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Verapamil: Drug information

Verapamil: Drug information
(For additional information see "Verapamil: Patient drug information" and see "Verapamil: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Calan SR;
  • Calan [DSC];
  • Verelan;
  • Verelan PM
Brand Names: Canada
  • APO-Verap;
  • Isoptin SR;
  • MYLAN-Verapamil;
  • MYLAN-Verapamil SR;
  • PMS-Verapamil SR;
  • RIVA-Verapamil SR [DSC]
Pharmacologic Category
  • Antianginal Agent;
  • Antiarrhythmic Agent, Class IV;
  • Antihypertensive;
  • Calcium Channel Blocker;
  • Calcium Channel Blocker, Nondihydropyridine
Dosing: Adult

Note : Avoid in patients taking a beta-blocker or who have heart failure with reduced ejection fraction, sinus node dysfunction, or second- or third-degree atrioventricular block unless a functioning pacemaker has been placed. Manufacturer's labeling for ER tablets suggests once-daily or twice-daily dosing (at higher doses), whereas ER capsules are administered once daily (regardless of dose). Use ER capsules (delayed-onset/PM formulation) only for hypertension.

Angina pectoris

Angina pectoris:

Chronic stable angina (alternative agent):

Note: Alternative therapy if there are contraindications to or unacceptable adverse effects with beta-blockade (ACCF/AHA [Fihn 2012]).

Oral:

Immediate release: Initial: 80 to 120 mg 3 times daily; increase as needed at ≥1- to 2-day intervals to effective antianginal dose; maximum dose: 480 mg/day in 3 divided doses (Hauf-Zachariou 1997; Kannam 2020; manufacturer's labeling).

Extended release: Initial: 180 mg once daily; increase as needed at 7- to 14-day intervals to effective antianginal dose; maximum dose: 480 mg/day in 1 to 2 divided doses (Frishman 1999; Kannam 2020).

Vasospastic angina:

Note: May use alone or in combination with nitrates (ACCF/AHA [Fihn 2012]).

Oral:

Immediate release: Initial: 80 to 120 mg 3 times daily; increase as needed at ≥1- to 2-day intervals to effective antianginal dose; maximum dose: 480 mg/day in 3 divided doses.

Extended release: Initial: 180 mg once daily; increase as needed at 7- to 14-day intervals to effective antianginal dose; maximum dose: 480 mg/day in 1 to 2 divided doses.

Atrial fibrillation or atrial flutter, rate control

Atrial fibrillation or atrial flutter, rate control (alternative agent):

Note: For rate control in hemodynamically stable patients. Do not use in patients with preexcitation associated with an accessory pathway, as this can lead to ventricular arrhythmias (AHA/ACC/HRS [January 2014]). May be associated with more hypotension compared to diltiazem (Phillips 1997).

Acute ventricular rate control:

IV:

Bolus: Initial: 5 to 10 mg over ≥2 minutes; if there is inadequate response, dose may be repeated after 15 to 30 minutes; if there is adequate response after 1 to 2 bolus doses, then may begin a continuous infusion (Barbarash 1986; Knight 2022; Phillips 1997).

Continuous infusion: Initial: 5 mg/hour; titrate to goal heart rate up to a maximum of 20 mg/hour (AHA/ACC/HRS [January 2014]; Barbarash 1986; Knight 2022; Phillips 1997).

Chronic ventricular rate control:

Oral:

Immediate release: Initial: 40 mg 3 to 4 times daily; increase as needed to achieve rate control; maximum dose: 480 mg/day in 3 to 4 divided doses (Knight 2022; manufacturer's labeling).

Extended release (off-label use): Initial: 120 or 180 mg once daily; increase as needed to achieve rate control; maximum dose: 480 mg/day in 1 to 2 divided doses (AHA/ACC/HRS [January 2014]; Knight 2022).

Chest pain associated with cocaine ingestion, with or without evidence of acute coronary syndrome

Chest pain associated with cocaine ingestion, with or without evidence of acute coronary syndrome (off-label use):

Note: Adjunct or alternative agent in patients not controlled with nitroglycerin.

IV: Bolus: Initial: 2.5 to 5 mg over ≥2 minutes; may repeat after 15 minutes if needed (Morgan 2022).

Cluster headache, prevention

Cluster headache, prevention (off-label use):

Note: May be used as monotherapy or in combination with other preventive and/or bridging agents (eg, glucocorticoids [Obermann 2015; Obermann 2021]). Example regimens are presented below. Obtain an ECG prior to treatment and after each titration when dose is >480 mg/day (Koppen 2016).

Oral:

Immediate release: Initial: 40 to 80 mg 3 times daily; increase dose every 1 to 2 weeks until headaches subside or adverse reactions develop; usual effective dose: 240 to 480 mg/day in 3 to 4 divided doses (Bussone 1990; EFNS [May 2006]; Koppen 2016; Leone 2000; Obermann 2015; Obermann 2021; Petersen 2019).

Extended release: Initial: 240 mg in 2 divided doses; increase dose every 1 to 2 weeks until headaches subside or adverse reactions develop; usual effective dose: 240 to 480 mg/day in 2 divided doses (EFNS [May 2006]; Gabai 1989; Koppen 2016; Obermann 2015).

Hypertension

Hypertension (alternative agent):

Note: Reserve nondihydropyridine calcium channel blockers for patients with a relevant comorbidity (eg, rate control in atrial fibrillation or flutter) (Mann 2020). For patients who warrant combination therapy (BP >20/10 mm Hg above goal or suboptimal response to initial monotherapy), may use in combination with another appropriate agent (eg, angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, thiazide diuretic) (ACC/AHA [Whelton 2018]).

Oral:

Immediate release: Initial: 40 to 80 mg 3 times daily; increase dose as needed at weekly intervals; usual dose: 120 to 360 mg/day in 3 divided doses (ACC/AHA [Whelton 2018]); maximum dose: 480 mg/day in 3 divided doses.

Extended release: Initial: 120 or 180 mg once daily; increase dose as needed at weekly intervals; usual dose: 120 to 360 mg/day in 1 to 2 divided doses (ACC/AHA [Whelton 2018]); maximum dose: 480 mg/day in 1 to 2 divided doses.

Extended release (delayed-onset/PM formulation): Initial: 100 or 200 mg once daily at bedtime; increase dose as needed at weekly intervals; usual dose: 100 to 300 mg once daily at bedtime (ACC/AHA [Whelton 2018]); maximum dose: 400 mg once daily at bedtime.

Migraine, prevention

Migraine, prevention (off-label use):

Note: Tolerance may develop; consider increasing dose or switching to another calcium channel blocker if tolerance occurs (Schwedt 2022). An adequate trial for assessment of effect is considered to be at least 2 to 3 months at a therapeutic dose (EHF [Steiner 2019]).

Oral:

Immediate release: Initial: 40 mg 3 times daily; titrate every 1 to 2 weeks based on patient response and tolerability up to 480 mg/day in 3 to 4 divided doses (CHS [Pringsheim 2012]; Schwedt 2022; Soloman 1983).

Extended release: Initial: 120 mg once daily; titrate every 1 to 2 weeks based on patient response and tolerability up to 480 mg/day in 2 to 3 divided doses (Pelzer 2013; Razavi 2000; Schwedt 2022; Yu 2003).

Supraventricular tachycardia

Supraventricular tachycardia (eg, atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia, focal atrial tachycardia, multifocal atrial tachycardia) (alternative agent):

Note: For hemodynamically stable patients if vagal maneuvers and/or adenosine are unsuccessful. Do not use in patients with preexcitation associated with an accessory pathway, as this can lead to ventricular arrhythmias (ACC/AHA/HRS [Page 2016]).

Acute treatment (off-label use):

IV: Bolus: Initial: 5 to 10 mg over ≥2 minutes; if response is insufficient after 15 to 30 minutes, a second bolus dose of 10 mg over 2 minutes may be administered. If 2 bolus doses do not terminate the arrhythmia, consider alternative therapy (ACC/AHA/HRS [Page 2016]; Delaney 2011).

Chronic maintenance:

Oral:

Immediate release: Initial: 40 mg 3 to 4 times daily; increase as needed for heart rate control; maximum dose: 480 mg/day in 3 to 4 divided doses (ACC/AHA/HRS [Page 2016]; manufacturer's labeling).

Extended release (off-label use): Initial: 120 mg once daily; increase as needed for heart rate control; maximum dose: 480 mg/day in 1 to 2 divided doses (ACC/AHA/HRS [Page 2016]).

