Verapamil (Lexi-Drugs)

Pronunciation

(ver AP a mil)

Brand Names: US

Calan; Calan SR; Verelan; Verelan PM

Brand Names: Canada

APO-Verap; APO-Verap SR; DOM-Verapamil SR; Isoptin SR; MYLAN-Verapamil; MYLAN-Verapamil SR; NOVO-Veramil SR [DSC]; NOVO-Veramil [DSC]; PHL-VERAPAMIL SR [DSC]; PMS-Verapamil SR; PRO-Verapamil SR [DSC]; RIVA-Verapamil SR; Verelan

Dosing: Adult

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

Immediate release:

80 to 160 mg 3 times daily (ACC/AHA [Gibbons 2003])

Manufacturer’s labeling: Dosing in the prescribing information may not reflect current clinical practice. 80 to 120 mg 3 times daily; in patients with increased response to verapamil (eg, small stature): 40 mg 3 times daily; maximum: 480 mg/day

Atrial fibrillation (rate control):

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

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

Oral:

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

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

Cluster headaches: Oral: Immediate release: Initial: 240 mg in 3 divided doses; may increase dose by 80 mg every 1 to 2 weeks until headaches subside or adverse reactions develop; maximum dose 960 mg/day (EFNS [May 2006]; Obermann 2015). Some experts recommend ECGs at baseline and after dose increases above 480 mg/day (Koppen 2016). Additional data may be necessary to further define the role of verapamil in this condition.

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

Immediate release: Usual dosage: 120 to 360 mg/day in 3 divided doses (ACC/AHA [Whelton 2017]); maximum: 480 mg/day

Extended release: Note: There is no evidence of additional benefit with doses >360 mg/day.

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

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

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

Idiopathic ventricular tachycardia (off-label use):

IV: 2.5 to 5 mg every 15 to 30 minutes (AHA/ACC/HRS [Al-Khatib 2017])

Oral:

Immediate release: 360 mg/day in 3 divided doses (Gill 1992a; Gill 1992b; Gill 1993)

Extended release: 240 to 480 mg once daily (AHA/ACC/HRS [Al-Khatib 2017])

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

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

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

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

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

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

Dosing: Geriatric

Hypertension: Oral: Note: When switching from immediate-release to extended-release formulations, the total daily dose remains the same unless formulation strength does not allow for equal conversion. Consider lower initial doses and titrating to response (ACCF/AHA [Aronow 2011]).

Immediate release: Initial: 40 mg 3 times daily

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

Other indications: Refer to adult dosing.

Dosing: Renal Impairment: Adult

Manufacturer’s labeling:

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

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

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

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

Dosing: Hepatic Impairment: Adult

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

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

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

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

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

Atrial fibrillation (rate control):

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

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

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

Guideline recommendations: The 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults recommends if monotherapy is warranted, in the absence of comorbidities (eg, cerebrovascular disease, chronic kidney disease, diabetes, heart failure, ischemic heart disease, etc), that thiazide-like diuretics or dihydropyridine calcium channel blockers may be preferred options due to improved cardiovascular endpoints (eg, prevention of heart failure and stroke). ACE inhibitors and ARBs are also acceptable for monotherapy. Combination therapy may be required to achieve blood pressure goals and is initially preferred in patients at high risk (stage 2 hypertension or atherosclerotic cardiovascular disease [ASCVD] risk ≥10%) (ACC/AHA [Whelton 2017]). Note: When a calcium channel blocker is selected, the dihydropyridine class (eg, amlodipine) is typically preferred, if tolerated, over the non-dihydropyridine class (eg, diltiazem or verapamil).

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

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

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

Use: Off-Label: Adult

  Acute coronary syndrome (ACS)Level of Evidence [G]

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

  Cluster headachesLevel of Evidence [C, G]

Data in 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. Additional data may be necessary to further define the role of verapamil in this condition.

