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Diltiazem

Pronunciation

Pronunciation

(dil TYE a zem)

Index Terms

  • Diltiazem HCl in 0.9% NaCl
  • Diltiazem Hcl/D5w
  • Diltiazem Hydrochloride

Dosage Forms

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

Capsule Extended Release 12 Hour, Oral, as hydrochloride:

Generic: 60 mg, 90 mg, 120 mg

Capsule Extended Release 24 Hour, Oral, as hydrochloride:

Cardizem CD: 120 mg, 180 mg, 240 mg, 300 mg, 360 mg [contains brilliant blue fcf (fd&c blue #1)]

Cartia XT: 120 mg, 180 mg, 240 mg, 300 mg

Dilacor XR: 240 mg [DSC]

Dilt-CD: 120 mg [DSC]

Dilt-CD: 180 mg [DSC], 240 mg [DSC] [contains brilliant blue fcf (fd&c blue #1)]

Dilt-CD: 300 mg [DSC]

Dilt-XR: 120 mg, 180 mg, 240 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40, fd&c yellow #10 (quinoline yellow)]

DiltiaZEM CD: 120 mg

DiltiaZEM CD: 180 mg [contains brilliant blue fcf (fd&c blue #1), fd&c yellow #10 (quinoline yellow)]

DiltiaZEM CD: 240 mg, 300 mg [contains fd&c yellow #10 (quinoline yellow)]

Diltzac: 120 mg [DSC] [contains brilliant blue fcf (fd&c blue #1)]

Diltzac: 180 mg [DSC]

Diltzac: 240 mg [DSC], 300 mg [DSC] [contains brilliant blue fcf (fd&c blue #1)]

Diltzac: 360 mg [DSC]

Taztia XT: 120 mg [contains brilliant blue fcf (fd&c blue #1), fd&c blue #1 aluminum lake, fd&c blue #2 aluminum lake, fd&c red #40, fd&c red #40 aluminum lake, fd&c yellow #10 aluminum lake]

Taztia XT: 180 mg [contains brilliant blue fcf (fd&c blue #1), fd&c blue #1 aluminum lake, fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake, fd&c yellow #10 (quinoline yellow), fd&c yellow #10 aluminum lake, fd&c yellow #6 (sunset yellow)]

Taztia XT: 240 mg [contains brilliant blue fcf (fd&c blue #1), fd&c blue #1 aluminum lake, fd&c blue #2 aluminum lake, fd&c red #40, fd&c red #40 aluminum lake, fd&c yellow #10 aluminum lake]

Taztia XT: 300 mg [contains brilliant blue fcf (fd&c blue #1), fd&c blue #1 aluminum lake, fd&c blue #2 aluminum lake, fd&c red #40, fd&c red #40 aluminum lake, fd&c yellow #10 aluminum lake, fd&c yellow #6 (sunset yellow)]

Taztia XT: 360 mg [contains brilliant blue fcf (fd&c blue #1), fd&c blue #1 aluminum lake, fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake, fd&c yellow #10 aluminum lake]

Tiazac: 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]

Generic: 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg

Solution, Intravenous, as hydrochloride:

Generic: 25 mg/5 mL (5 mL); 50 mg/10 mL (10 mL); 125 mg/25 mL (25 mL)

Solution, Intravenous, as hydrochloride [preservative free]:

Generic: 25 mg/5 mL (5 mL [DSC]); 50 mg/10 mL (10 mL); 125 mg/25 mL (25 mL)

Solution Reconstituted, Intravenous, as hydrochloride:

Generic: 100 mg (1 ea)

Tablet, Oral, as hydrochloride:

Cardizem: 30 mg

Cardizem: 30 mg [contains fd&c blue #1 aluminum lake, fd&c yellow #10 aluminum lake]

Cardizem: 60 mg [DSC] [scored]

Cardizem: 60 mg [scored; contains fd&c blue #1 aluminum lake, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake, methylparaben]

Cardizem: 90 mg [DSC] [scored]

Cardizem: 120 mg [DSC] [contains fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake, methylparaben]

Cardizem: 120 mg [scored; contains fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake, methylparaben]

Generic: 30 mg, 60 mg, 90 mg, 120 mg

Tablet Extended Release 24 Hour, Oral, as hydrochloride:

Cardizem LA: 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg

Matzim LA: 180 mg, 240 mg, 300 mg, 360 mg, 420 mg

Generic: 180 mg, 240 mg, 300 mg, 360 mg, 420 mg

Brand Names: U.S.