Ventricular arrhythmias

Ventricular arrhythmias:

Idiopathic left ventricular tachycardia (off-label use):

Note: In patients with wide QRS complex ventricular tachycardia of unknown origin, calcium channel blockers are potentially harmful. However, verapamil is safe and effective in patients with idiopathic left ventricular tachycardia (AHA/ACC/HRS [Al-Khatib 2017]).

Acute idiopathic left ventricular tachycardia:

IV: Bolus: 5 to 10 mg over ≥2 minutes; if no response after 15 to 30 minutes, may give 1 additional 10 mg bolus dose (AHA/ACC/HRS [Al-Khatib 2017]; Callans 2020).

Prevention of idiopathic left ventricular arrhythmias:

Oral:

Immediate release: 120 mg 3 times daily (Gill 1992a; Gill 1992b; Gill 1993).

Extended release: 240 to 480 mg/day in 1 to 2 divided doses (AHA/ACC/HRS [Al-Khatib 2017]).

Nonsustained ventricular tachycardia or ventricular premature beats, symptomatic (alternative agent) (off-label use):

Note: A beta-blocker is the preferred initial therapy; if there are ongoing symptoms on beta-blocker therapy, verapamil may be added with close monitoring of heart rate; verapamil may be used as an alternative therapy if beta-blockade cannot be tolerated (AHA/ACC/HRS [Al-Khatib 2018]; EHRA/HRS/APHRS [Pedersen 2014]; Manolis 2022; Zimetbaum 2022).

Oral:

Immediate release: Initial: 40 or 80 mg 3 times daily; titrate as needed based on symptom control and tolerability; maximum dose: 360 mg/day in 3 to 4 divided doses (Manolis 2022; Zimetbaum 2022).

Extended release: Initial: 120 or 180 mg once daily; titrate as needed based on symptom control and tolerability; maximum dose: 360 mg/day in 1 to 2 divided doses (Manolis 2022; Zimetbaum 2022).

Conversion between oral formulations: When switching from IR to ER formulations, the total daily dose remains the same unless formulation strength does not allow for equal conversion. At higher doses, some ER products are recommended to be given twice daily.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

Manufacturer's labeling:

Oral: Extended release (delayed-onset/PM formulation): Initial: 100 mg once daily at bedtime; titrate similar to adult dosing. Note: There are no dosage adjustments provided in the manufacturer's labeling for the other products; however, use with caution and consider additional ECG monitoring.

Injection: There are no dosage adjustments provided in the manufacturer's labeling; however, repeated injections in patients with renal failure may lead to accumulation. If repeated injections are essential, monitor BP and PR interval closely and use smaller doses.

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

Dosing: Hepatic Impairment: Adult

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

Extended release: Administer 30% of the normal dose in severe hepatic impairment.

Extended release (delayed-onset/PM formulation): Initial: 100 mg once daily at bedtime.

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

Dosing: Pediatric

(For additional information see "Verapamil: Pediatric drug information")

Supraventricular tachycardia

Supraventricular tachycardia (SVT): Note: Although verapamil is effective in the treatment of SVT, it is not included in the PALS tachyarrhythmia algorithm due to its adverse effects (PALS [Kleinman 2010]).

IV:

Infants: Note: May decrease cardiac output resulting in hypotension and possible cardiac arrest in infants; some experts consider verapamil use contraindicated (Kliegman 2016). If used, it should only be with expert consultation and continuous ECG monitoring with IV calcium at the bedside: 0.1 to 0.2 mg/kg/dose (usual: 0.75 to 2 mg/dose) may repeat dose after at least 30 minutes if response inadequate; optimal interval not defined; patient should be monitored closely (Gal 2007; Nelson 1996)

Children and Adolescents 1 to 15 years: 0.1 to 0.3 mg/kg/dose (usual dose: 2 to 5 mg/dose); maximum dose: 5 mg/dose; may repeat dose in 15 to 30 minutes if response inadequate; maximum dose for second dose: 10 mg/dose (Kliegman 2016; PALS [Kleinman 2010]; Park 2014). Note: May also be administered intraosseous. Optimal interval for subsequent doses is unknown and must be individualized for each specific patient.

Adolescents ≥16 years:

Initial dose:

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

Manufacturer's labeling: 5 to 10 mg (0.075 to 0.15 mg/kg/dose); maximum dose: 10 mg/dose (Kugler 1996); similar dosing recommended in the adult ACC/AHA/HRS SVT guidelines: 5 to 10 mg (0.075 to 0.15 mg/kg) over 2 minutes (ACC/AHA/HRS [Page 2015])

Repeat dose: May repeat dose in 15 to 30 minutes if adequate response not achieved; maximum dose for second dose: 10 mg/dose (Kliegman 2016; PALS [Kleinman 2010]; Park 2014). Note: Optimal interval for subsequent doses is unknown and must be individualized for each specific patient.

Oral: Limited data available: Children and Adolescents: Immediate release: 2 to 8 mg/kg/day in 3 divided doses; maximum daily dose: 480 mg/day (Kliegman 2016). A mean daily dose of ~5 mg/kg/day (range: 2.3 to 8.1 mg/kg/day) was used in 22 children 15 days to 17 years of age receiving chronic oral therapy for SVT (n=20) or hypertrophic cardiomyopathy (n=2) (Piovan 1995).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

There are no pediatric specific recommendations. Based on experience in adult patients, use with caution and consider additional ECG monitoring; data suggest clearance of verapamil and its metabolite (norverapamil) is decreased; dosing adjustment suggested.

Dialysis: Not removed by hemodialysis; supplemental dose is not necessary.

Dosing: Hepatic Impairment: Pediatric

There are no pediatric specific recommendations; based on in experience in adult patients, dosing adjustment suggested.

Dosing: Older Adult

Hypertension: Oral:

Immediate release: Initial: 40 mg 3 times daily; titrate similar to adult dosing.

Extended release: Initial: 120 mg once daily in the morning; titrate similar to adult dosing.

Extended release (delayed-onset/PM formulation): Initial: 100 mg once daily at bedtime; titrate similar to adult dosing.

Other indications: Refer to adult dosing.

Dosage Forms: US

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 (allura red ac dye), methylparaben, propylparaben]

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

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

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)

Solution, Intravenous, as hydrochloride [preservative free]:

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

Tablet, Oral, as hydrochloride:

Calan: 120 mg [DSC]

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 [contains fd&c blue #2 (indigo carm) aluminum lake, quinoline (d&c yellow #10) aluminum lake]

Calan SR: 240 mg [DSC] [scored; contains fd&c blue #2 (indigo carm) aluminum lake, quinoline (d&c yellow #10) aluminum lake]

Generic: 120 mg, 180 mg, 240 mg

Generic Equivalent Available: US

Yes

Dosage Forms Considerations

Some ER oral products may be referred to as sustained release in the manufacturer's labeling; however, there are generally no differences between products of the same dosage form described as ER or sustained release. All products are referred to as ER throughout the monograph.

Dosage Forms: Canada

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

Solution, Intravenous, as hydrochloride:

Generic: 2.5 mg/mL (2 mL)

Tablet, Oral, as hydrochloride:

Generic: 80 mg, 120 mg

Tablet Extended Release, Oral, as hydrochloride:

Isoptin SR: 120 mg, 180 mg

Isoptin SR: 240 mg [contains fd&c blue #2 (indigo carm) aluminum lake, quinoline (d&c yellow #10) aluminum lake]

Generic: 120 mg, 180 mg, 240 mg

Tablet Extended Release 24 Hour, Oral, as hydrochloride:

Generic: 240 mg [DSC]

Administration: Adult

Oral: Do not crush or chew ER products.

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

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

Bariatric surgery: Tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. ER tablet should be swallowed whole. Do not crush or chew. IR tablet and injectable formulations are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, selection of IR formulation or alternative therapy is advised for cardiovascular and other high-risk labeled and off-label indications.

IV: Administer IV push over ≥2 minutes; in older patients for the acute treatment of supraventricular tachycardia, Advanced Cardiac Life Support guidelines recommend administering over 3 minutes (ACLS [Neumar 2010]).

Administration: Pediatric

Oral: Immediate release: Can be administered with or without food.

Parenteral: IV: Administer undiluted dose over 2 to 3 minutes; infuse over 3 to 4 minutes if blood pressure is in the lower range of normal

Use: Labeled Indications

Angina: Treatment of angina at rest, including chronic stable angina, vasospastic angina, and unstable angina.

Atrial fibrillation or atrial flutter, rate control:

Oral: IR tablet: Control of ventricular rate at rest and during stress in chronic atrial flutter and/or fibrillation.