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 (EFNS) guideline on the treatment of cluster headache, verapamil is the drug of first choice for headache prophylaxis in patients with episodic and chronic cluster headaches Ref. The EFNS guidelines and other expert opinions recommend checking an EKG at baseline and periodically when using verapamil for this indication 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 or dyspnea) in patients with obstructive or nonobstructive hypertrophic cardiomyopathy who do not tolerate beta-blockers or are unresponsive to beta-blockers.

  Idiopathic ventricular tachycardiaLevel of Evidence [C, G]

Data in a limited number of small prospective observational studies have shown that verapamil can suppress ventricular tachycardia (VT) in patients with idiopathic VT. Additional data may be necessary to further define the role of verapamil in this condition Ref.

Based on the American Heart Association/American College of Cardiology/Heart Rhythm Society 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 ventricular tachycardia originating from the right ventricular outflow tract or related to interfascicular reentry. Note: Calcium channel blockers should not be given to patients with ventricular tachycardia 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.

Level of Evidence Definitions
  Level of Evidence Scale
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

AATS, “2014 AATS Guidelines for the Prevention and Management of Perioperative Atrial Fibrillation and Flutter for Thoracic Surgical Procedures,” June 2014

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

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

Canadian Cardiovascular Society, “2016 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation,” 2016

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 – 2018,” January 2018

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

AHA/ACC/CDC, “AHA/ACC/CDC Science Advisory: An Effective Approach to High Blood Pressure Control” November 2013

ASH/ISH “Clinical Practice Guidelines for the Management of Hypertension in the Community: A Statement by the American Society of Hypertension and the International Society of Hypertension,” January 2014

Eighth Joint National Committee (JNC 8), “2014 Evidence-based Guideline for the Management of High Blood Pressure in Adults,” December 2013

Hypertrophic Cardiomyopathy:

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

“ACC/ESC Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy,” November 2003

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

AHA/ACC, “2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes,” September 2014.

ACCF/AHA, “2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction,” December 2012.

Other:

American Urological Association (AUA), “Peyronie’s Disease,” April 2015

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 extended-release products.

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

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

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

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

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

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

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

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

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 AV block (except in patients with a functioning artificial ventricular pacemaker); atrial flutter or fibrillation and an accessory bypass tract (Wolff-Parkinson-White [WPW] syndrome, Lown-Ganong-Levine syndrome)

Canadian labeling: Additional contraindications: Complicated myocardial infarction (ventricular failure manifested by pulmonary congestion); marked bradycardia; concurrent use of ivabradine.

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

Warnings/Precautions

Concerns related to adverse effects:

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

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

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

Disease-related concerns:

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

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

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

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

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

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

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

Concurrent drug therapy issues:

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

Special populations:

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

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.

Use during pregnancy may cause adverse fetal effects (bradycardia, heart block, hypotension) (Tan 2001).

Women with hypertrophic cardiomyopathy who are controlled with verapamil prior to pregnancy may continue therapy, but increased fetal monitoring is recommended (Gersh 2011). Verapamil may be used IV for the acute treatment of supraventricular tachycardia (SVT) in pregnant women when adenosine or beta-blockers are ineffective or contraindicated. Verapamil may also be used for the ongoing management of SVT in highly symptomatic patients. The lowest effective dose is recommended; avoid use during the first trimester if possible (Page [ACC/AHA/HRS 2016]). Untreated chronic maternal hypertension is associated with adverse events in the fetus, infant, and mother. If treatment for hypertension during pregnancy is needed, other agents are preferred (ACOG 2013). Additional guidelines are available for management of cardiovascular diseases during pregnancy (ESG [Regitz-Zagrosek 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 (Anderson 1983; Andersen 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
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

Allergy and Idiosyncratic Reactions
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 

Abemaciclib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Abemaciclib. 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: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. 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 and/or indication. 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

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 the betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. 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

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Risk C: Monitor therapy

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

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

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

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

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. 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 the concomitant use of cobimetinib and moderate CYP3A4 inhibitors. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose to 20 mg daily. Risk X: Avoid combination