  • Cardizem
  • Cardizem CD
  • Cardizem LA
  • Cartia XT
  • Dilacor XR [DSC]
  • Dilt-CD [DSC]
  • Dilt-XR
  • DiltiaZEM CD
  • Diltzac [DSC]
  • Matzim LA
  • Taztia XT
  • Tiazac

Pharmacologic Category

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

Pharmacology

Nondihydropyridine calcium channel blocker which inhibits calcium ion from entering the “slow channels” or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization, producing a relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina

Absorption

Immediate release tablet: >90%; Extended release capsule: ~93%

Distribution

Vd: 3 to 13 L/kg

Metabolism

Hepatic (extensive first-pass effect) via CYP-450 and conjugation; forms metabolites N-monodesmethyldiltiazem, desacetyldiltiazem, desacetyl-Nmonodesmethyldiltiazem, desacetyl-O-desmethyldiltiazem, and desacetyl-N, O-desmethyldiltiazem following single IV injection, plasma concentrations of N-monodesmethyldiltiazem and desacetyldiltiazem are typically undetectable; however, these metabolites accumulate to detectable concentrations following 24-hour constant rate infusion.

Excretion

Urine (2% to 4% as unchanged drug); feces

Onset of Action

Oral: Immediate release tablet: 30 to 60 minutes; IV: Bolus: 3 minutes

Time to Peak

Serum: Immediate release tablet: 2 to 4 hours; Extended release tablet: 11 to 18 hours; Extended release capsule: 10 to 14 hours

Duration of Action

IV: Bolus: 1 to 3 hours; Continuous infusion (after discontinuation): 0.5 to 10 hours

Half-Life Elimination

Immediate release tablet: 3 to 4.5 hours; Extended release tablet: 6 to 9 hours; Extended release capsules: 5 to 10 hours; IV: single dose: ~3.4 hours; continuous infusion: 4 to 5 hours

Protein Binding

70% to 80%

Special Populations: Hepatic Function Impairment

Bioavailability is increased, and half-life is prolonged.

Use: Labeled Indications

Oral: Primary hypertension; chronic stable angina or angina from coronary artery spasm

Guideline recommendations:

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

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

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

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

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

Chronic kidney disease (CKD) and hypertension: Regardless of race or diabetes status, the use of an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) as initial therapy is recommended to improve kidney outcomes. In the general nonblack population (without CKD) including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic, calcium channel blocker, ACEI, or ARB. In the general black population (without CKD) including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic or a calcium channel blocker instead of an ACEI or ARB.

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]).

Injection: Control of rapid ventricular rate in patients with atrial fibrillation or atrial flutter; conversion of paroxysmal supraventricular tachycardia (PSVT)

Use: Unlabeled

ACLS guidelines: Injection: Stable narrow-complex tachycardia uncontrolled or unconverted by adenosine or vagal maneuvers or if SVT is recurrent

Atrial fibrillation (rate control) (oral); hypertrophic cardiomyopathy; pediatric hypertension

Contraindications

Oral: Hypersensitivity to diltiazem or any component of the formulation; sick sinus syndrome (except in patients with a functioning artificial pacemaker); second- or third-degree AV block (except in patients with a functioning artificial pacemaker); hypotension (systolic <90 mm Hg); acute MI and pulmonary congestion