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

Hypertension: Oral: IR tablet/ER capsule and tablet: Management of hypertension.

Supraventricular tachycardia:

Oral: IR tablet: Prophylaxis of supraventricular tachycardia, such as atrioventricular (AV) nodal reentrant tachycardia, AV reentrant tachycardia, focal atrial tachycardia, or multifocal atrial tachycardia.

IV: Rapid conversion to sinus rhythm.

Use: Off-Label: Adult

Chest pain associated with cocaine ingestion, with or without evidence of acute coronary syndrome; Cluster headache, prevention; Hypertrophic cardiomyopathy; Idiopathic left ventricular tachycardia; Migraine, prevention; Nonsustained ventricular tachycardia or ventricular premature beats, symptomatic

Medication Safety Issues
Sound-alike/look-alike issues:

Calan may be confused with Colace, dilTIAZem

Isoptin may be confused with Isopto Tears

Verelan may be confused with Voltaren

Pediatric patients: High-risk medication:

KIDs List: Verapamil, when used in infants <1 year of age, is identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list; use should be avoided due to risk of asystole (weak recommendation; low quality of evidence) (PPA [Meyers 2020]).

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication (IV formulation) among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Administration issues:

Significant differences exist between oral and IV dosing. Use caution when converting from one route of administration to another.

International issues:

Dilacor [Brazil] may be confused with Dilacor XR brand name for dilTIAZem [US]

Adverse Reactions (Significant): Considerations
Acute decompensated heart failure

In patients with left ventricular systolic dysfunction, use of verapamil may result in acute decompensation and deterioration with development of pulmonary edema and/or hypotension (Ref). Acute cardiac failure associated with verapamil in patients with no prior history of chronic heart failure have also been reported (Ref). Decompensated state should return to baseline after discontinuation (Ref).

Mechanism: Dose-related; related to the pharmacologic action. Exhibits significant negative inotropic and vasodilator properties. Patients with left ventricular dysfunction may not be able to compensate or tolerate these hemodynamic effects (Ref).

Onset: Rapid; typically within 4 to 5 days of therapy initiation (Ref).

Risk factors:

• Severe left ventricular dysfunction (Ref)

• Older patients (Ref)

• Cardiac amyloidosis (Ref)

Bradyarrhythmias

Verapamil may cause first-, second-, or third-degree atrioventricular (AV) block or sinus bradycardia (Ref). Although reversal is possible after discontinuation, some patients continue to have symptoms (Ref). In patients whose symptoms resolve after discontinuation, permanent pacemaker (PPM) therapy will likely not be necessary; however, cases with recurrent or unresolved symptoms after discontinuation may warrant PPM placement (Ref).

Mechanism: Dose-related; related to the pharmacologic action. Verapamil blocks L-type calcium channels, leading to prolonged refractoriness and slowing of conduction through the AV node (Ref).

Onset: Varied; in one study, bradycardia occurred 5 minutes after administration with a peak effect at 30 to 60 minutes (Ref). Other studies have suggested that conduction abnormalities may take a few weeks to develop (Ref).

Risk factors:

• Concurrent use with other AV nodal-blocking agents (eg, beta-blockers) (Ref)

• Sick sinus syndrome (Ref)

• Underlying AV node dysfunction (Ref)

Hepatic effects

Mild-to-moderate increased serum transaminases, increased serum alkaline phosphatase, and increased serum bilirubin have been reported, including self-limited jaundice (Ref). Complete recovery is generally expected within 2 to 6 weeks of discontinuation and may resolve with continuation of therapy (Ref). Rechallenge may result in rapid recurrence of hepatocellular injury (Ref).

Mechanism: Non–dose-related; immunologic or idiosyncratic (Ref). Mechanism of hepatotoxicity is likely related to hypersensitivity (Ref). Verapamil is a derivative of papaverine, which is known to cause allergic hepatitis (Ref). The idiosyncratic cause may be due to mutations in efflux transport of verapamil (Ref).

Onset: Varied; symptoms such as jaundice, fatigue, or weakness usually occur 2 to 8 weeks after initiation of therapy, although the onset may be 5 to 6 months (Ref).

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions presented are for the oral formation unless otherwise indicated.

>10%: Nervous system: Headache (IV, oral: 1% to 12%)

1% to 10%:

Cardiovascular: Acute myocardial infarction (≤1%), angina pectoris (≤1%), ankle edema (1%), atrioventricular block (IV, oral: ≤1%), atrioventricular dissociation (≤1%), bradycardia (IV, oral: ≤1%), cardiac failure (≤2%), cerebrovascular accident (≤1%), chest pain (≤1%), claudication (≤1%), ECG abnormality (≤2%), edema (2%), hypotension (IV, oral: 2% to 3%, can be symptomatic), palpitations (≤1%), peripheral edema (4%) (table 1), syncope (≤1%), tachycardia (IV: 1%; severe)

Verapamil: Adverse Reaction: Peripheral Edema

Drug (Verapamil)

Placebo

Dosage Form

Dose

Number of Patients (Verapamil)

Number of Patients (Placebo)

4%

0.9%

Extended release

All doses studied

297

116

Dermatologic: Alopecia (≤1%), diaphoresis (IV, oral: ≤1%), ecchymoses (≤1%), erythema multiforme (≤1%), hyperkeratosis (≤1%), macular eruption (≤1%), skin rash (≤1%), Stevens-Johnson syndrome (≤1%), urticaria (≤1%)

Endocrine & metabolic: Galactorrhea not associated with childbirth (≤1%), gynecomastia (≤1%), hyperprolactinemia (≤1%), spotty menstruation (≤1%)

Gastrointestinal: Constipation (4% to 9%) (table 2), diarrhea (≤1%), dyspepsia (3%), gastrointestinal distress (≤1%), gingival hyperplasia (≤1%), nausea (IV, oral: ≤3%), xerostomia (≤1%)

Verapamil: Adverse Reaction: Constipation

Drug (Verapamil)

Placebo

Dosage Form

Dose

Number of Patients (Verapamil)

Number of Patients (Placebo)

9%

0.9%

Extended release

All doses studied

297

116

7%

N/A

Immediate release

N/A

285

N/A

7%

N/A

Extended release

N/A

4,954

N/A

4%

N/A

Extended release

200 mg/day

N/A

N/A

Genitourinary: Impotence (≤1%)

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

Hepatic: Increased serum transaminases (≤2%)

Nervous system: Balance impairment (≤1%), confusion (≤1%), dizziness (IV, oral: 1% to 4%), drowsiness (IV, oral: ≤1%), extrapyramidal reaction (≤1%), fatigue (2%), insomnia (≤1%), lethargy (3%), paresthesia (≤1%), psychosis (≤1%), shakiness (≤1%), sleep disorder (1%)

Neuromuscular & skeletal: Arthralgia (≤1%), asthenia (≤2%), muscle cramps (≤1%), myalgia (1%)

Ophthalmic: Blurred vision (≤1%)

Otic: Tinnitus (≤1%)

Renal: Polyuria (≤1%)

Respiratory: Dyspnea (≤1%), flu-like symptoms (4%), pulmonary edema (≤2%)

<1%:

Cardiovascular: Asystole, flushing, ventricular tachycardia

Gastrointestinal: Abdominal distress, paralytic ileus (nonobstructive)

Postmarketing:

Cardiovascular: Ventricular fibrillation

Dermatologic: Psoriasis (Song 2021)

Hepatic: Increased serum alkaline phosphatase (LiverTox 2017), increased serum bilirubin (LiverTox 2017), jaundice (LiverTox 2017)

Nervous system: Depression (Dassylva 1993), seizure (during IV injection) (Maiteh 2001), vertigo

Neuromuscular & skeletal: Muscle fatigue

Ophthalmic: Rotary nystagmus

Respiratory: Respiratory failure (Zalman 1983)

Contraindications

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

Canadian labeling: Additional contraindications (not in US labeling): Complicated myocardial infarction (MI) (ventricular failure manifested by pulmonary congestion); severe congestive heart failure and/or severe left ventricular dysfunction (eg, ejection fraction <40%) unless secondary to a supraventricular tachycardia amendable to oral verapamil; marked bradycardia; concurrent use of ivabradine or flibanserin; concurrent use with beta-blockers in patients with poor ventricular function and in the treatment of hypertension; concurrent use of grapefruit juice; breastfeeding.

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

Canadian labeling: Additional contraindications (not in US labeling): Complicated MI (ventricular failure manifested by pulmonary congestion); severe left ventricular dysfunction; marked bradycardia; concurrent use of ivabradine or flibanserin; breastfeeding.