Codeine: CYP3A4 Inhibitors (Moderate) may decrease 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

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 D: Consider therapy modification

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

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

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. 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

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

Encorafenib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Encorafenib. Management: Avoid concomitant use of encorafenib and moderate CYP3A4 inhibitors whenever possible. If concomitant administration is unavoidable, decrease the encorafenib dose to one-half of the encorafenib dose used prior to initiation of the CYP3A4 inhibitor. 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

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: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for most indications. See full monograph or prescribing information for specific dose adjustment and monitoring recommendations. Risk D: Consider therapy modification

Everolimus: Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for most indications. See full monograph or prescribing information for specific dose adjustment and monitoring recommendations. Risk D: Consider therapy modification

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

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. 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

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 are required; consult full monograph content for specific age- and weight-based recommendations. No dose adjustment is needed when using ivacaftor/lumacaftor with a moderate CYP3A4 inhibitor. 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

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: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Risk D: Consider therapy modification

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

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

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

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. Risk X: Avoid combination

Neratinib: CYP3A4 Inhibitors (Moderate) 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 in patients being treated with olaparib, if possible. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 150 mg twice daily. Risk D: Consider therapy modification

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

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

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

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

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Risk D: Consider therapy modification

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 adult dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.). 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

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

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 maximum simvastatin dose to 10 mg/day, and avoid Simcor (simvastatin/niacin) because fixed simvastatin doses in the product exceed this maximum. 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

St John’s Wort: May decrease the serum concentration 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

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

Tacrolimus (Topical): Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Tacrolimus (Topical). 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. After a period of 3 to 5 times the half-life of verapamil, increase the talazoparib dose to the dose used before initiation of verapamil. Risk D: Consider therapy modification

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

Telithromycin: May enhance the bradycardic effect of Verapamil. Telithromycin may enhance the hypotensive effect of Verapamil. 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: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tezacaftor. Management: When combined with moderate CYP3A4 inhibitors, tezacaftor/ivacaftor (100 mg/150 mg) should be given in the morning, every other day. Ivacaftor (150 mg) alone should be given in the morning, every other day on alternate days from tezacaftor/ivacaftor. Risk D: Consider therapy modification

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

Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Management: Jynarque dose requires adjustment when used with a moderate CYP3A4 inhibitor. See labeling or full interaction monograph for specific recommendations. Use of Samsca with moderate CYP3A4 ihibitors should generally be avoided. 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

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

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

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. 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

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).

Monitoring Parameters

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

Consult individual institutional policies and procedures.

Hypertension: The 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults (ACC/AHA [Whelton 2017]):

Confirmed hypertension and known CVD or 10-year ASCVD risk ≥10%: Target blood pressure <130/80 mm Hg is recommended

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

Diabetes and hypertension: The American Diabetes Association (ADA) guidelines (ADA 2018):

Patients ≥18 to ≤65 years: Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

Patients ≥18 to ≤65 years and at high risk of cardiovascular disease: Goal of therapy is SBP <130 mm Hg and DBP <80 mm Hg (if can be achieved without undue treatment burden).

Patients ≥65 years (healthy or complex/intermediate health): Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

Patients ≥65 years (very complex/poor health): Goal of therapy is SBP <150 mm Hg and DBP <90 mm Hg.

Advanced Practitioners Physical Assessment/Monitoring

Obtain periodic liver function tests and ECG (in patients with renal or hepatic impairment). Monitor blood pressure and heart rate. Dosage adjustment may be needed in liver impairment.

Nursing Physical Assessment/Monitoring

Check ordered labs and report abnormalities. Monitor blood pressure and heart rate.

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 [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.