Intravenous (IV): Hypersensitivity to diltiazem or any component of the formulation; sick sinus syndrome (except in patients with a functioning artificial pacemaker); second- or third-degree AV block (except in patients with a functioning artificial pacemaker); severe hypotension; cardiogenic shock; administration concomitantly or within a few hours of the administration of IV beta-blockers; atrial fibrillation or flutter associated with accessory bypass tract (eg, Wolff-Parkinson-White syndrome, short PR syndrome); ventricular tachycardia (with wide-complex tachycardia [QRS ≥0.12 seconds], must determine whether origin is supraventricular or ventricular)

Canadian labeling: Additional contraindications (not in U.S. labeling): IV and Oral: Pregnancy; use in women of childbearing potential; concurrent use with intravenous dantrolene

Dosing: Adult

Angina: Oral:

Capsule, extended release:

Dilacor XR, Dilt-XR: Initial: 120 mg once daily; titrate over 7 to 14 days; usual dose range (ACC/AHA [Gibbons 2002]): 120 to 320 mg daily: maximum: 480 mg daily

Cardizem CD, Cartia XT: Initial: 120 to 180 mg once daily; titrate over 7 to 14 days; usual dose range (ACC/AHA [Gibbons 2002]): 120 to 320 mg daily; maximum: 480 mg daily

Tiazac, Taztia XT: Initial: 120 to 180 mg once daily; titrate over 7 to 14 days; usual dose range (ACC/AHA [Gibbons 2002]): 120 to 320 mg daily; maximum: 540 mg daily

Tablet, extended release (Cardizem LA, Matzim LA, Tiazac XC [Canadian product]): 180 mg once daily; may increase at 7- to 14-day intervals; usual dose range (ACC/AHA [Gibbons 2002]): 120 to 320 mg/day; maximum: 360 mg daily

Tablet, immediate release (Cardizem): Usual starting dose: 30 mg 4 times daily; titrate dose gradually at 1- to 2-day intervals; usual dose range (ACC/AHA [Gibbons 2002]): 120 to 320 mg daily in 4 divided doses

Hypertension: Oral:

Capsule, extended release (once-daily dosing):

Cardizem CD, Cartia XT: Initial: 180 to 240 mg once daily; dose adjustment may be made after 14 days; usual dose range (ASH/ISH [Weber 2014]): 240 to 360 mg daily; maximum: 480 mg daily

Dilacor XR, Dilt-XR: Initial: 180 to 240 mg once daily; dose adjustment may be made after 14 days; usual dose range (ASH/ISH [Weber 2014]): 240 to 360 mg daily; maximum: 540 mg daily

Tiazac, Taztia XT: Initial: 120 to 240 mg once daily; dose adjustment may be made after 14 days; usual dose range (ASH/ISH [Weber 2014]): 240 to 360 mg daily; maximum: 540 mg daily

Capsule, extended release (twice-daily dosing): Initial: 60 to 120 mg twice daily; dose adjustment may be made after 14 days; usual range: 240 to 360 mg daily

Note: Diltiazem is available as a generic intended for either once- or twice-daily dosing, depending on the formulation; verify appropriate extended release capsule formulation is administered.

Tablet, extended release (Cardizem LA, Matzim LA, Tiazac XC [Canadian product]): Initial: 180 to 240 mg once daily; dose adjustment may be made after 14 days; usual dose range (ASH/ISH [Weber 2014]): 240 to 360 mg daily; maximum: 540 mg daily

Atrial fibrillation, atrial flutter, PSVT: IV:

Initial bolus dose: 0.25 mg/kg actual body weight over 2 minutes (average adult dose: 20 mg); ACLS guideline recommends 15 to 20 mg

Repeat bolus dose (may be administered after 15 minutes if the response is inadequate): 0.35 mg/kg actual body weight over 2 minutes (average adult dose: 25 mg); ACLS guideline recommends 20 to 25 mg

Continuous infusion (infusions >24 hours or infusion rates >15 mg/hour are not recommended): Initial infusion rate of 10 mg/hour; rate may be increased in 5 mg/hour increments up to 15 mg/hour as needed; some patients may respond to an initial rate of 5 mg/hour.

