Verapamil

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) formulation only for hypertension.

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 (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]).

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; Ganz 2020; 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; Ganz 2020; 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 (Ganz 2020; 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]; Ganz 2020).

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 2020).

Cluster headache, prevention (off-label use):

Note: May be used as monotherapy or in combination with other preventive agents (May 2020). Obtain an ECG prior to treatment and after each titration when dose is >480 mg/day (Koppen 2016).

Oral:

Immediate release: Initial: 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; 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 (alternative agent):

Note: Some experts 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): 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 prophylaxis (off-label use):

Oral:

Immediate release: Initial: 40 mg 3 times daily; titrate every 1 to 2 weeks based on patient response and tolerability up to 360 mg/day in 3 to 4 divided doses (CHS [Pringsheim 2012]; Smith 2020).

Extended release: Initial: 120 mg once daily; titrate every 1 to 2 weeks based on patient response and tolerability up to 360 mg/day in 2 to 3 divided doses (Pelzer 2013; Razavi 2000; Smith 2020; Yu 2003).

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:

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 (Manolis 2020; Zimetbaum 2020).

Oral:

Immediate release: Initial: 80 mg 3 times daily; if needed, titrate for symptom control and tolerability; maximum dose: 480 mg/day in 3 to 4 divided doses (Manolis 2020; Zimetbaum 2020).

Extended release: Initial: 240 mg/day in 1 to 2 divided doses; if needed, titrate for symptom control and tolerability; maximum dose: 480 mg/day in 1 to 2 divided doses (Manolis 2020; Zimetbaum 2020).

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.

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

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): Initial: 100 mg once daily at bedtime; titrate similar to adult dosing.

Other indications: Refer to adult dosing.

Dosing: Renal Impairment: Adult

Manufacturer's labeling:

Oral: Extended release (delayed onset): 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): 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

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 (Kliegman 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).

Dosing: Renal 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.

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.

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Chest pain associated with cocaine ingestion, with or without evidence of acute coronary syndromeLevel of Evidence [C]

Clinical experience suggests that nondihydropyridine calcium channel blockers (eg, verapamil) may be useful as adjunctive therapy in patients with recurrent symptoms of ischemia despite optimal therapy with nitroglycerin Ref.

Cluster headache, preventionLevel of Evidence [C, G]

Data from a limited number of patients suggest that verapamil may be beneficial for decreasing severity and frequency of headaches and use of rescue analgesics when used prophylactically in patients with chronic or episodic cluster headaches Ref.

Based on the American Headache Society guidelines for the treatment of cluster headache, verapamil is possibly effective at reducing headache frequency when used prophylactically in patients with episodic and chronic headaches Ref. Based on the European Federation of Neurological Societies guidelines on the treatment of cluster headache and other trigeminal autonomic cephalalgias, verapamil is the drug of first choice for headache prophylaxis in patients with episodic and chronic cluster headaches Ref.

Hypertrophic cardiomyopathyLevel of Evidence [G]

Based on the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline for the diagnosis and treatment of hypertrophic cardiomyopathy, verapamil is an effective and recommended alternative agent for the treatment of symptoms (eg, angina, dyspnea) in patients with obstructive or nonobstructive hypertrophic cardiomyopathy who do not tolerate beta-blockers or are unresponsive to beta-blockers Ref.

Idiopathic left ventricular tachycardiaLevel of Evidence [C, G]

Data from a limited number of small, prospective, observational studies have shown that verapamil can suppress idiopathic left ventricular tachycardia (VT) Ref.

Based on the American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guideline for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death, verapamil is an effective and recommended therapy for termination and prevention of recurrence of idiopathic VT originating from the right ventricular outflow tract or related to interfascicular reentry. Note: Calcium channel blockers should not be given to patients with VT and heart failure with a reduced ejection fraction. Calcium channel blockers are not effective for all forms of VT and may be harmful. These agents should not be given to patients with VT of unknown origin Ref.