Warnings/Precautions

Disease-related concerns:

• Accessory pathway (eg, Wolff-Parkinson-White syndrome): During an episode of atrial fibrillation or flutter in patients with an accessory pathway or preexcitation syndrome, use has been associated with increased anterograde conduction down the accessory pathway leading to ventricular fibrillation; avoid use in such patients (ACLS [Neumar 2010]; AHA/ACC/HRS [January 2014]).

• Arrhythmia: Considered contraindicated in patients with wide complex tachycardias unless known to be supraventricular in origin; severe hypotension likely to occur upon administration (AHA [Panchal 2020]).

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

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

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

• Left ventricular dysfunction: Avoid use in patients with heart failure due to lack of benefit and/or worse outcomes with calcium channel blockers in general (AHA/ACC/HFSA [Heidenreich 2022]; AHA [Panchal 2020]).

• Renal impairment: Use with caution in patients with renal impairment; monitor hemodynamics and possibly ECG in severe impairment.

Special populations:

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

Warnings: Additional Pediatric Considerations

Although effective in terminating SVT in older children, verapamil is not the drug of choice (due to adverse effects) and is not included in the current PALS tachyarrhythmia algorithm.

Metabolism/Transport Effects

Substrate of CYP1A2 (minor), CYP2B6 (minor), CYP2C9 (minor), CYP2E1 (minor), CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak), CYP3A4 (moderate), P-glycoprotein/ABCB1

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Abemaciclib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Abemaciclib. Management: Monitor for increased abemaciclib toxicities if combined with moderate CYP3A4 inhibitors. Consider reducing the abemaciclib dose in 50 mg decrements if necessary. Risk C: Monitor therapy

Acalabrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Acalabrutinib. Management: Reduce acalabrutinib dose to 100 mg once daily with concurrent use of a moderate CYP3A4 inhibitor. Monitor patient closely for both acalabrutinib response and evidence of adverse effects with any concurrent use. Risk D: Consider therapy modification

Adagrasib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Adagrasib. Risk C: Monitor therapy

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: If combined, administer the P-gp inhibitor simultaneously with, or after, the dose of afatinib. Monitor closely for signs and symptoms of afatinib toxicity and if the combination is not tolerated, reduce the afatinib dose by 10 mg. Risk D: Consider therapy modification

Alfentanil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Alfentanil. Management: If use of alfentanil and moderate CYP3A4 inhibitors is necessary, consider dosage reduction of alfentanil until stable drug effects are achieved. Frequently monitor patients for respiratory depression and sedation when these agents are combined. Risk D: Consider therapy modification

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

Alfuzosin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Alfuzosin. Risk C: Monitor therapy

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

Alitretinoin (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Alitretinoin (Systemic). Risk C: Monitor therapy

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

ALPRAZolam: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ALPRAZolam. Management: Consider alternatives to this combination when possible. If combined, consider an alprazolam dose reduction and monitor for increased alprazolam effects and toxicities (eg, sedation, lethargy). Risk D: Consider therapy modification

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification

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

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

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

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

Apixaban: Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Apixaban. Risk C: Monitor therapy

Aprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Aprepitant. Risk X: 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, indication, or dosage form. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapy

ARIPiprazole Lauroxil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole Lauroxil. Risk C: Monitor therapy

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

Astemizole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Astemizole. Management: Avoid concomitant use of astemizole and moderate CYP3A4 inhibitors whenever possible. If combined, monitor closely for increased astemizole toxicities, especially for QTc interval prolongation. Risk D: Consider therapy modification

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

Atazanavir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Atazanavir. Risk C: Monitor therapy

Atogepant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Atogepant. Risk C: Monitor therapy

Atorvastatin: May increase the serum concentration of Verapamil. Verapamil may increase the serum concentration of Atorvastatin. Management: Consider using lower doses of atorvastatin when used together with verapamil, and monitor closely for signs of HMG-CoA reductase inhibitor toxicity (eg, myositis, rhabdomyolysis, hepatotoxicity). Risk D: 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. Risk C: Monitor therapy

Avacopan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avacopan. Risk C: Monitor therapy

Avanafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil. Management: The maximum avanafil 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 (eg, hypotension, syncope, priapism). Risk D: Consider therapy modification

Avapritinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avapritinib. Management: Avoid use of moderate CYP3A4 inhibitors with avapritinib. If this combination cannot be avoided, reduce the avapritinib dose to 100 mg daily for the treatment of GIST or to 50 mg daily for the treatment of advanced systemic mastocytosis. Risk D: Consider therapy modification

Axitinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Axitinib. Risk C: Monitor therapy

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

Barnidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Barnidipine. Risk C: Monitor therapy

Bedaquiline: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Bedaquiline. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bedaquiline. Risk C: Monitor therapy

Benidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Benidipine. Risk C: Monitor therapy

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

Benzhydrocodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Benzhydrocodone. Specifically, the concentration of hydrocodone may be increased. Risk C: Monitor therapy

Berotralstat: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Berotralstat. Management: Decrease the berotralstat dose to 110 mg daily when combined with P-glycoprotein (P-gp) inhibitors. Risk D: Consider therapy modification

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

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

Bortezomib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bortezomib. Risk C: Monitor therapy

Bosutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosutinib. Risk X: Avoid combination

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

Brigatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inhibitors when possible. If such a combination cannot be avoided, reduce the dose of brigatinib by approximately 40% (ie, from 180 mg to 120 mg, from 120 mg to 90 mg, or from 90 mg to 60 mg). Risk D: Consider therapy modification

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: 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. Risk D: Consider therapy modification

Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination

Budesonide (Oral Inhalation): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Oral Inhalation). Risk C: Monitor therapy

Budesonide (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic). Management: Avoid the concomitant use of CYP3A4 inhibitors and oral budesonide. If patients receive both budesonide and CYP3A4 inhibitors, they should be closely monitored for signs and symptoms of corticosteroid excess. Risk D: Consider therapy modification

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

Buprenorphine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Buprenorphine. Risk C: Monitor therapy

BusPIRone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of BusPIRone. Risk C: Monitor therapy

Cabozantinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cabozantinib. Risk C: Monitor therapy

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

Cannabis: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Risk C: 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 alternatives to this combination when possible. If combined, monitor for increased carbamazepine concentrations and toxicities and monitor for decreased calcium channel blocker efficacy. Risk D: 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. Risk C: Monitor therapy

Cariprazine: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Cariprazine. Specifically, concentrations of didesmethylcariprazine (DDCAR), the primary active metabolite of cariprazine, may increase. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cariprazine. Risk C: Monitor therapy

Celiprolol: Verapamil may enhance the bradycardic effect of Celiprolol. Verapamil may increase the serum concentration of Celiprolol. Management: Concomitant use of verapamil and celiprolol is not recommended, particularly in patients with pre-existing conduction abnormalities. When switching from one agent to the other, a drug-free period is recommended, and heart rate should be monitored closely. Risk D: Consider therapy modification

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. Risk D: Consider therapy modification

Cilostazol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Decrease the dose of cilostazol to 50 mg twice daily when combined with moderate CYP3A4 inhibitors. Risk D: Consider therapy modification

Cimetidine: May increase the serum concentration of Calcium Channel Blockers. Risk C: Monitor therapy

Cisapride: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cisapride. Management: Consider alternatives to this combination. Prescribing information for some moderate CYP3A4 inhibitors state coadministration with cisapride is contraindicated, while some others recommend monitoring and dose titration. Risk D: Consider therapy modification

Clindamycin (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Clindamycin (Systemic). Risk C: Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

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

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

Cobimetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib. Management: Avoid this combination when possible. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose from 60 mg to 20 mg daily. Avoid concomitant use in patients already receiving reduced cobimetinib doses. Risk D: Consider therapy modification

Codeine: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Codeine. Risk C: Monitor therapy

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. See interaction monograph for details. Use extra caution in patients with impaired renal and/or hepatic function. Risk D: 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-gp inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See interaction monograph for details. Risk D: Consider therapy modification

Conivaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Conivaptan. Risk C: Monitor therapy

Copanlisib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Copanlisib. Risk C: Monitor therapy

Crizotinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Crizotinib. Risk C: 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). Risk C: Monitor therapy

CycloSPORINE (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Verapamil. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Verapamil. Management: Consider alternatives to this combination. If combined, monitor for reduced verapamil efficacy. Verapamil dose increases may be necessary. Risk D: Consider therapy modification

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Verapamil. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Verapamil. Risk C: Monitor therapy