If diltiazem injection is administered by continuous infusion for >24 hours, the possibility of decreased diltiazem clearance, prolonged elimination half-life, and increased diltiazem and/or diltiazem metabolite plasma concentrations should be considered.

Atrial fibrillation (rate control) (off-label use): Oral: Extended release (capsule or tablet): Usual maintenance dose: 120 to 360 mg once daily (AHA/ACC/HRS [January 2014])

Conversion from IV diltiazem to oral diltiazem:

Oral dose (mg daily) is approximately equal to [rate (mg/hour) x 3 + 3] x 10.

3 mg/hour = 120 mg daily

5 mg/hour = 180 mg daily

7 mg/hour = 240 mg daily

11 mg/hour = 360 mg daily

Dosing: Geriatric

Refer to adult dosing. In the management of hypertension, consider lower initial doses (eg, 120 mg once daily using extended release capsule) and titrate to response (Aronow 2011).

Dosing: Pediatric

Children: Minimal information available; some centers use the following:

Hypertension (off-label use): Oral: Initial: 1.5-2 mg/kg/day in 3 divided doses (maximum: 6 mg/kg/day, up to 360 mg daily) (Flynn 2000)

Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Dialysis: Not removed by hemo- or peritoneal dialysis; supplemental dose is not necessary.

Dosing: Hepatic Impairment

There are no dosage adjustment provided in the manufacturer’s labeling; use with caution; extensively metabolized by the liver; half-life is increased in patients with cirrhosis.

Reconstitution

Solution for injection: Continuous IV infusion: Further dilute with NS, D5W, or D51/2NS to a maximum final concentration of 1 mg/mL.

Solution reconstituted, IV (ADD-Vantage): Refer to manufacturer’s labeling.

Extemporaneously Prepared

A 12 mg/mL oral suspension may be made from tablets (regular, not extended release) and one of three different vehicles (cherry syrup, a 1:1 mixture of Ora-Sweet® and Ora-Plus®, or a 1:1 mixture of Ora-Sweet® SF and Ora-Plus®). Crush sixteen 90 mg tablets in a mortar and reduce to a fine powder. Add 10 mL of the chosen vehicle 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” and “protect from light". Stable for 60 days when stored in amber plastic prescription bottles in the dark at room temperature or refrigerated. Note: The tablets used within the supportive study were tablets manufactured using a direct compression technique and were not film-coated. Use of film-coated tablets to prepare an oral suspension has not been formally evaluated and may result in an unsuitable suspension. The manufacturers of the film-coated tablets do not recommend crushing. Brand name Cardizem tablets are prepared using a direct compression technique and may be crushed.

Allen LV and Erickson MA, “Stability of Baclofen, Captopril, Diltiazem Hydrochloride, Dipyridamole, and Flecainide Acetate in Extemporaneously Compounded Oral Liquids,” Am J Health Syst Pharm, 1996, 53(18):2179-84.8879325

Administration

Oral:

Immediate release tablet (eg, Cardizem): Administer before meals and at bedtime. The manufacturers of the film-coated tablets recommend to swallow the tablet whole; do not split, crush, or chew. According to these manufacturers, crushing immediate release tablets may alter pharmacokinetics. However, crushing tablets that are prepared using a direct compression technique is acceptable. An oral suspension has been made using the immediate release tablets manufactured using a direct compression technique (Allen 1996). Brand name Cardizem tablets are prepared using a direct compression technique and may be crushed.

Long acting dosage forms: Do not open, chew, or crush; swallow whole. Administer at same time of day either morning or evening.

Cardizem CD, Cardizem LA, Cartia XT, Matzim LA: Administer without regard to meals.

Dilacor XR: Administer on an empty stomach.

Dilt XR: Administer on an empty stomach in the morning.

