Verelan

Anti-anginal Agents, other
Anti-arrhythmics, Class IV
Phenylakylamine Calcium Channel Blockers

Oral Administration

Avoid grapefruit juice before or after administration to avoid potential increases in verapamil bioavailability.

Oral Solid Formulations

Regular-release tablets: Verapamil may be administered without regard to food.
Sustained-release capsules, 24 hour formulation (Verelan and generic equivalents): May be administered without regard to food. The capsule should be swallowed whole; the contents of the capsule should not be crushed or chewed.
Sustained-release tablets, 12 hour formulation (Isoptin SR, Calan SR, and generic equivalents): Administer with food to decrease the difference between peak and trough concentrations. Bioavailability is not decreased by halving the tablets. The tablets should be swallowed whole and should not be crushed or chewed.
Covera-HS extended-release tablets, controlled onset: Administer once daily at bedtime. The tablets should be swallowed whole and should not be crushed or chewed.
Verelan PM extended-release capsules, controlled onset: Administer once daily at bedtime. The capsule should be swallowed whole; the contents of the capsule should not be crushed or chewed. The contents of the capsule may be sprinkled onto applesauce.

Extemporaneous Compounding-Oral

Extemporaneous preparation of 50 mg/ml verapamil oral suspension†:
With a mortar and pestle, grind seventy-five 80 mg regular release verapamil tablets into a fine powder.
In a separate container make the base solution by mixing one of the following: 1) 60 ml of Ora-Sweet with 60 ml of Ora-Plus; or 2) 60 ml of Ora-Sweet SF with 60 ml of Ora-Plus; or 3) 120 ml of cherry syrup.
Add a small amount of the base solution to the fine powder and mix into a uniform paste. Add geometric amounts of the base solution to make almost 120 ml while mixing. Transfer to a graduated cylinder and adjust to a total volume of 120 ml while mixing.
Place in amber plastic bottles. Shake well before each use and protect from light. These oral suspensions are stable for 60 days when stored in the dark at room temperature (25 degrees C) or under refrigeration (5 degrees C).

Injectable Administration

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Intravenous Administration

No dilution necessary.
 
Direct IV injection:
Administer verapamil IV over a period of not less than 2 minutes (3 minutes in geriatric patients) under continuous ECG and blood pressure monitoring.

Severe

stroke / Early / 0-2.0
vasculitis / Delayed / 0-2.0
Stevens-Johnson syndrome / Delayed / 0-2.0
erythema multiforme / Delayed / 0-2.0
heart failure / Delayed / 1.8-1.8
pulmonary edema / Early / 1.8-1.8
AV block / Early / 1.2-1.7
bradycardia / Rapid / 1.2-1.4
ventricular fibrillation / Early / Incidence not known
asystole / Rapid / Incidence not known
seizures / Delayed / Incidence not known
bronchospasm / Rapid / Incidence not known
laryngospasm / Rapid / Incidence not known

Moderate

constipation / Delayed / 7.3-11.7
peripheral edema / Delayed / 3.7-3.7
edema / Delayed / 1.7-3.0
hypotension / Rapid / 0.7-2.5
confusion / Early / 0-2.0
blurred vision / Early / 0-2.0
gingival hyperplasia / Delayed / 0-2.0
elevated hepatic enzymes / Delayed / 0-2.0
galactorrhea / Delayed / 0-2.0
hyperprolactinemia / Delayed / 0-2.0
impotence (erectile dysfunction) / Delayed / 0-2.0
dyspnea / Early / 0-2.0
orthostatic hypotension / Delayed / 0.4-0.4
palpitations / Early / Incidence not known
PR prolongation / Rapid / Incidence not known
sinus tachycardia / Rapid / Incidence not known
chest pain (unspecified) / Early / Incidence not known
peripheral vasodilation / Rapid / Incidence not known
nystagmus / Delayed / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known

Mild

headache / Early / 1.2-12.1
dizziness / Early / 1.2-4.7
fatigue / Early / 1.7-4.5
dyspepsia / Early / 0-2.7
nausea / Early / 0.9-2.7
diarrhea / Early / 0-2.4
syncope / Early / 0-2.0
tremor / Early / 0-2.0
paresthesias / Delayed / 0-2.0
tinnitus / Delayed / 0-2.0
asthenia / Delayed / 0-2.0
drowsiness / Early / 0-2.0
muscle cramps / Delayed / 0-2.0
insomnia / Early / 0-2.0
abdominal pain / Early / 0-2.0
xerostomia / Early / 0-2.0
breakthrough bleeding / Delayed / 0-2.0
gynecomastia / Delayed / 0-2.0
hyperkeratosis / Delayed / 0-2.0
arthralgia / Delayed / 0-2.0
ecchymosis / Delayed / 0-2.0
diaphoresis / Early / 0-2.0
purpura / Delayed / 0-2.0
alopecia / Delayed / 0-2.0
pruritus / Rapid / 0-2.0
urticaria / Rapid / 0-2.0
maculopapular rash / Early / 0-2.0
rash / Early / 0-2.0
flushing / Rapid / 0.6-0.8
vertigo / Early / Incidence not known

Calan, Calan SR, Isoptin, Isoptin SR, Verelan, Verelan PM

Rx

Oral and IV calcium-channel blocker; used for angina, HTN, and supraventricular tachyarrhythmias; class IV antiarrhythmic agent; more effective than digoxin for controlling ventricular rate in AFIB; other uses include mania and migraine prophylaxis.