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Risk C: Monitor therapy

Dabrafenib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dabrafenib. Risk C: Monitor therapy

Dantrolene: May enhance the hyperkalemic effect of Calcium Channel Blockers. Dantrolene may enhance the negative inotropic effect of Calcium Channel Blockers. Risk X: Avoid combination

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

Daridorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Daridorexant. Management: Limit the daridorexant dose to 25 mg, no more than once per night, when combined with moderate CYP3A4 inhibitors. Risk D: Consider therapy modification

Darifenacin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Darifenacin. Risk C: Monitor therapy

Dasatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dasatinib. Risk C: Monitor therapy

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

Delamanid: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Delamanid. Risk C: Monitor therapy

DexAMETHasone (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DexAMETHasone (Systemic). Risk C: Monitor therapy

Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy

DiazePAM: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DiazePAM. Risk C: Monitor therapy

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

DilTIAZem: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DilTIAZem. Risk C: Monitor therapy

Disopyramide: Verapamil may enhance the adverse/toxic effect of Disopyramide. Of particular concern is the potential for profound depression of myocardial contractility. Management: Concurrent use of disopyramide within 48 hours prior to or 24 hours after verapamil should be avoided. Risk X: Avoid combination

DOCEtaxel: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOCEtaxel. Risk C: Monitor therapy

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

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

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination

DOXOrubicin (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Liposomal). Risk C: Monitor therapy

Dronabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Risk C: 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 and only increase calcium channel blocker dose after obtaining ECG-based evidence that the combination is being well-tolerated. Monitor closely during coadministration. Risk D: Consider therapy modification

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

Ebastine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ebastine. Risk C: Monitor therapy

Edoxaban: Verapamil may increase the serum concentration of Edoxaban. Management: In patients treated for DVT/PE, reduce the edoxaban dose to 30 mg daily when combined with verapamil. No dose adjustment is recommended for patients treated for atrial fibrillation. Monitor for increased edoxaban toxicities (ie, bleeding) when combined. Risk D: Consider therapy modification

Elbasvir and Grazoprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Elbasvir and Grazoprevir. Risk C: Monitor therapy

Eletriptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eletriptan. Risk X: Avoid combination

Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Management: When combined with moderate CYP3A4 inhibitors, two elexacaftor/tezacaftor/ivacaftor (100 mg/50 mg/75 mg) tablets should be given in the morning, every other day. Ivacaftor (150 mg) should be given in the morning, every other day on alternate days. Risk D: Consider therapy modification

Eliglustat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Reduce eliglustat dose to 84 mg daily in CYP2D6 EMs when used with moderate CYP3A4 inhibitors. Avoid use of moderate CYP3A4 inhibitors in CYP2D6 IMs or PMs. Use in CYP2D6 EMs or IMs also taking strong or moderate CYP2D6 inhibitors is contraindicated. Risk D: Consider therapy modification

Encorafenib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Encorafenib. Management: Avoid use of encorafenib and moderate CYP3A4 inhibitors when possible. If combined, decrease the encorafenib dose from 450 mg to 225 mg; 300 mg to 150 mg; and 225 mg or 150 mg to 75 mg. Resume prior dose once inhibitor discontinued for 3 to 5 half-lives. Risk D: Consider therapy modification

Entrectinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Entrectinib. Management: Avoid moderate CYP3A4 inhibitors during treatment with entrectinib. Reduce dose to 200 mg/day if combination cannot be avoided in adults and those 12 yrs of age or older with a BSA of at least 1.5 square meters. Avoid if BSA is less than 1.5 square meters Risk D: Consider therapy modification

Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: If coadministered with moderate CYP3A4 inhibitors, the max dose of eplerenone is 25 mg daily if used for heart failure; if used for hypertension initiate eplerenone 25 mg daily, titrate to max 25 mg twice daily. Risk D: Consider therapy modification

Ergot Derivatives (Vasoconstrictive CYP3A4 Substrates): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ergot Derivatives (Vasoconstrictive CYP3A4 Substrates). Risk C: Monitor therapy

Erlotinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Erlotinib. Risk C: Monitor therapy

Erythromycin (Systemic): May increase the serum concentration of Calcium Channel Blockers (Nondihydropyridine). Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Erythromycin (Systemic). Risk C: Monitor therapy

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. Risk D: Consider therapy modification

Eszopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eszopiclone. Risk C: Monitor therapy

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

Etoposide Phosphate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide Phosphate. Risk C: Monitor therapy

Etravirine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Etravirine. Risk C: Monitor therapy

Everolimus: Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Everolimus. Management: Afinitor: For TSC-associated SEGA or TSC-associated seizures reduce everolimus dose 50%. For other Afinitor indications, reduce everolimus dose to 2.5 mg/day, increase to 5 mg/day if tolerated. Zortress: Monitor for increased everolimus concentrations. Risk D: Consider therapy modification

Fedratinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fedratinib. Risk C: Monitor therapy

Felodipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Felodipine. Risk C: Monitor therapy

FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Management: Consider fentanyl dose reductions when combined with a moderate CYP3A4 inhibitor. Monitor for respiratory depression and sedation. Upon discontinuation of a CYP3A4 inhibitor, consider a fentanyl dose increase; monitor for signs and symptoms of withdrawal. Risk D: Consider therapy modification

Fexinidazole: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole. Risk X: Avoid combination

Finerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Finerenone. Risk C: Monitor therapy

Fingolimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Fingolimod. Management: Consult with the prescriber of any bradycardia-causing agent to see if the agent could be switched to an agent that does not cause bradycardia prior to initiating fingolimod. If combined, perform continuous ECG monitoring after the first fingolimod dose. Risk D: Consider therapy modification

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

Flibanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin. Management: Use of flibanserin with moderate CYP3A4 inhibitors is contraindicated. If starting flibanserin, start 2 weeks after the last dose of the CYP3A4 inhibitor. If starting a CYP3A4 inhibitor, start 2 days after the last dose of flibanserin. Risk X: Avoid combination

Flunarizine: May enhance the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy

Fluticasone (Nasal): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fluticasone (Nasal). Risk C: Monitor therapy

Fluticasone (Oral Inhalation): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fluticasone (Oral Inhalation). Risk C: Monitor therapy

Fosamprenavir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fosamprenavir. Risk C: Monitor therapy

Fosaprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fosaprepitant. Risk X: Avoid combination

Fosphenytoin-Phenytoin: Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease the serum concentration of Calcium Channel Blockers (Nondihydropyridine). Management: Consider alternatives to this combination when possible. If combined, monitor for increased phenytoin concentrations and toxicities and monitor for decreased calcium channel blocker efficacy. Risk D: Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Futibatinib: Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Futibatinib. Risk C: Monitor therapy

Gilteritinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Gilteritinib. Risk C: Monitor therapy

Glasdegib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Glasdegib. Risk C: Monitor therapy

Glecaprevir and Pibrentasvir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Glecaprevir and Pibrentasvir. Risk C: Monitor therapy

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

GuanFACINE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of GuanFACINE. Management: Reduce the extended-release guanfacine dose 50% when combined with a moderate CYP3A4 inhibitor. Monitor for increased guanfacine toxicities when these agents are combined. Risk D: Consider therapy modification

Halofantrine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine. Risk C: Monitor therapy

Herbal Products with Blood Pressure Increasing Effects: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy

Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

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

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

Ibrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib. Management: When treating B-cell malignancies, decrease ibrutinib to 280 mg daily when combined with moderate CYP3A4 inhibitors. When treating graft versus host disease, monitor patients closely and reduce the ibrutinib dose as needed based on adverse reactions. Risk D: Consider therapy modification

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

Iloperidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Iloperidone. Risk C: Monitor therapy

Infigratinib: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Infigratinib. Risk X: Avoid combination

Inhalational Anesthetics: May enhance the hypotensive effect of Calcium Channel Blockers. Risk C: Monitor therapy

Irinotecan Products: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, the serum concentration of SN-38 may be increased. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Irinotecan Products. Risk C: Monitor therapy

Isavuconazonium Sulfate: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inhibitors (Moderate) may increase isavuconazole serum concentrations. Risk C: Monitor therapy

Isradipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Isradipine. Risk C: Monitor therapy

Itraconazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Itraconazole. Risk C: Monitor therapy

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

Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions may be required; consult full drug interaction monograph content for age- and weight-specific dosage recommendations. Risk D: Consider therapy modification

Ivosidenib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivosidenib. Management: Avoid use of moderate CYP3A4 inhibitors with ivosidenib whenever possible. If combined, monitor for increased ivosidenib toxicities, including QTc prolongation. Risk D: Consider therapy modification