Migraine prophylaxisLevel of Evidence [C, G]

Data from a limited number of patients suggest that verapamil may be beneficial for decreasing severity and frequency of migraine when used prophylactically Ref.

Based on the Canadian Headache Society guideline for migraine prophylaxis, verapamil may be used as prophylaxis against migraine headaches Ref.

Nonsustained ventricular tachycardia or ventricular premature beats, symptomaticLevel of Evidence [C, G]

Based on the AHA/ACC/HRS guideline for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death and recommendations from other experts , verapamil may be used to treat symptoms (eg, palpitations) associated with nonsustained VT or ventricular premature beats Ref.

Level of Evidence Definitions

Level of Evidence Scale

Class and Related Monographs

Calcium Channel Blocking Agents

Clinical Practice Guidelines

Advanced Cardiac Life Support (ACLS)/Emergency Cardiovascular Care (ECC):

AHA, “2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care,” October 2015.

AHA, "2010 Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care,” November 2010.

Arrhythmias:

AHA/ACC/HRS, “2017 AHA/ACC/HRS Guideline for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death,” October 2017

ACC/AHA/HRS, “Guideline for the Management of Adult Patients with Supraventricular Tachycardia,” 2015

AHA/ACC/HRS, "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation," January 2019

AHA/ACC/HRS, "2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation," March 2014

Cluster Headaches:

American Headache Society, “Treatment of cluster headache: The American Headache Society evidence-based guidelines,” July 2016

European Federation of Neurological Societies (EFNS), “EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias,” October 2006

Diabetes Mellitus:

American Diabetes Association, “Standards of Medical Care in Diabetes - 2019,” January 2019

Hypertension:

"2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults," November 2017.

AHA/ACC/ASH, “Treatment of Hypertension in Patients with Coronary Artery Disease: A Scientific Statement by the American Heart Association, American College of Cardiology and American Society of Hypertension,” May 2015

"ACCF/AHA Expert Consensus Document on Hypertension in the Elderly," 2011

Hypertrophic Cardiomyopathy:

“2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy,” November 2011

Ischemic Heart Disease:

ACC/AHA/AATS/PCNA/SCAI/STS, "2014 Focused Update of the Guideline for the Diagnosis and Management of Patients with Stable Ischemic Heart Disease," July 2014

ACCF/AHA/ACP/AATS/PCNA/SCAI/STS, “2012 Guideline for the Diagnosis and Management of Patients with Stable Ischemic Heart Disease,” November 2012

Administration: IV

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

Administration: Injectable Detail

pH: 4.1 to 6

Administration: 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.

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

Storage/Stability

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

Oral:

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

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

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

Compatibility

See Trissel’s IV Compatibility Database

Open Trissel's IV Compatibility

Extemporaneously Prepared

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

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

Allen LV Jr and Erickson MA 3rd, "Stability of Labetalol Hydrochloride, Metoprolol Tartrate, Verapamil Hydrochloride, and Spironolactone With Hydrochlorothiazide in Extemporaneously Compounded Oral Liquids," Am J Health Syst Pharm, 1996, 53(19):304-9.[PubMed 8893069]

Nahata MC, "Stability of Verapamil in an Extemporaneous Liquid Dosage Form," J Appl Ther Res, 1997,1(3):271-3.

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to treat high blood pressure.

• It is used to treat certain types of abnormal heartbeats.

• It is used to treat some types of chest pain (angina).

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Constipation

• Headache

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Liver problems like dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes.

• Slow heartbeat

• Abnormal heartbeat

• Severe dizziness

• Passing out

• Shortness of breath

• Excessive weight gain

• Swelling of arms or legs

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

High alert medication:

Administration issues:

International issues:

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); marked bradycardia; concurrent use of ivabradine or flibanserin.

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; breastfeeding.

Warnings/Precautions

Concerns related to adverse effects:

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

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

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

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 (ACLS [Neumar 2010]).

