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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

Well absorbed

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: 1-2 hours; IV: Peak effect: 1-5 minutes

Time to Peak

Serum: Oral:

Immediate release: 1-2 hours

Extended release (Covera-HS, Verelan PM): ~11 hours, drug release delayed ~ 4-5 hours

Sustained release: 5.21 hours (Calan SR, Isoptin SR); 7-9 hours (Verelan)

Duration of Action

Oral: Immediate release tablets: 6-8 hours; IV: 10-20 minutes

Half-Life Elimination

Infants: 4.4-6.9 hours; Adults: Single dose: 3-7 hours, Multiple doses: 4.5-12 hours; severe hepatic impairment: 14-16 hours

Protein Binding

Neonates: ~60%; Adults: ~90%

Special Populations: Hepatic Function Impairment

Metabolism is delayed and plasma clearance is reduced to ~30% of normal.

Special Populations: Gender

A gender difference was not observed in the clinical trials of verapamil. Conflicting data in the literature suggest that verapamil Cl decreased with age in women to a greater degree than in men.

Body Weight

Lean body weight affects verapamil pharmacokinetics inversely.

Use: Labeled Indications

IV: Supraventricular tachyarrhythmia (PSVT, atrial fibrillation/flutter [rate control])

Oral: Treatment of hypertension; angina pectoris (vasospastic, chronic stable, unstable) (Calan, Covera-HS); supraventricular tachyarrhythmia (PSVT, atrial fibrillation/flutter [rate control])

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 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.

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

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)

IV: Additional contraindications include concurrent use of IV beta-blocking agents; ventricular tachycardia

Dosing: Adult

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

Immediate release: Initial: 80 to 120 mg 3 times daily (elderly or small stature: 40 mg 3 times daily); Usual dose range (Gibbons, 2003): 80 to 160 mg 3 times daily

Extended release (Covera-HS): Initial: 180 mg once daily at bedtime; if inadequate response, may increase dose at weekly intervals to 240 mg once daily, then 360 mg once daily, then 480 mg once daily; maximum dose: 480 mg daily

PSVT prophylaxis: Oral:

Manufacturer’s labeling: Immediate release: 240 to 480 mg daily in 3 to 4 divided doses

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 daily in divided doses (immediate release) or once daily (extended release) (ACC/AHA/HRS [Page 2015])

Hypertension: Oral: Note: When switching from immediate-release to extended/sustained 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; usual dose range (ASH/ISH [Weber, 2014]): 240 to 480 mg daily

Sustained 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: Initial: 180 mg once daily in the morning (elderly or small stature: 120 mg daily); if inadequate response, 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); maximum dose: 240 mg twice daily.

Verelan: Initial: 180 mg once daily in the morning (elderly or small stature: 120 mg/day); if inadequate response, may increase dose at weekly intervals to 240 mg once daily, then 360 mg once daily, then 480 mg once daily; maximum dose: 480 mg daily

Extended release: Usual dosage range (ASH/ISH [Weber, 2014]): 240 to 480 mg daily

Covera-HS: Initial: 180 mg once daily at bedtime; if inadequate response, may increase dose at weekly intervals to 240 mg once daily, then 360 mg once daily, then 480 mg once daily; maximum dose: 480 mg daily

Verelan PM: Initial: 200 mg once daily at bedtime (elderly or small stature: 100 mg daily); if inadequate response, may increase dose at weekly intervals to 300 mg once daily, then 400 mg once daily; maximum dose: 400 mg daily

Atrial fibrillation (rate control):

IV: Initial: 0.075 to 0.15 mg/kg (usual dose: 5 to 10 mg) administered as a bolus over 2 minutes; if no response, may give an additional 10 mg 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 range: 180 to 480 mg once daily (AHA/ACC/HRS [January, 2014])

Immediate release: 240 to 480 mg daily in 3 to 4 divided doses

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

ACLS guidelines: 2.5 to 5 mg over 2 minutes; 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 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

Refer to adult dosing.

Hypertension: Oral: Note: When switching from immediate release to extended or sustained 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

Sustained release: Calan SR, Isoptin SR,Verelan: Initial: 120 mg once daily in the morning

Extended release:

Covera-HS: Initial: 180 mg once daily at bedtime

Verelan PM: Initial: 100 mg once daily at bedtime

ACCF/AHA Expert Consensus recommendations: Consider lower initial doses and titrating to response (Aronow, 2011)

Dosing: Pediatric

SVT: Note: Verapamil is no longer included in the Pediatric Advanced Life Support (PALS) tachyarrhythmia algorithm.