Ixabepilone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ixabepilone. Risk C: Monitor therapy

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

Lapatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lapatinib. Risk C: Monitor therapy

Larotrectinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Larotrectinib. Risk C: Monitor therapy

Lefamulin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects. Risk D: Consider therapy modification

Lemborexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lemborexant. Risk X: Avoid combination

Lercanidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lercanidipine. Risk C: Monitor therapy

Levamlodipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Levamlodipine. Risk C: Monitor therapy

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy

Levoketoconazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Levoketoconazole. Risk C: Monitor therapy

Levomethadone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Levomethadone. Risk C: Monitor therapy

Levomilnacipran: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Levomilnacipran. Risk C: Monitor therapy

Lidocaine (Systemic): CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Lidocaine (Systemic). Specifically, concentrations of monoethylglycinexylidide (MEGX) may be increased. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lidocaine (Systemic). Risk C: 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. Risk C: Monitor therapy

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

Lonafarnib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lonafarnib. Risk X: Avoid combination

Loop Diuretics: May enhance the hypotensive effect of Antihypertensive Agents. Risk C: Monitor therapy

Lopinavir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lopinavir. Risk C: Monitor therapy

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

Lovastatin: Verapamil may increase the serum concentration of Lovastatin. Management: Initiate immediate release lovastatin at a dose of 10 mg/day, and do not exceed 20 mg/day for immediate or extended release lovastatin, in patients receiving verapamil. Monitor closely for signs of lovastatin toxicity (eg, myositis, rhabdomyolysis). Risk D: Consider therapy modification

Lumateperone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lumateperone. Management: Limit the lumateperone dose to 21 mg once daily when used with a moderate CYP3A4 inhibitor. Risk D: Consider therapy modification

Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Management: US labeling recommends reducing lurasidone dose by 50% with a moderate CYP3A4 inhibitor and initiating 20 mg/day, max 80 mg/day. Some non-US labels recommend initiating lurasidone 20 mg/day, max 40 mg/day. Avoid concurrent use of grapefruit products. Risk D: Consider therapy modification

Lurbinectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurbinectedin. Management: Avoid concomitant use of lurbinectedin and moderate CYP3A4 inhibitors when possible. If combined, consider a lurbinectedin dose reduction as clinically indicated. Risk D: Consider therapy modification

Macitentan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Macitentan. Risk C: Monitor therapy

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

Maraviroc: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Maraviroc. Risk C: Monitor therapy

Mavacamten: Calcium Channel Blockers (Nondihydropyridine) may enhance the adverse/toxic effect of Mavacamten. Specifically, negative inotropic effects may be increased. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Mavacamten. Management: Start mavacamten at 5 mg/day if stable on a non-DHP CCB. For those stable on mavacamten who are initiating a non-DHP CCB, reduce mavacamten dose by one dose level. Monitor for excessive negative inotropic effects. Risk D: Consider therapy modification

Meperidine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Meperidine. Risk C: Monitor therapy

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

Methadone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Methadone. Management: If coadministration with moderate CYP3A4 inhibitors is necessary, consider methadone dose reductions until stable effects are achieved. Monitor patients closely for respiratory depression and sedation. Risk D: Consider therapy modification

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

MethylPREDNISolone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of MethylPREDNISolone. Risk C: Monitor therapy

Methysergide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Methysergide. Risk X: Avoid combination

Midazolam: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Midazolam. Management: Avoid concomitant use of nasal midazolam and moderate CYP3A4 inhibitors. Consider alternatives to use with oral midazolam whenever possible and consider using lower midazolam doses. Monitor patients for sedation and respiratory depression if combined. Risk D: Consider therapy modification

Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Midostaurin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Midostaurin. Risk C: Monitor therapy

MiFEPRIStone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of MiFEPRIStone. Risk C: Monitor therapy

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

Mitapivat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mitapivat. Management: When coadministered with moderate CYP3A4 inhibitors, doses of mitapivat should not exceed 20 mg twice daily. Additionally, patients should be monitored for changes in hemoglobin response and increased mitapivat adverse effects. Risk D: Consider therapy modification

Mobocertinib: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Mobocertinib. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mobocertinib. Management: Avoid use of moderate CYP3A4 inhibitors with mobocertinib when possible. If combined, the mobocertinib dose should be reduced by approximately 50% (ie, from 160 mg to 80 mg, 120 mg to 40 mg, or 80 mg to 40 mg). Monitor QTc interval closely. Risk D: Consider therapy modification

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

Morphine (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Morphine (Systemic). Risk C: Monitor therapy

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

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

Naldemedine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naldemedine. Risk C: Monitor therapy

Nalfurafine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nalfurafine. Risk C: Monitor therapy

Naloxegol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol. Management: The use of naloxegol and moderate CYP3A4 inhibitors should be avoided. If concurrent use is unavoidable, reduce naloxegol dose to 12.5 mg once daily and monitor for signs of opiate withdrawal (eg, hyperhidrosis, chills, diarrhea, anxiety, irritability). Risk D: Consider therapy modification

Neratinib: Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Neratinib. Risk X: Avoid combination

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

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

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

NIFEdipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NIFEdipine. Risk C: Monitor therapy

Nilotinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nilotinib. Risk C: Monitor therapy

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

Nintedanib: Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Nintedanib. Risk C: Monitor therapy

Nisoldipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nisoldipine. Risk X: Avoid combination

Nitrendipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nitrendipine. Risk C: Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: 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. Risk D: Consider therapy modification

Olaparib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib. Management: Avoid use of moderate CYP3A4 inhibitors with olaparib, if possible. If such concurrent use cannot be avoided, the dose of olaparib tablets should be reduced to 150 mg twice daily and the dose of olaparib capsules should be reduced to 200 mg twice daily. Risk D: Consider therapy modification

Oliceridine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Oliceridine. Risk C: Monitor therapy

Olmutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olmutinib. Risk C: Monitor therapy

Orelabrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Orelabrutinib. Risk X: Avoid combination

OxyCODONE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased. Risk C: Monitor therapy

Ozanimod: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

PACLitaxel (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of PACLitaxel (Conventional). Risk C: Monitor therapy

PACLitaxel (Protein Bound): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of PACLitaxel (Protein Bound). Risk C: Monitor therapy

Pacritinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pacritinib. Risk X: Avoid combination

Palbociclib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Palbociclib. Risk C: Monitor therapy

Palovarotene: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Palovarotene. Risk C: Monitor therapy

Panobinostat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Panobinostat. Risk C: Monitor therapy

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

Pemigatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pemigatinib. Management: If combined use cannot be avoided, reduce the pemigatinib dose from 13.5 mg daily to 9 mg daily, or from 9 mg daily to 4.5 mg daily. Resume prior pemigatinib dose after stopping the moderate inhibitor once 3 half-lives of the inhibitor has passed. Risk D: Consider therapy modification

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

Pexidartinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pexidartinib. Management: Avoid use of pexidartinib with moderate CYP3A4 inhibitors if possible. If combined, the pexidartinib dose should be reduced. Decrease 800 mg or 600 mg daily doses to 200 mg twice daily. Decrease doses of 400 mg per day to 200 mg once daily. Risk D: Consider therapy modification

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy

Pimavanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pimavanserin. Risk C: Monitor therapy

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

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

Piperaquine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Piperaquine. Risk C: Monitor therapy

PONATinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of PONATinib. Risk C: Monitor therapy

Ponesimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Ponesimod. Management: Avoid coadministration of ponesimod with drugs that may cause bradycardia when possible. If combined, monitor heart rate closely and consider obtaining a cardiology consult. Do not initiate ponesimod in patients on beta-blockers if HR is less than 55 bpm. Risk D: Consider therapy modification

Pralsetinib: Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Pralsetinib. Risk C: Monitor therapy

Pramipexole: Verapamil may enhance the hypotensive effect of Pramipexole. Verapamil may increase the serum concentration of Pramipexole. Risk C: Monitor therapy

Prazepam: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Prazepam. Risk C: Monitor therapy

Praziquantel: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Praziquantel. Risk C: Monitor therapy

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

QUEtiapine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of QUEtiapine. Risk C: Monitor therapy

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

QuiNIDine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of QuiNIDine. Risk C: Monitor therapy

Quinidine (Non-Therapeutic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Quinidine (Non-Therapeutic). Risk C: Monitor therapy

QuiNINE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of QuiNINE. Risk C: Monitor therapy

Ranolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine. Management: Limit the ranolazine dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors. Monitor for increased ranolazine effects and toxicities during concomitant use. Risk D: 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. Management: Initiate immediate release lovastatin at a dose of 10 mg/day, and do not exceed 20 mg/day for immediate or extended release lovastatin. Monitor closely for signs of lovastatin toxicity (eg, myositis, rhabdomyolysis). Risk D: Consider therapy modification

Regorafenib: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Regorafenib. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Regorafenib. Risk C: Monitor therapy

Relugolix: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Relugolix. Management: Avoid coadministration of relugolix with oral P-gp inhibitors whenever possible. If combined, take relugolix at least 6 hours prior to the P-gp inhibitor and monitor patients more frequently for adverse reactions. Risk D: Consider therapy modification

Relugolix, Estradiol, and Norethindrone: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Relugolix, Estradiol, and Norethindrone. Management: Avoid use of relugolix/estradiol/norethindrone with P-glycoprotein (P-gp) inhibitors. If concomitant use is unavoidable, relugolix/estradiol/norethindrone should be administered at least 6 hours before the P-gp inhibitor. Risk D: Consider therapy modification

Ribociclib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ribociclib. Risk C: Monitor therapy

Rifabutin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rifabutin. Risk C: Monitor therapy

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

Rimegepant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rimegepant. Management: If taking rimegepant for the acute treatment of migraine, avoid a second dose of rimegepant within 48 hours when used concomitantly with moderate CYP3A4 inhibitors. No dose adjustment needed if using rimegepant for prevention of episodic migraine. Risk D: Consider therapy modification

Rimegepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Rimegepant. Management: Avoid administration of another dose of rimegepant within 48 hours if given concomitantly with a P-glycoprotein (P-gp) inhibitor. Risk D: Consider therapy modification

Riociguat: Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Riociguat. Risk C: Monitor therapy

RisperiDONE: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RisperiDONE. Risk C: 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. Do not use this combination in patients with estimated creatinine clearance 15 to 80 mL/min unless prospective benefits outweigh the risks. Risk D: Consider therapy modification

Roflumilast-Containing Products: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Roflumilast-Containing Products. Risk C: Monitor therapy

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

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

Ruxolitinib (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ruxolitinib (Systemic). Risk C: Monitor therapy

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

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

Saquinavir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Saquinavir. Risk C: Monitor therapy

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

Selpercatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Selpercatinib. Management: Avoid combination if possible. If use is necessary, reduce selpercatinib dose as follows: from 120 mg twice/day to 80 mg twice/day, or from 160 mg twice/day to 120 mg twice/day. Risk D: Consider therapy modification

Selumetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Selumetinib. Management: Avoid concomitant use when possible. If combined, selumetinib dose reductions are recommended and vary based on body surface area and selumetinib dose. For details, see the full drug interaction monograph or selumetinib prescribing information. Risk D: Consider therapy modification

Sertindole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sertindole. Risk X: Avoid combination

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

Silodosin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Silodosin. Risk C: Monitor therapy

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

Simvastatin: Verapamil may increase serum concentrations of the active metabolite(s) of Simvastatin. Verapamil may increase the serum concentration of Simvastatin. Management: Carefully consider the potential risks and benefits of this combination. If coadministered, limit adult simvastatin dose to 10 mg daily, and monitor closely for signs of simvastatin toxicity (eg, myositis, rhabdomyolysis). Risk D: Consider therapy modification

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modification

Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. If combined, consider obtaining a cardiology consult regarding patient monitoring. Risk D: Consider therapy modification

Sirolimus (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sirolimus (Conventional). Management: Monitor for increased serum concentrations of sirolimus if combined with a moderate CYP3A4 inhibitor. Lower initial sirolimus doses or sirolimus dose reductions will likely be required. Risk D: Consider therapy modification

Sirolimus (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus (Conventional). Management: Avoid concurrent use of sirolimus with P-glycoprotein (P-gp) inhibitors when possible and alternative agents with lesser interaction potential with sirolimus should be considered. Monitor for increased sirolimus concentrations/toxicity if combined. Risk D: Consider therapy modification

Sirolimus (Protein Bound): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus (Protein Bound). Risk X: Avoid combination

Solifenacin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Solifenacin. Risk C: Monitor therapy

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). Risk D: Consider therapy modification

SUNItinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of SUNItinib. Risk C: Monitor therapy

Suvorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Suvorexant. Management: The recommended dose of suvorexant is 5 mg daily in patients receiving a moderate CYP3A4 inhibitor. The dose can be increased to 10 mg daily (maximum dose) if necessary for efficacy. Risk D: Consider therapy modification

Tacrolimus (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy

Tacrolimus (Topical): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tacrolimus (Topical). Risk C: Monitor therapy

Tadalafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tadalafil. Risk C: Monitor therapy

Talazoparib: Verapamil may increase the serum concentration of Talazoparib. Management: If concurrent use cannot be avoided, reduce talazoparib dose to 0.75 mg once daily. When verapamil is discontinued, increase the talazoparib dose to the dose used before initiation of verapamil after 3 to 5 times the half-life of verapamil. Risk D: Consider therapy modification

Tamsulosin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tamsulosin. Risk C: Monitor therapy

Tazemetostat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tazemetostat. Management: Avoid when possible. If combined, reduce tazemetostat dose from 800 mg twice daily to 400 mg twice daily, from 600 mg twice daily to 400 mg in AM and 200 mg in PM, or from 400 mg twice daily to 200 mg twice daily. Risk D: Consider therapy modification

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

Telithromycin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Telithromycin. Risk C: Monitor therapy

Temsirolimus: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Temsirolimus. Specifically, concentrations of sirolimus may be increased. Risk C: Monitor therapy

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

Tenofovir Disoproxil Fumarate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tenofovir Disoproxil Fumarate. Risk C: Monitor therapy

Terfenadine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Terfenadine. Risk C: Monitor therapy

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

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

Tezacaftor and Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tezacaftor and Ivacaftor. Management: If combined with moderate CYP3A4 inhibitors, give tezacaftor/ivacaftor in the morning, every other day; give ivacaftor in the morning, every other day on alternate days. Tezacaftor/ivacaftor dose depends on age and weight; see full Lexi-Interact monograph Risk D: Consider therapy modification

Theophylline Derivatives: Verapamil may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Thiotepa: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Thiotepa. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Thiotepa. Risk C: Monitor therapy

Ticagrelor: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ticagrelor. Risk C: Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Risk D: Consider therapy modification

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

Tofacitinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tofacitinib. Risk C: Monitor therapy

Tolterodine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolterodine. Risk C: Monitor therapy

Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Management: Avoid this combination with Samsca brand of tolvaptan. Reduce dose for Jynarque brand: 90 mg AM and 30 mg PM, reduce to 45 mg AM and 15 mg PM; 60 mg AM and 30 mg PM, reduce to 30 mg AM and 15 mg PM; 45 mg AM and 15 mg PM, reduce to 15 mg AM and PM. Risk D: Consider therapy modification

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

Toremifene: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Toremifene. Risk C: Monitor therapy

Trabectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin. Risk C: Monitor therapy

TraMADol: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of TraMADol. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of TraMADol. Risk C: Monitor therapy

TraZODone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of TraZODone. Risk C: Monitor therapy

Triazolam: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Triazolam. Management: Consider triazolam dose reduction in patients receiving concomitant moderate CYP3A4 inhibitors. Risk D: Consider therapy modification

Ubrogepant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and avoid a second dose for 24 hours when used with moderate CYP3A4 inhibitors. Risk D: Consider therapy modification

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

Ulipristal: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal. Risk C: Monitor therapy

Valbenazine: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Valbenazine. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Valbenazine. Risk C: Monitor therapy

Vardenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vardenafil. Management: Limit Levitra (vardenafil) dose to a single 5 mg dose within a 24-hour period if combined with moderate CYP3A4 inhibitors. Avoid concomitant use of Staxyn (vardenafil) and moderate CYP3A4 inhibitors. Combined use is contraindicated outside of the US. Risk D: Consider therapy modification

Vemurafenib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vemurafenib. Risk C: Monitor therapy

Venetoclax: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring concomitant treatment with moderate CYP3A4 inhibitors. Resume the previous venetoclax dose 2 to 3 days after discontinuation of moderate CYP3A4 inhibitors. Risk D: Consider therapy modification

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

VinBLAStine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of VinBLAStine. Risk C: Monitor therapy

VinCRIStine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of VinCRIStine. Risk C: Monitor therapy

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

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

Vinflunine: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Vinflunine. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vinflunine. Risk C: Monitor therapy

Voclosporin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Voclosporin. Management: Decrease the voclosporin dose to 15.8 mg in the morning and 7.9 mg in the evening when combined with moderate CYP3A4 inhibitors. Risk D: Consider therapy modification

Vorapaxar: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vorapaxar. Risk C: Monitor therapy

Zanubrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zanubrutinib. Management: Decrease the zanubrutinib dose to 80 mg twice daily during coadministration with a moderate CYP3A4 inhibitor. Further dose adjustments may be required for zanubrutinib toxicities, refer to prescribing information for details. Risk D: Consider therapy modification

Zopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zopiclone. Risk C: Monitor therapy

Food Interactions

Ethanol: Verapamil may increase blood ethanol levels and prolong its effects. Management: Monitor patients and caution about increased effects.