Capsule Extended Release 24 Hour, Oral, as hydrochloride:

Verelan: 120 mg, 180 mg, 240 mg

Solution, Intravenous, as hydrochloride:

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

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

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): $1.96 – $5.59

120 mg (per each): $1.75 – $5.37

180 mg (per each): $1.83 – $2.03

200 mg (per each): $2.53 – $7.20

240 mg (per each): $2.06 – $2.29

300 mg (per each): $3.67 – $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): $9.89 – $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 – $2.32

180 mg (per each): $1.44 – $2.70

240 mg (per each): $1.64 – $3.09

Tablets (Calan Oral)

120 mg (per each): $5.47

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 tablets: 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: Gingival hyperplasia. 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 240-360 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.

Effects on Bleeding

No information available to require special precautions

Index Terms

Iproveratril Hydrochloride; Verapamil HCl; Verapamil Hydrochloride

FDA Approval Date
August 12, 1981
References

Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society [published online ahead of print October 30, 2017]. Circulation. 2017. doi: 10.1161/CIR.0000000000000549.[PubMed 29084731]

American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122(5):1122-1131. doi: 10.1097/01.AOG.0000437382.03963.88.[PubMed 24150027]

American Diabetes Association (ADA). Standards of medical care in diabetes—2018. Diabetes Care. 2018;41(suppl 1):S1-S159. http://care.diabetesjournals.org/content/41/Supplement_1. Accessed June 18, 2018.

Amsterdam EA, Wenger NK, Brindis RG, et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons; American Association for Clinical Chemistry. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [published correction appears in J Am Coll Cardiol. 2014;64(24):2713-2714]. J Am Coll Cardiol. 2014;64(24):e139-e228. doi: 10.1016/j.jacc.2014.09.017.[PubMed 25260718]

Andersen HJ. Excretion of verapamil in human milk. Eur J Clin Pharmacol. 1983;25(2):279-280.[PubMed 6628513]

Anderson P, Bondesson U, Mattiasson I, Johansson BW. Verapamil and norverapamil in plasma and breast milk during breast feeding. Eur J Clin Pharmacol. 1987;31(5):625-627.[PubMed 3830249]

Anderson PO, Sauberan JB. Modeling drug passage into human milk. Clin Pharmacol Ther. 2016;100(1):42-52.[PubMed 27060684]

Antman EM, Anbe SC, Alpert JS, et al, “ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction – Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction),” Circulation, 2004, 110(5):588-636.[PubMed 15289388]

Aronow WS, Fleg JL, Pepine CJ, et al, “ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents,” Circulation, 2011, 123(21):2434-506.[PubMed 21518977]

Barbarash RA, Bauman JL, Lukazewski AA, Srebro JP, Rich S. Verapamil infusions in the treatment of atrial tachyarrhythmias. Crit Care Med. 1986;14(10):886-888.[PubMed 3757529]

Beyerlein C, Csaszar G, Hollmann M, et al, “Verapamil in Antihypertensive Treatment of Patients on Renal Replacement Therapy — Clinical Implications and Pharmacokinetics,” Eur J Clin Pharmacol, 1990, 39(Suppl 1):35-7.[PubMed 2261942]

Black HR, Elliott WJ, Grandits G, et al, “Principal Results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) Trial,” JAMA, 2003, 289(16):2073-82.[PubMed 1270946]

Braunwald E, Antman EM, Beasley JW, et al, “ACC/AHA 2002 Guideline Update for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction – Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina),” J Am Coll Cardiol, 2002, 40(7):1366-74.[PubMed 12383588]

Bussone G, Leone M, Peccarisi C, et al. Double blind comparison of lithium and verapamil in cluster headache prophylaxis. Headache. 1990;30(7):411-417.[PubMed 2205598]

Calan (verapamil) [prescribing information]. New York, NY: Pfizer; September 2017.

Calan SR (verapamil) [prescribing information]. New York, NY: Pfizer; September 2017.

Chow T, Galvin J, and McGovern B, “Antiarrhythmic Drug Therapy in Pregnancy and Lactation,” Am J Cardiol, 1998, 82(4A):58I-62I.[PubMed 9737655]

Covera-HS (verapamil) [prescribing information]. New York, NY: Pfizer; September 2017.