Children: 1-15 years: IV: 0.1 to 0.3 mg/kg/dose over 2 minutes; maximum: 5 mg/dose, may repeat dose in 30 minutes if inadequate response; maximum for second dose: 10 mg

Dosing: Renal Impairment

Manufacturer recommends caution and additional ECG monitoring in patients with renal insufficiency. The manufacturer of Verelan PM recommends an initial dose of 100 mg daily at bedtime. Note: 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

In cirrhosis, reduce dose to 20% and 50% of normal for oral and intravenous administration, respectively, and monitor ECG (Somogyi, 1981). The manufacturer of Verelan PM recommends an initial adult dose of 100 mg/day at bedtime. The manufacturers of Calan, Calan SR, Covera-HS, Isoptin SR, and Verelan recommend giving 30% of the normal dose to patients with severe hepatic impairment.

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 sustained or extended release products.

Calan SR, Isoptin SR: Administer with food.

Verelan, Verelan PM: Capsules may be opened and the contents sprinkled on 1 tablespoonful of applesauce, then swallowed immediately without chewing. Do not subdivide contents of capsules.

IV: Rate of infusion: Over 2 minutes; over 3 minutes in older patients (ACLS, 2010)

Dietary Considerations

Calan SR and Isoptin SR products may be taken with food or milk, other formulations may be administered without regard to meals; sprinkling contents of Verelan or Verelan PM capsule onto applesauce does not affect oral absorption.

Compatibility

Stable in dextran 40 10% in NS, dextran 75 6% in NS, D5LR, D51/2NS, D5NS, D5W, LR, 1/2NS, NS. Note: Physically compatible in solutions of pH of 3-6, but may precipitate in solutions having a pH >6.

Y-site administration: Incompatible with albumin, amphotericin B cholesteryl sulfate complex, ampicillin, nafcillin, oxacillin, pantoprazole, sodium bicarbonate.

Compatibility in syringe: Incompatible with pantoprazole.

Storage

Store at controlled room temperature of 15°C to 30°C (59°F to 86°F). Protect from light.

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

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

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

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

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

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

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

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

Nafcillin: May increase the metabolism of Calcium Channel Blockers. Consider therapy modification

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 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit 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 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

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).

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: Can cause first-degree AV block or sinus bradycardia; other conduction abnormalities are rare. Use is contraindicated in patients with sick sinus syndrome, second- or third-degree AV block (except in patients with a functioning artificial pacemaker), or an accessory bypass tract (eg, WPW syndrome).

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

• Increased hepatic enzymes: Rare increases in liver function tests have been observed.

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 with verapamil; use with caution in patients with attenuated neuromuscular transmission (Duchenne's muscular dystrophy, myasthenia gravis); dosage reduction may be required.

• Heart failure: Avoid use in heart failure; can exacerbate condition. Use is contraindicated in severe left ventricular dysfunction.

• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage reduction may be required; monitor hemodynamics and possibly ECG if severe impairment.

• 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).

• Renal impairment: Use with caution; monitor hemodynamics and possibly ECG if severe impairment, particularly if concomitant hepatic impairment.

Concurrent drug therapy issues:

• Agents with SA/AV nodal-blocking properties: Use caution when using verapamil together with a beta-blocker. Administration of IV verapamil and an IV beta-blocker within a few hours of each other may result in asystole and should be avoided; simultaneous administration is contraindicated. Use with other agents known to reduce SA node function and/or AV nodal conduction (eg, digoxin) or reduce sympathetic outflow (eg, clonidine) may increase the risk of serious bradycardia.

• Digoxin: Verapamil significantly increases digoxin serum concentrations; adjust digoxin dose.

• Neuromuscular-blocking agents: May prolong recovery from nondepolarizing neuromuscular-blocking agents.

Special populations:

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

Dosage form specific issues:

• Extended-release delivery system (Covera-HS): Use with caution in patients with severe GI narrowing. In patients with extremely short GI transit times (eg, <7 hours), dosage adjustment may be required; inadequate pharmacokinetic data.

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 were 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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