Food: Grapefruit juice may increase the serum concentration of verapamil. Management: Use with caution and monitor for effects.

Pregnancy Considerations

Verapamil crosses the placenta.

Chronic maternal hypertension may increase the risk of birth defects, low birth weight, preterm delivery, stillbirth, and neonatal death. Actual fetal/neonatal risks may be related to duration and severity of maternal hypertension. Untreated hypertension may also increase the risks of adverse maternal outcomes, including gestational diabetes, myocardial infarction, preeclampsia, stroke, and delivery complications (ACOG 203 2019).

Calcium channel blockers may be used to treat hypertension in patients who are pregnant; however, agents other than verapamil are more commonly used (ACOG 203 2019; ESC [Regitz-Zagrosek 2018]). Patients with preexisting hypertension may continue their medication during pregnancy unless contraindications exist (ESC [Regitz-Zagrosek 2018]).

Patients with hypertrophic cardiomyopathy who are controlled with verapamil prior to pregnancy may continue therapy, but increased fetal monitoring is recommended (AHA/ACC [Ommen 2020]). Verapamil may be used IV for the acute treatment of supraventricular tachycardia (SVT) in patients who are pregnant 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 (ACC/AHA/HRS [Page 2016]). Additional guidelines are available for management of cardiovascular diseases during pregnancy (ESC [Regitz-Zagrosek 2018]).

Breastfeeding Considerations

Verapamil and norverapamil are present in breast milk (Anderson 1987; Miller 1986).

Data related to the presence of verapamil in breast milk are available from multiple case reports. Following maternal use of verapamil 80 to 120 mg three times daily in patients ≤3 months postpartum, the relative infant dose (RID) of verapamil was calculated to be ≤1% of the weight-adjusted maternal dose. Adverse events were not observed in breastfed infants (Andersen 1983; Anderson 1987; Inoue 1984; Miller 1986). In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).

Although breastfeeding is not recommended by some manufacturers (consider the risk of infant exposure), verapamil is considered compatible with breastfeeding (WHO 2002).

Monitoring Parameters

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

Consult individual institutional policies and procedures.

Reference Range

BP goals: May vary depending on clinical condition, different clinical practice guidelines, and expert opinion. Refer to clinical practice guidelines for specific treatment goals.

Mechanism of Action

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.

Pharmacokinetics

Note: Lean body weight affects verapamil pharmacokinetics inversely.

Onset of action: Peak effect: Oral: Immediate release: 1 to 2 hours (Singh 1978); IV bolus: 3 to 5 minutes.

Duration: Oral: Immediate release: 6 to 8 hours; IV: 0.5 to 6 hours (Marik 2011).

Absorption: Oral: Well absorbed (>90%).

Distribution: Vd: 3.89 L/kg (Storstein 1984).

Protein binding: ~90%.

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

Bioavailability: Oral: 20% to 35%.

Half-life elimination:

Injection: Terminal: 2 to 5 hours.

Oral:

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

Extended release: ~12 hours.

Severe hepatic impairment: 14 to 16 hours.

Time to peak, serum: Oral:

Immediate release: 1 to 2 hours.

Extended release:

Calan SR: 5.21 hours.

Verelan: 7 to 9 hours.

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

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

Pharmacokinetics: Additional Considerations

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

Older adult: Elimination half-life may be prolonged and bioavailability may be higher in older adults.

Sex: Conflicting data suggest that verapamil clearance decreased with age in females to a greater degree than in males.

Pricing: US

Capsule ER 24 Hour Therapy Pack (Verapamil HCl ER Oral)

100 mg (per each): $5.59

120 mg (per each): $1.75 - $5.37

180 mg (per each): $1.83 - $2.03

200 mg (per each): $7.20

240 mg (per each): $2.06 - $2.29

300 mg (per each): $10.47

360 mg (per each): $6.38

Capsule ER 24 Hour Therapy Pack (Verelan Oral)

120 mg (per each): $7.68

180 mg (per each): $8.05

240 mg (per each): $9.08

360 mg (per each): $13.35

Capsule ER 24 Hour Therapy Pack (Verelan PM Oral)

100 mg (per each): $6.21

200 mg (per each): $8.00

300 mg (per each): $11.64

Solution (Verapamil HCl Intravenous)

2.5 mg/mL (per mL): $6.00 - $19.29

Tablet, controlled release (Calan SR Oral)

120 mg (per each): $7.36

180 mg (per each): $9.70

240 mg (per each): $11.10

Tablet, controlled release (Verapamil HCl ER Oral)

120 mg (per each): $1.07

180 mg (per each): $1.44

240 mg (per each): $1.64

Tablets (Verapamil HCl Oral)

40 mg (per each): $0.28

80 mg (per each): $0.31 - $0.53

120 mg (per each): $0.39 - $0.68

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Angimil (BD);
  • Anpec (AU, HK, TW);
  • Beaptin SR (SG);
  • Calan (PH);
  • Calan SR (LK);
  • Calaptin (IN);
  • Calcicard (ZA);
  • Cardiolen (CL);
  • Cardiomil (EG);
  • Caveril (AE, BB, BH, BM, BS, BZ, CY, ET, GH, GY, IL, JM, JO, KE, LB, MT, MU, OM, PR, QA, SR, SY, TT, TZ, YE);
  • Cintsu (TW);
  • Cordilat (BR);
  • Cordilox (AU, GB);
  • Cronovera (MX);
  • Devincil (LU);
  • Dilacoran (BR, CR, DO, GT, HN, MX, NI, PA, SV);
  • Dilacoran Retard (CR, DO, GT, HN, NI, PA, SV);
  • Fibrocard (LU);
  • Flamon (BB, BM, BS, BZ, CH, GY, JM, PR, SR, TT);
  • Hexasoptin (DK);
  • Hormitol (JP);
  • Hypover (BD);
  • Ikacor (IL);
  • Ikapress (IL);
  • Isoptin (AE, AT, AU, BG, BH, CH, CO, CY, CZ, DE, DK, EC, EE, EG, FI, GR, HK, HR, HU, IE, IT, JO, KR, KW, LB, LU, MY, NO, NZ, PE, PH, PK, PL, PT, QA, RO, RU, SA, SE, SG, SI, SK, TR, VN, ZA);
  • Isoptin Retard (EE, IS, LT, LV);
  • Isoptin RR (HR, RO, SI);
  • Isoptin SR (AE, BG, BH, CN, CY, CZ, EG, HK, ID, JO, KR, KW, LB, NL, PL, QA, SA, SG, SK, ZA, ZW);
  • Isoptine (BE, FR);
  • Isoptino (AR, PY, UY);
  • Lekoptin (HR);
  • Lexoptin (UA);
  • Librapamil (EC);
  • Lodixal (BE);
  • Manidon (ES, VE);
  • Quasar (IT);
  • Securon (GB, MT);
  • Singen (TW);
  • Sinrox (TW);
  • Staveran (PL);
  • Vasolan (BD, JP);
  • Vasomil (ZA, ZW);
  • Vepiltax (CR, DO, GT, HN, NI, PA, SV);
  • Veracaps (AU);
  • Veracor (VE);
  • Verahexal (LU);
  • Verahexal 240SR (ZW);
  • Veral (AR);
  • Veraloc (DK);
  • Veramet (PH);
  • Veramil (IE, IN);
  • Verap (IE);
  • Verapamil Hydrochloride (AE, BH, CY, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE);
  • Verapamil Pharmavit (HU);
  • Verapil (BD);
  • Verapress 240 SR (IL);
  • Verapress MR (MT);
  • Veratad (CO);
  • Veratens (EG);
  • Vermine (TH);
  • Verpamil (AE, BH, CY, FI, HU, IL, IQ, IR, JO, KW, LB, LY, MY, NZ, OM, QA, SA, SY, YE);
  • Zolvera (GB)


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