Taztia XT, Tiazac: Capsules may be opened and sprinkled on a spoonful of applesauce. Applesauce should not be hot and should be swallowed without chewing, followed by drinking a glass of water.

Tiazac XC [Canadian product]: Administer at bedtime

IV: Bolus doses given over 2 minutes with continuous ECG and blood pressure monitoring. Continuous infusion should be via infusion pump. May increase infusion rate in 5 mg/hour increments as needed (maximum: 15 mg/hour). Response to bolus may require several minutes to reach maximum. Response may persist for several hours after infusion is discontinued.

Compatibility

Stable in D51/2NS, D5W, NS.

Y-site administration: Incompatible with diazepam, furosemide, micafungin, phenytoin, rifampin, thiopental.

Compatibility in syringe: Incompatible with ceftriaxone.

Storage

Capsule, tablet: Store 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light. Avoid excessive heat (>30°C) and humidity.

Solution for injection: Store in refrigerator at 2°C to 8°C (36°F to 46°F); do not freeze. May be stored at room temperature for up to 1 month. Following dilution to ≤1 mg/mL with D51/2NS, D5W, or NS, solution is stable for 24 hours at room temperature (15°C to 30°C (59°F to 86°F) or under refrigeration.

Solution reconstituted, intravenous (ADD-Vantage): Store at 20°C to 25°C (68°F to 77°F); do not freeze. Following reconstitution, solution is stable for 24 hours at room temperature or under refrigeration (2°C to 8°C [36°F to 46°F]).

Drug Interactions

Alfentanil: DiltiaZEM may increase the serum concentration of Alfentanil. Monitor therapy

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

ARIPiprazole: CYP2D6 Inhibitors (Weak) 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 DiltiaZEM. DiltiaZEM may increase the serum concentration of AtorvaSTATin. Management: Consider using lower atorvastatin doses when used together with diltiazem. 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

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

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

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

Colestipol: May decrease the absorption of DiltiaZEM. Monitor therapy

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

Corticosteroids (Systemic): DiltiaZEM may increase the serum concentration of Corticosteroids (Systemic). Monitor therapy

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

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

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

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

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

Efavirenz: May decrease the serum concentration of DiltiaZEM. 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

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

Fingolimod: DiltiaZEM may enhance the bradycardic effect of Fingolimod. 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 DiltiaZEM. The active metabolite aprepitant is likely responsible for this effect. DiltiaZEM may increase the serum concentration of Fosaprepitant. Specifically, diltiazem may increase the concentration of the active metabolite aprepitant. 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 DiltiaZEM. 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

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 prescribing information for specific age- and weight-based recommendations. 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

Lovastatin: May increase the serum concentration of DiltiaZEM. DiltiaZEM 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 diltiazem. 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: U.S. labeling: start at 20 mg/day and limit to max of 80 mg/day with moderate CYP3A4 inhibitor. Canadian labeling: limit to max of 40 mg/day with moderate CYP3A4 inhibitor; avoid concomitant 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

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

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

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

Perhexiline: CYP2D6 Inhibitors (Weak) may increase the serum concentration of Perhexiline. 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

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

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

QuiNIDine: DiltiaZEM 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

RifAMPin: May decrease the serum concentration of DiltiaZEM. Avoid combination

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

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

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: May increase the serum concentration of DiltiaZEM. DiltiaZEM may increase the serum concentration of Simvastatin. Management: Avoid concurrent use of diltiazem with simvastatin when possible. If used together, limit adult doses to simvastatin 10 mg/day and diltiazem 240 mg/day; avoid Simcor (simvastatin/niacin) because fixed simvastatin doses exceed the 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

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

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

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

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

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

Adverse Reactions

Note: Frequencies represent ranges for various dosage forms. Patients with impaired ventricular function and/or conduction abnormalities may have higher incidence of adverse reactions.