For the treatment of variant angina (Prinzmetal angina) and chronic stable angina. Oral dosage (immediate-release) Adults

40 to 120 mg PO 3 times daily. Usual dose: 80 to 120 mg PO 3 times daily. Adjust dose daily or weekly until desired clinical response is achieved.

For rapid conversion of narrow-complex paroxysmal supraventricular tachycardia (PSVT) (including those associated with accessory bypass tracts such as Wolff-Parkinson-White or Lown-Ganong-Levine) to sinus rhythm. Intravenous dosage Adults

2.5 to 5 mg IV bolus, followed by 5 to 10 mg IV bolus every 15 to 30 minutes as needed. Max: 30 mg. The FDA-approved dosage is 0.075 to 0.15 mg/kg (Usual dose: 5 to 10 mg) IV bolus; may administer an additional 0.15 mg/kg (Usual dose: 10 mg) IV bolus 30 minutes after initial bolus if no response. Intravenous verapamil can be effective for acute treatment in persons with hemodynamically stable SVT at a regular rate in the absence of significant heart failure. It is reasonable to use verapamil if adenosine or vagal maneuvers fail to convert PSVT, PSVT recurs after such treatment, or if these treatments disclose another form of SVT.

Children and Adolescents

0.1 mg/kg/dose (Max: 5 mg/dose) IV bolus, followed by 1 to 7 mcg/kg/minute continuous IV infusion. May repeat bolus 30 minutes after initial bolus if no response, up to a maximum of 10 mg. Initial doses of 0.2 to 0.3 mg/kg (Max: 5 mg/dose) IV have also been suggested.

Infants

Use of verapamil in infants younger than 1 year is not recommended and has been associated with refractory hypotension and cardiac arrest. 0.1 to 0.2 mg/kg IV bolus under continuous ECG monitoring. May repeat bolus 30 minutes after initial bolus if no response.

For paroxysmal supraventricular tachycardia (PSVT) prophylaxis due to re-entry. Oral dosage (regular-release tablets) Adults

240 to 480 mg/day PO, given in 3 to 4 divided doses.

Children† and Adolescents†

Limited data are available regarding long-term use of verapamil in pediatric patients. However, doses of 2 to 7 mg/kg/day PO (up to a maximum of 480 mg/day) divided into 3 daily doses has been suggested.

For the treatment of atrial flutter or atrial fibrillation. For acute, temporary ventricular rate control in cases of atrial flutter or atrial fibrillation except when associated with Wolff-Parkinson-White or Lown-Ganong-Levine syndrome. Intravenous dosage Adults

0.075 to 0.15 mg/kg (Usual dose: 5 to 10 mg) IV bolus; may administer an additional 0.15 mg/kg (Usual dose: 10 mg) IV bolus 30 minutes after initial bolus if no response, followed by 0.005 mg/kg/minute continuous IV infusion. Guidelines recommend an intravenous nondihydropyridine calcium channel blocker to control ventricular heart rate in persons with paroxysmal, persistent, or permanent atrial fibrillation in persons without pre-excitation and only in the absence of significant heart failure or hemodynamic instability. A nondihydropyridine calcium channel blocker is the preferred agent in persons with chronic obstructive pulmonary disease.

For ventricular rate control in persons with chronic atrial flutter and/or atrial fibrillation in combination with digoxin. Oral dosage (immediate-release) Adults

240 to 320 mg/day PO in 3 to 4 divided doses.

For ventricular rate control in patients with chronic atrial flutter or atrial fibrillation. Oral dosage (extended-release, once daily†) Adults

180 to 480 mg PO once daily. Guidelines recommend a nondihydropyridine calcium channel blocker to control ventricular heart rate in persons with paroxysmal, persistent, or permanent atrial fibrillation in the absence of pre-excitation, significant heart failure, or left ventricular systolic dysfunction.

For the treatment of hypertension. Oral dosage (immediate-release) Adults

80 mg PO 3 times daily, initially. May increase the dose weekly if further control is needed. Daily dosages of 360 and 480 mg have been used, but there is no evidence that dosages more 360 mg/day provided added effect. Usual dose: 120 to 360 mg/day in 3 divided doses.

Older or Small Stature Adults

40 mg PO 3 times daily, initially. May increase the dose weekly if further control is needed. Daily dosages of 360 and 480 mg have been used, but there is no evidence that dosages more 360 mg/day provided added effect. Usual dose: 120 to 360 mg/day in 3 divided doses.