Effect of verapamil on mortality and major events after acute myocardial infarction (the Danish verapamil infarction trial II—DAVIT II). Am J Cardiol. 1990;66(10):779-785.[PubMed 2220572]

Field JM, Hazinski MF, Sayre MR, et al, “Part 1: Executive Summary: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care,” Circulation, 2010, 122 (18 Suppl 3):640-56.[PubMed 20956217]

Fihn SD, Gardin JM, Abrams J, et al, “2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons,” Circulation, 2012, 126(25):3097-137.[PubMed 23166211]

Gersh BJ, Maron BJ, Bonow RO, et al, “2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines,” Circulation, 2011, 124(24):e783-831.[PubMed 22068434]

Gibbons RJ, Abrams J, Chatterjee K, et al, “ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina – Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina),” J Am Coll Cardiol, 2003, 41(1):159-68.[PubMed 12570960]

Gill JS, Blaszyk K, Ward DE, Camm AJ. Verapamil for the suppression of idiopathic ventricular tachycardia of left bundle branch block-like morphology. Am Heart J. 1993;126(5):1126-1133.[PubMed 8237755]

Gill JS, Mehta D, Ward DE, Camm AJ. Efficacy of flecainide, sotalol, and verapamil in the treatment of right ventricular tachycardia in patients without overt cardiac abnormality. Br Heart J. 1992a;68(4):392-397.[PubMed 1449923]

Gill JS, Ward DE, Camm JA. Comparison of verapamil and diltiazem in the suppression of idiopathic ventricular tachycardia. Pacing Clin Electrophysiol. 1992b;15(11 pt 2):2122-2126.[PubMed 1279611]

Griffith MJ, Garratt CJ, Rowland E , Ward DE, Camm AJ. Effects of intravenous adenosine on verapamil-sensitive “idiopathic” ventricular tachycardia. Am J Cardiol. 1994;15;73(11):759-764.[PubMed 8160612]

Go AS, Bauman M, King SM, et al. An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention [published online November 15, 2013]. Hypertension.[PubMed 24243703]

Hanyok JJ, Chow MS, Kluger J, et al, “An Evaluation of the Pharmacokinetics, Pharmacodynamics, and Dialyzability of Verapamil in Chronic Hemodialysis Patients,” J Clin Pharmacol, 1988, 28(9):831-6.[PubMed 3230150]

Inoue H, Unno N, Ou MC, Iwama Y, Sugimoto T. Level of verapamil in human milk. Eur J Clin Pharmacol. 1984;26(5):657-658.[PubMed 6468488]

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Ito S. Drug therapy for breast-feeding women. N Engl J Med. 2000;343(2):118-126.[PubMed 10891521]

James PA, Oparil S, Carter BL, et al. 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520.[PubMed 24352797]

January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society [published online March 28, 2014]. Circulation. doi: 10.1161/CIR.0000000000000041[PubMed 24682347]

Kleinman ME, Chameides L, Schexnayder SM, et al. Part 14: Pediatric Advanced Life Support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18 Suppl 3):S876-S908. doi: 10.1161/CIRCULATIONAHA.110.971101.[PubMed 24682347]

Kliegman RM, Stanton BMD, St. Geme J, Schor NF, eds. Nelson’ s Textbook of Pediatrics. 20th ed. Philadelphia, PA: Saunders Elsevier; 2016.