>10%:

Cardiovascular: Edema (2% to 15%)

Central nervous system: Headache (5% to 12%)

2% to 10%:

Cardiovascular: Atrioventricular block (2% to 8%; first degree), edema (2% to 8%; lower limb), bradycardia (2% to 6%), hypotension (<2% to 4%), vasodilatation (2% to 3%), extrasystoles (2%), flushing (1% to 2%), palpitations (1% to 2%)

Central nervous system: Dizziness (3% to 10%), pain (6%), nervousness (2%)

Dermatologic: Skin rash (1% to 4%)

Endocrine & metabolic: Gout (1% to 2%)

Gastrointestinal: Dyspepsia (1% to 6%), constipation (<2% to 4%), vomiting (2%), diarrhea (1% to 2%)

Local: Injection site reaction (4%; itching, burning)

Neuromuscular & skeletal: Weakness (1% to 4%), myalgia (2%)

Respiratory: Rhinitis (<2% to 10%), pharyngitis (2% to 6%), dyspnea (1% to 6%), bronchitis (1% to 4%), cough (≤3), sinus congestion (1% to 2%)

<2% (Limited to important or life-threatening): Amblyopia, amnesia, atrioventricular block (second or third degree), bundle branch block, cardiac arrhythmia, cardiac failure, depression, dysgeusia, extrapyramidal reaction, gingival hyperplasia, hemolytic anemia, hypersensitivity reaction, increased serum alkaline phosphatase, increased serum ALT, increased serum AST, petechiae, skin photosensitivity, Stevens-Johnson syndrome, syncope, tachycardia, thrombocytopenia, tremor, toxic epidermal necrolysis

Warnings/Precautions

Concerns related to adverse effects:

• Conduction abnormalities: May cause first-, second-, and third-degree AV block or sinus bradycardia; risk increases with agents known to slow cardiac conduction.

• Dermatologic reactions: Transient dermatologic reactions have been observed with use; if reaction persists, discontinue. Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and/or exfoliative dermatitis have been reported.

• Hepatic effects: Mild elevations of transaminases with and without concomitant elevation in alkaline phosphatase and bilirubin have been observed and frequently resolve spontaneously. Significant elevations in hepatic transaminases (eg, alkaline phosphatase, LDH, AST, ALT) and signs of acute hepatic injury have also been observed. One to 8 weeks after therapy initiation and have been reversible upon discontinuation.

• 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.

• Peripheral edema: The most common side effect is peripheral edema.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Hypertrophic obstructive cardiomyopathy (HOCM): Use with caution in patients with HOCM; routine use is currently not recommended due to insufficient evidence (Maron 2003).

• Left ventricular dysfunction: Use with caution in left ventricular dysfunction; due to negative inotropic effects, may exacerbate condition. 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 (ACCF/AHA [Yancy 2013]).

• Renal impairment: Use with caution in patients with renal impairment.

Concurrent drug therapy:

• 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.

Other warnings/precautions:

• Appropriate use: IV: Unless otherwise contraindicated, appropriate vagal maneuvers should be attempted prior to administration of IV diltiazem. Use with caution in patients hemodynamically compromised; continuously monitor ECG and blood pressure during administration (especially during continuous IV infusion). Initial use should be, if possible, in a setting where monitoring and resuscitation equipment, including DC cardioversion/defibrillation, are present.

Monitoring Parameters

Liver function tests, kidney function, blood pressure, ECG, heart rate; consult individual institutional policies and procedures. Ventricular rate control in patients with atrial fibrillation or flutter: Patients who respond, usually have at least a 20% decrease in ventricular response rate or a rate <100 beats/minute.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. 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). The Canadian labeling contraindicates use in pregnant women or women of childbearing potential. Women with hypertrophic cardiomyopathy who are controlled with diltiazem prior to pregnancy may continue therapy, but increased fetal monitoring is recommended (Gersh 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 flushing, headache, nausea, loss of strength and energy, rhinorrhea, pharyngitis, or injection site irritation. 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), severe dizziness, passing out, bradycardia, arrhythmia, shortness of breath, excessive weight gain, swelling of arms or legs, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

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

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

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