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

• 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: Use with caution in left ventricular dysfunction; due to negative inotropic effects, may exacerbate condition. Avoid use in patients with heart failure due to lack of benefit and/or worse outcomes with calcium channel blockers in general (ACCF/AHA [Yancy 2013]).

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

Concurrent drug therapy issues:

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

Special populations:

• Pediatric: In neonates and young infants, avoid IV use for 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]).

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

Elderly may experience a greater hypotensive response. Constipation may be more of a problem in the elderly. Calcium channel blockers are no more effective in the elderly than other therapies; however, they do not cause significant CNS effects which is an advantage over some antihypertensive agents. Generic verapamil products which are bioequivalent in young adults may not be bioequivalent in the elderly; use generics cautiously.

The AHA/ACC/ASH 2015 scientific statement on the treatment of hypertension in patients with CAD warns to use caution to avoid decreases in DBP <60 mm Hg especially in patients >60 years of age since reduced coronary perfusion may occur. When lowering SBP in older hypertensive patients with wide pulse pressures, very low DBP values (<60 mm Hg) may result. In patients with obstructive CAD, clinicians should lower blood pressure slowly and carefully monitor for any untoward signs or symptoms, especially those resulting from myocardial ischemia and worsening heart failure (AHA/ACC/ASH [Rosendorff 2015]).

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.

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 pregnant women; however, agents other than verapamil are more commonly used (ACOG 203 2019; ESC [Regitz-Zagrosek 2018]). Females with preexisting hypertension may continue their medication during pregnancy unless contraindications exist (ESC [Regitz-Zagrosek 2018]).

Women with hypertrophic cardiomyopathy who are controlled with verapamil prior to pregnancy may continue therapy, but increased fetal monitoring is recommended (Gersh 2011). Verapamil may be used IV for the acute treatment of supraventricular tachycardia (SVT) in pregnant women when adenosine or beta-blockers are ineffective or contraindicated. Verapamil may also be used for the ongoing management of SVT in highly symptomatic patients. The lowest effective dose is recommended; avoid use during the first trimester if possible (Page [ACC/AHA/HRS 2016]). Additional guidelines are available for management of cardiovascular diseases during pregnancy (ESC [Regitz-Zagrosek 2018]).

Breast-Feeding Considerations

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

The relative infant dose (RID) of verapamil is ≤1% of the weight-adjusted maternal dose

In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).

The RID of verapamil was calculated by the authors of several case reports following maternal use of verapamil 80 to 120 mg three times daily in women ≤3 months' postpartum. Adverse events were not observed in breastfed infants (Andersen 1983; Anderson 1987; Inoue 1984; Miller 1986).

Although breastfeeding is not recommended by some manufacturers, verapamil is considered compatible with breastfeeding (WHO 2002).

Briggs' Drugs in Pregnancy & Lactation

• Verapamil

Adverse Reactions

>10%:

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

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

1% to 10%:

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

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

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

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

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

Genitourinary: Impotence (oral: ≤1%)

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

Hepatic: Increased liver enzymes (1%)

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

Ophthalmic: Blurred vision (oral: ≤1%)

Otic: Tinnitus (oral: ≤1%)

Renal: Polyuria (oral: ≤1%)

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

<1%, postmarketing, and/or case reports: Asystole, bronchospasm (IV administration), depression (IV administration), diaphoresis (IV administration), drowsiness (IV administration), eosinophilia, exfoliative dermatitis, gastrointestinal obstruction, hair discoloration, laryngospasm (IV administration), muscle fatigue (IV administration), paralytic ileus, Parkinsonian-like syndrome, pruritus (IV administration), respiratory failure (IV administration), rotary nystagmus (IV administration), seizure (IV administration), shock, urticaria (IV administration), vertigo (IV administration), ventricular fibrillation

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• Verapamil Allergy

Toxicology

• Calcium Channel Blockers

Metabolism/Transport Effects

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

Drug Interactions Open Interactions

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

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Reduce afatinib by 10 mg if not tolerated. Some non-US labeling recommends avoiding combination if possible. If used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Risk D: Consider therapy modification