Koppen H, Stolwijk J, Wilms EB, van Driel V, Ferrari MD, Haan J. Cardiac monitoring of high-dose verapamil in cluster headache: An international Delphi study. Cephalalgia. 2016;36(14):1385-1388.[PubMed 26868817]

Leone M, D’Amico D, Frediani F, et al. Verapamil in the prophylaxis of episodic cluster headache: a double-blind study versus placebo. Neurology. 2000;54(6):1382-1385.[PubMed 10746617]

Lichtenwalner MR, Mencken T, Tully R, et al, “False-Positive Immunochemical Screen for Methadone Attributable to the Metabolites of Verapamil,” Clin Chem, 1998, 44(5):1039-41.[PubMed 9590378]

Magee LA, Schick B, Donnenfeld AE, et al, “The Safety of Calcium Channel Blockers in Human Pregnancy: A Prospective, Multicenter Cohort Study,” Am J Obstet Gynecol, 1996, 174(3):823-8.[PubMed 8633650]

Marik PE, Rivera R. Hypertensive emergencies: an update. Curr Opin Crit Care. 2011;17(6):569-580. doi: 10.1097/MCC.0b013e32834cd31d.[PubMed 21986463]

Maron BJ, McKenna WJ, Danielson GK, et al, “American College of Cardiology/European Society of Cardiology Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy. A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines,” J Am Coll Cardiol, 2003, 42(9):1687-713.[PubMed 14607462]

May A, Leone M, Afra J, et al; EFNS Task Force. EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. Eur J Neurol. 2006;13(10):1066-1077.[PubMed 16987158]

Miller MR, Withers R, Bhamra R, Holt DW. Verapamil and breast-feeding. Eur J Clin Pharmacol. 1986;30(1):125-126.[PubMed 3709626]

Mooy J, Schols M, v Baak M, et al, “Pharmacokinetics of Verapamil in Patients With Renal Failure,” Eir J Clin Pharmacol, 1985, 28(4):405-10.[PubMed 4029246]

Neumar RW, Otto CW, Link MS, et al, “Part 8: Adult Advanced Cardiovascular Life Support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care,” Circulation, 2010, 122(18 Suppl 3):729-67.

Nishimura RA and Holmes DR Jr, “Clinical Practice. Hypertrophic Obstructive Cardiomyopathy,” N Engl J Med, 2004, 350(13):1320-7.[PubMed 15044643]

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O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines [published correction appears in Circulation. 2013;128(25):e481.] Circulation. 2013;127(4):e362-e425.[PubMed 23247304]

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Phillips BG, Gandhi AJ, Sanoski CA, Just VL, Bauman JL. Comparison of intravenous diltiazem and verapamil for the acute treatment of atrial fibrillation and atrial flutter. Pharmacotherapy. 1997;17(6):1238-1245.[PubMed 9399606]

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Verelan PM (verapamil) [prescribing information]. Princeton, NJ: Kremers Urban; October 2014.

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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, MX); 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, TR, TW, VN, ZA); Isoptin Retard (AT, CH, CR, DE, DO, EE, FI, GR, GT, HN, IS, IT, LT, LV, NI, PA, PT, SE, SV); 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, 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); 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)

Verapamil (Patient Education – Adult Medication)
You must carefully read the “Consumer Information Use and Disclaimer” below in order to understand and correctly use this information
Pronunciation

(ver AP a mil)

