil crosses the placenta. Use during pregnancy may cause adverse fetal effects (bradycardia, heart block, hypotension) (Tan 2001). Women with hypertrophic cardiomyopathy who are controlled with verapamil prior to pregnancy may continue therapy, but increased fetal monitoring is recommended (Gersh 2011). Verapamil may be used IV for the acute treatment of supraventricular tachycardia (SVT) in pregnant women when adenosine or beta-blockers are ineffective or contraindicated. Verapamil may also be used for the ongoing management of SVT in highly symptomatic patients. The lowest effective dose is recommended; avoid use during the first trimester if possible (Page [ACC/AHA/HRS 2015]). Untreated chronic maternal hypertension is associated with adverse events in the fetus, infant, and mother. If treatment for hypertension during pregnancy is needed, other agents are preferred (ACOG 2013). Additional guidelines are available for management of cardiovascular diseases during pregnancy (ESG [Regitz-Zagrosek 2011]).

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 or headache. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), bradycardia, arrhythmia, severe dizziness, passing out, shortness of breath, excessive weight gain, or swelling of arms or legs (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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