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

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

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

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

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

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

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: CYP3A4 Inhibitors (Moderate) 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

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

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

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

Avanafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil. Management: The maximum avanafil adult dose is 50 mg per 24-hour period when used together with a moderate CYP3A4 inhibitor. Patients receiving such a combination should also be monitored more closely for evidence of adverse effects. 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 from 300 mg once daily to 100 mg once daily. Risk D: Consider therapy modification

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

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

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

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

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-gp inhibitor. Avoid concomitant use of betrixaban and P-gp inhibitors in patients with severe renal impairment (CrCL less than 30 mL/min). Risk D: Consider therapy modification

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

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

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

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

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. 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 (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic). Risk X: Avoid combination

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

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

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

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

Cannabidiol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabidiol. 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 empiric reductions in carbamazepine dose with initiation of nondihydropyridine calcium channel blockers. Monitor for increased toxic effects of carbamazepine and reduced therapeutic effects of the calcium channel blocker. 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

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. Exceptions are discussed in separate monographs. Risk D: Consider therapy modification

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

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

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

CloNIDine: May enhance the AV-blocking effect of Calcium Channel Blockers (Nondihydropyridine). Sinus node dysfunction may also be enhanced. 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. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. 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 full 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-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details. Risk D: Consider therapy modification

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

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

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

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

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination. Some combinations are specifically contraindicated by manufacturers; others may have recommended dose adjustments. If combined, monitor for increased substrate effects. Risk D: Consider therapy modification

CYP3A4 Substrates (High risk with Inhibitors): CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Exceptions: Alitretinoin (Systemic); Praziquantel; Trabectedin; Vinorelbine. 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: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Risk D: Consider therapy modification

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

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

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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

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

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

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

Domperidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Domperidone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk X: Avoid combination

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

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

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 (i.e., verapamil, diltiazem), and only consider increasing calcium channel blocker dose after obtaining ECG-based evidence that the combination is being well-tolerated. Risk D: Consider therapy modification

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

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

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

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

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

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. Use in CYP2D6 EMs who are also taking strong or moderate CYP2D6 inhibitors is contraindicated. Avoid use of moderate CYP3A4 inhibitors in CYP2D6 IMs or PMs. 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. No alternative dosing provided for others. Risk D: Consider therapy modification

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

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

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

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

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. 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

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

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

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

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

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

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

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

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

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

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

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

Halofantrine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine. Management: Extreme caution, with possibly increased monitoring of ECGs, should be used if halofantrine is combined with moderate CYP3A4 inhibitors. Drugs listed as exceptions to this monograph are discussed in separate drug interaction monographs. Risk C: Monitor therapy

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

Herbs (Hypotensive Properties): 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

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

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

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

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

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

Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions may be required; consult full 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. Drugs listed as exceptions are discussed in further detail in separate drug interaction monographs. Risk D: Consider therapy modification

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

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

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

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Risk X: Avoid combination

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

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

Lorlatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lorlatinib. 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 lovastatin at a maximum adult dose of 10 mg/day, and do not exceed 20 mg/day, in patients receiving verapamil. Monitor closely for signs of HMG-CoA reductase inhibitor toxicity (e.g., myositis, rhabdomyolysis). Risk D: Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

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

Naldemedine: P-glycoprotein/ABCB1 Inhibitors 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

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

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

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

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

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

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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 use cannot be avoided, the pexidartinib dose should be reduced. Decrease 800 mg or 600 mg daily doses to 200 mg twice daily. Decrease doses of 400 mg/day to 200 mg/day. Risk D: Consider therapy modification

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

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

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

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

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

Propafenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Propafenone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk C: Monitor therapy

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

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

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

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

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

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

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. Risk C: Monitor therapy

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

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

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

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

RisperiDONE: Verapamil 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. US labeling recommends avoidance in patients with estimated creatinine clearance 15 to 80 mL/min unless prospective benefits outweigh the risks. Other non-US labels may differ. Risk D: Consider therapy modification