Brand Names: US

Calan; Calan SR; Verelan; Verelan PM

Brand Names: Canada

Covera-HS; Isoptin SR; Verapamil Hydrochloride Injection, USP; Verelan

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.
What do I need to tell my doctor BEFORE I take this drug?
  • If you have an allergy to verapamil or any other part of this drug.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have any of these health problems: Heart failure (weak heart); certain types of abnormal heartbeats like heart block, Lown-Ganong-Levine syndrome, sick sinus syndrome, or Wolff-Parkinson-White syndrome; low blood pressure; or a slow heartbeat.
  • If you are taking any of these drugs: Dofetilide, ivabradine, or quinidine.
  • If you have taken disopyramide in the last 48 hours.
  • If you are breast-feeding. Do not breast-feed while you take this drug.
  • This is not a list of all drugs or health problems that interact with this drug.
  • Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this drug with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.
What are some things I need to know or do while I take this drug?
  • Tell all of your health care providers that you take this drug. This includes your doctors, nurses, pharmacists, and dentists.
  • Avoid driving and doing other tasks or actions that call for you to be alert until you see how this drug affects you.
  • To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
  • Check blood pressure and heart rate as the doctor has told you. Talk with the doctor.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • If you are taking this drug and have high blood pressure, talk with your doctor before using OTC products that may raise blood pressure. These include cough or cold drugs, diet pills, stimulants, ibuprofen or like products, and some natural products or aids.
  • Talk with your doctor before you drink alcohol.
  • If you drink grapefruit juice or eat grapefruit often, talk with your doctor.
  • This drug may affect how much of some other drugs are in your body. If you are taking other drugs, talk with your doctor. You may need to have your blood work checked more closely while taking this drug with your other drugs.
  • If you are 65 or older, use this drug with care. You could have more side effects.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this drug while you are pregnant.
What are some side effects that I need to call my doctor about right away?
  • WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:
  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
  • Slow heartbeat.
  • A new or worse heartbeat that does not feel normal.
  • Very bad dizziness or passing out.
  • Shortness of breath, a big weight gain, or swelling in the arms or legs.
What are some other side effects of this drug?
  • All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:
  • Dizziness.
  • Headache.
  • Constipation.
  • These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.
  • You may report side effects to your national health agency.
How is this drug best taken?
  • Use this drug as ordered by your doctor. Read all information given to you. Follow all instructions closely.
  • All long-acting products:
  • Swallow whole. Do not chew or crush.
  • Long-acting tablets:
  • Take this drug with food.
  • Take in the morning if taking once a day.
  • Some products may be broken in half. If you are not sure if you can break this product in half, talk with the doctor.
  • Long-acting capsules:
  • Some products are to be taken at bedtime. For some products it does not matter. Check with your pharmacist about how to take this drug.
  • You may sprinkle contents of capsule on 1 tablespoon (15 mL) of applesauce. Take right away and do not chew granules.
  • Do not mix with hot applesauce.
  • All oral products:
  • To gain the most benefit, do not miss doses.
  • Keep taking this drug as you have been told by your doctor or other health care provider, even if you feel well.
  • Injection:
  • It is given as a shot into a vein over a period of time.
What do I do if I miss a dose?
  • All oral products:
  • Take a missed dose as soon as you think about it.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.
  • Injection:
  • Call your doctor to find out what to do.
How do I store and/or throw out this drug?
  • All oral products:
  • Store at room temperature.
  • Protect from light.
  • Store in a dry place. Do not store in a bathroom.
  • Injection:
  • If you need to store this drug at home, talk with your doctor, nurse, or pharmacist about how to store it.
  • All products:
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.
General drug facts
  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else’s drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.
Verapamil (Patient Education – Pediatric Medication)
You must carefully read the “Consumer Information Use and Disclaimer” below in order to understand and correctly use this information
Pronunciation

(ver AP a mil)

Brand Names: US

Calan; Calan SR; Verelan; Verelan PM

Brand Names: Canada

Covera-HS; Isoptin SR; Verapamil Hydrochloride Injection, USP; Verelan

What is this drug used for?
  • Tablets:
  • It is used to treat high blood pressure.
  • It is used to treat some types of chest pain (angina).
  • Injection and tablet:
  • It is used to treat certain types of abnormal heartbeats.
  • It may be given to your child for other reasons. Talk with the doctor.
  • All long-acting products:
  • If your child has been given this form of this drug, talk with the doctor for information about the benefits and risks. Talk with the doctor if you have questions or concerns about giving this drug to your child.
What do I need to tell the doctor BEFORE my child takes this drug?
  • If your child has an allergy to this drug or any part of this drug.
  • If your child is allergic to any drugs like this one or any other drugs, foods, or other substances. Tell the doctor about the allergy and what signs your child had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If your child has any of these health problems: Heart failure (weak heart); certain types of abnormal heartbeats like heart block, Lown-Ganong-Levine syndrome, sick sinus syndrome, or Wolff-Parkinson-White syndrome; low blood pressure; or a slow heartbeat.
  • If your child is taking any of these drugs: Dofetilide, ivabradine, or quinidine.
  • If your child has taken disopyramide in the last 48 hours.
  • If your child is breast-feeding a baby:
  • Be sure your child does not breast-feed a baby while taking this drug.
  • This is not a list of all drugs or health problems that interact with this drug.
  • Tell the doctor and pharmacist about all of your child’s drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for your child to take this drug with all of his/her drugs and health problems. Do not start, stop, or change the dose of any drug your child takes without checking with the doctor.
What are some things I need to know or do while my child takes this drug?
  • Tell all of your child’s health care providers that your child is taking this drug. This includes your child’s doctors, nurses, pharmacists, and dentists.
  • Have your child avoid tasks or actions that call for alertness until you see how this drug affects your child. These are things like riding a bike, playing sports, or using items such as scissors, lawnmowers, electric scooters, toy cars, or motorized vehicles.
  • To lower the chance of feeling dizzy or passing out, have your child rise slowly if your child has been sitting or lying down. Have your child be careful going up and down stairs.
  • Have your child’s blood pressure and heart rate checked often. Talk with your child’s doctor.
  • Have your child’s blood work checked often. Talk with your child’s doctor.
  • If your child drinks grapefruit juice or eats grapefruit often, talk with your child’s doctor.
  • If your child is taking this drug and has high blood pressure, talk with the doctor before giving OTC products that may raise blood pressure. These include cough or cold drugs, diet pills, stimulants, ibuprofen or like products, and some natural products or aids.
  • Alcohol may interact with this drug. Be sure your child does not drink alcohol.
  • This drug may affect how much of some other drugs are in the body. If your child is taking other drugs, talk with the doctor. Your child may need to have blood work checked more closely while taking this drug with other drugs.
  • If your child is pregnant:
  • Tell the doctor if your child is pregnant or becomes pregnant. You will need to talk about the benefits and risks of your child using this drug while pregnant.
What are some side effects that I need to call my child’s doctor about right away?
  • WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your child’s doctor or get medical help right away if your child has any of the following signs or symptoms that may be related to a very bad side effect:
  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
  • Slow heartbeat.
  • A new or worse heartbeat that does not feel normal.
  • Very bad dizziness or passing out.
  • Shortness of breath, a big weight gain, or swelling in the arms or legs.
What are some other side effects of this drug?
  • All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your child’s doctor or get medical help if any of these side effects or any other side effects bother your child or do not go away:
  • Dizziness.
  • Headache.
  • Constipation.
  • These are not all of the side effects that may occur. If you have questions about side effects, call your child’s doctor. Call your child’s doctor for medical advice about side effects.
  • You may report side effects to your national health agency.
How is this drug best given?
  • Give this drug as ordered by your child’s doctor. Read all information given to you. Follow all instructions closely.
  • Tablet:
  • To gain the most benefit, do not miss giving your child doses.
  • Keep giving this drug to your child as you have been told by your child’s doctor or other health care provider, even if your child feels well.
  • Injection:
  • It is given as a shot into a vein over a period of time.
What do I do if my child misses a dose?
  • Tablet:
  • Give a missed dose as soon as you think about it.
  • If it is close to the time for your child’s next dose, skip the missed dose and go back to your child’s normal time.
  • Do not give 2 doses at the same time or extra doses.
  • Injection:
  • Call your child’s doctor to find out what to do.
How do I store and/or throw out this drug?
  • Tablet:
  • Store at room temperature.
  • Protect from light.
  • Store in a dry place. Do not store in a bathroom.
  • Injection:
  • If you need to store this drug at home, talk with your child’s doctor, nurse, or pharmacist about how to store it.
  • All products:
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.
General drug facts
  • If your child’s symptoms or health problems do not get better or if they become worse, call your child’s doctor.
  • Do not share your child’s drug with others and do not give anyone else’s drug to your child.
  • Keep a list of all your child’s drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your child’s doctor.
  • Talk with your child’s doctor before giving your child any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your child’s doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.