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

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

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

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

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

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

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 selumetinib prescribing information or the Pediatric and Neonatal Lexi-Drugs monograph Risk D: Consider therapy modification

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

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

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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

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

Simvastatin: Verapamil may increase the serum concentration of Simvastatin. Management: Avoid concurrent use of verapamil with simvastatin when possible. If used together, limit adult 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. Risk D: Consider therapy modification

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

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

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

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): Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism 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: May enhance the bradycardic effect of Verapamil. Telithromycin may enhance the hypotensive effect of Verapamil. Management: Consider use of a non-interacting macrolide antibiotic (eg, azithromycin) when possible. Monitor patients for signs and symptoms of hypotension, bradycardia, and lactic acidosis when using telithromycin and verapamil in combination. Risk D: Consider therapy modification

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

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

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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

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

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

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

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

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

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Resume the previous venetoclax dose 2 to 3 days after discontinuation of a P-gp inhibitor. Risk D: Consider therapy modification

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

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. 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. Management: The starting adult dose of zopiclone should not exceed 3.75 mg if combined with a moderate CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Risk D: Consider therapy modification

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

Test Interactions

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

Genes of Interest

• Cytochrome P450 3A4
• P-Glycoprotein

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.

Hypertension: The 2017 guideline for the prevention, detection, evaluation, and management of high blood pressure in adults (ACC/AHA [Whelton 2018]):

Confirmed hypertension and known atherosclerotic cardiovascular disease (ASCVD) or 10-year ASCVD risk ≥10%: Target BP <130/80 mm Hg is recommended.

Confirmed hypertension without markers of increased ASCVD risk: Target BP <130/80 mm Hg may be reasonable.

Diabetes and hypertension: The American Diabetes Association guidelines (ADA 2019):

Patients 18 to 65 years of age, without ASCVD, and 10-year ASCVD risk <15%: Target BP <140/90 mm Hg is recommended.

Patients 18 to 65 years of age and known ASCVD or 10-year ASCVD risk >15%: Target BP <130/80 mm Hg may be appropriate if it can be safely attained.

Patients >65 years of age (healthy or complex/intermediate health): Target BP <140/90 mm Hg is recommended.

Patients >65 years of age (very complex/poor health): Target BP <150/90 mm Hg is recommended.

Advanced Practitioners Physical Assessment/Monitoring

Obtain liver function tests and kidney function tests. Assess and monitor blood pressure, heart rate, and rhythm. Obtain and evaluate periodic ECGs. Screen for history of heart failure with reduced ejection fraction, sinus node dysfunction, AV-block, or other heart rhythm disturbance. Assess other medication patient may be taking; alternate therapy or dosage adjustments may be needed. IV use requires continuous cardiovascular and hemodynamic monitoring.

Nursing Physical Assessment/Monitoring

Check ordered labs and report any abnormalities. Monitor blood pressure, heart rate, rhythm, and ECG. IV infusions require an infusion pump and continuous cardiac and hemodynamic monitoring. Educate patient about limiting grapefruit juice while taking this medicine. Instruct patient to take extra care if drinking alcohol while taking this medicine.

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, methylparaben, propylparaben]

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

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

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

Solution, Intravenous, as hydrochloride:

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

Solution, Intravenous, as hydrochloride [preservative free]:

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

Tablet, Oral, as hydrochloride:

Calan: 80 mg [DSC], 120 mg [DSC] [scored]

Generic: 40 mg, 80 mg, 120 mg

Tablet Extended Release, Oral, as hydrochloride:

Calan SR: 120 mg

Calan SR: 180 mg [scored]

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

Generic: 120 mg, 180 mg, 240 mg

Dosage Forms: Canada

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, 240 mg

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 aluminum lake, fd&c yellow #10 aluminum lake]

Generic: 120 mg, 180 mg, 240 mg

Tablet Extended Release 24 Hour, Oral, as hydrochloride:

Generic: 240 mg [DSC]

Anatomic Therapeutic Chemical (ATC) Classification

• C08DA01

Generic Available (US)

Yes

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): $6.25 - $19.29

Tablet, controlled release (Calan SR Oral)

120 mg (per each): $7.32

180 mg (per each): $9.28

240 mg (per each): $10.62

Tablet, controlled release (Verapamil HCl ER Oral)

120 mg (per each): $1.07 - $2.13

180 mg (per each): $1.44 - $2.70

240 mg (per each): $1.64 - $3.09

Tablets (Verapamil HCl Oral)

40 mg (per each): $0.28

80 mg (per each): $0.31 - $0.57

120 mg (per each): $0.39 - $0.75

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.

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.

Pharmacodynamics/Kinetics

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%).

Pharmacodynamics/Kinetics: 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.

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

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

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Frequent occurrence of gingival hyperplasia has been reported. Calcium channel blockers (CCB) have been reported to cause gingival hyperplasia (GH). Verapamil-induced GH has appeared 11 months or more after subjects took daily doses of 240 to 360 mg. The severity of hyperplastic syndrome does not seem to be dose dependent. Gingivectomy is only successful if CCB therapy is discontinued. GH regresses markedly 1 week after CCB discontinuance with all symptoms resolving in 2 months. If a patient must continue CCB therapy, begin a program of professional cleaning and patient plaque control to minimize severity and growth rate of gingival tissue. Infrequent occurrence of erythema multiforme, Stevens-Johnson syndrome, and xerostomia have also been reported.

Effects on Bleeding

No information available to require special precautions

Related Information

• Antiarrhythmic Drugs
• Beers Criteria 2019: Potentially Inappropriate Medication Use in Older Adults ≥65 Years of Age
• Calcium Channel Blockers − Comparative Pharmacokinetics
• Dosing Considerations for the Critically Ill Patient With Morbid Obesity
• Inhibitors and Inducers of P-glycoprotein
• Oral Medications That Should Not Be Crushed or Altered
• Relative Infant Dose

Index Terms

Iproveratril Hydrochloride; Verapamil HCl; Verapamil Hydrochloride

FDA Approval Date

August 12, 1981

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Brand Names: International

Angimil (BD); Anpec (AU, HK, TW); Beaptin SR (SG); Calan SR (LK); Calaptin (IN); 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); Cordilat (BR); Cordilox SR (AU); Cronovera (MX); Devincil (LU); Dilacoran (BR, CR, DO, GT, HN, MX, NI, PA, SV); Dilacoran Retard (CR, DO, GT, HN, NI, PA, SV); Fibrocard (BE, LU); Flamon (BB, BM, BS, BZ, CH, GY, JM, MY, PR, SR, TT); Hexasoptin (DK, FI); 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, TH, TR, TW, VN, ZA); Isoptin Retard (AT, CH, DE, EE, FI, GR, IS, IT, LT, LV, PT, SE); Isoptin RR (HR, RO, SI); Isoptin SR (AE, AU, BG, BH, CN, CY, CZ, EG, HK, ID, JO, KR, KW, LB, NL, NZ, PL, QA, SA, SG, SK, TH, TW, ZA, ZW); Isoptine (BE, FR); Isoptino (AR, PY, UY); Lekoptin (HR); Lexoptin (UA); Librapamil (EC); Manidon (ES, VE); Manidon Retard (ES); Quasar (IT); Securon (GB, MT); Vasolan (BD); Vasomil (ZA, ZW); Vasopten (IN); Vepiltax (CR, DO, GT, HN, NI, PA, SV); Verahexal (DE, LU); Verahexal 240SR (ZW); Veraloc (DK); Veramet (PH); Veramex (DE); 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); Verelan (PH); Vermine (TH); Verpamil (AE, BH, CY, HU, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Vetrimil (TW); Zolvera (GB)

Last Updated 5/5/20