Children† and Adolescents†

Very limited data exist regarding the use of verapamil in pediatric patients for hypertension. Some authors have reported the successful use of initial doses of 3 to 4 mg/kg/day PO divided into 3 daily doses. The maximum dose reported by these authors was 8 mg/kg/day PO up to 480 mg/day. Others have recommended against the use of verapamil for the treatment of hypertension in pediatric patients and suggest using other calcium channel antagonists that have more pediatric data available.

Oral dosage (extended-release, once daily; e.g., Verelan) Adults

240 mg PO once daily, initially. May increase the dose by 120 mg/day weekly if further control is needed. Usual dose: 120 to 360 mg/day. Max: 480 mg/day.

Older or Small Stature Adults

120 mg PO once daily, initially. May increase the dose by 120 mg/day weekly if further control is needed. Usual dose: 120 to 360 mg/day. Max: 480 mg/day.

Children† and Adolescents†

Very limited data exist regarding the use of verapamil in pediatric patients for hypertension. Some authors have reported the successful use of initial doses of 3 to 4 mg/kg/day PO divided into the appropriate number of doses for a given dosage form. The maximum dose reported by these authors was 8 mg/kg/day PO; the adult maximum dose should not be exceeded. Others have recommended against the use of verapamil for the treatment of hypertension in pediatric patients and suggest using other calcium channel antagonists that have more pediatric data available.

Oral dosage (modified-release, once daily; e.g., Verelan PM) Adults

200 mg PO once daily, initially. May increase the dose by 100 mg/day weekly if further control is needed. Usual dose: 100 to 300 mg/day. Max: 400 mg/day.

Older or Small Stature Adults

100 mg PO once daily, initially. May increase the dose by 100 mg/day weekly if further control is needed. Usual dose: 100 to 300 mg/day. Max: 400 mg/day.

Children† and Adolescents†

Very limited data exist regarding the use of verapamil in pediatric patients for hypertension. Some authors have reported the successful use of initial doses of 3 to 4 mg/kg/day PO divided into the appropriate number of doses for a given dosage form. The maximum dose reported by these authors was 8 mg/kg/day PO; the adult maximum dose should not be exceeded. Others have recommended against the use of verapamil for the treatment of hypertension in pediatric patients and suggest using other calcium channel antagonists that have more pediatric data available.

Oral dosage (extended-release, twice daily; e.g., Calan SR, Isoptin SR) Adults

180 mg PO once daily, initially. May increase the dose by 120 mg/day weekly if additional control is needed. Usual dose: 120 to 360 mg/day in 1 or 2 divided doses. Max: 240 mg PO twice daily.

Older or Small Stature Adults

120 mg PO once daily, initially. May increase the dose by 120 mg/day weekly if additional control is needed. Usual dose: 120 to 360 mg/day in 1 or 2 divided doses. Max: 240 mg PO twice daily.

Children† and Adolescents†

Very limited data exist regarding the use of verapamil in pediatric patients for hypertension. Some authors have reported the successful use of initial doses of 3 to 4 mg/kg/day PO divided into the appropriate number of doses for a given dosage form. The maximum dose reported by these authors was 8 mg/kg/day PO; the adult maximum dose should not be exceeded. Others have recommended against the use of verapamil for the treatment of hypertension in pediatric patients and suggest using other calcium channel antagonists that have more pediatric data available.

For migraine prophylaxis†. Oral dosage (regular-release tablets) Adults

Dosage not established. 80 mg PO 3 to 4 times daily has been studied. Clinical practice guidelines classify verapamil as having inadequate or conflicting data to support or refute use for migraine prophylaxis.

For the treatment of acute mania†. Oral dosage (regular-release tablets) Adults

Limited data suggest oral verapamil is effective in controlling an acute manic episode either as a single agent or in combination with lithium. Dosages of 160 to 320 mg/day PO, administered in divided doses, have been used successfully.

Geriatric

See adult dosage. In general, use lower initial adult dosage (e.g., total dosage 120 mg/day PO). Adjust dosage based on clinical response.

For the treatment of intermittent claudication† due to peripheral vascular disease (PVD)†. Oral dosage (sustained-release tablets) Adults

120 to 480 mg PO once daily has been evaluated in small clinical studies. Titrate to effective dose. The data for verapamil improving maximum walking distance in patients with intermittent claudication are inconclusive; however, verapamil may be an option for some patients who have failed or not tolerated other therapies.

For the treatment of ongoing ischemia in acute myocardial infarction, STEMI†, acute myocardial infarction, NSTEMI†, or unstable angina. Oral dosage (immediate-release) Adults

80 to 160 mg PO 3 times daily. Guidelines for STEMI recommend a nondihydropyridine calcium channel blocker to relieve ischemia, lower blood pressure, or control the ventricular response rate in persons with atrial fibrillation who are intolerant of beta blockers. Guidelines for NSTEMI recommend a nondihydropyridine calcium channel blocker after appropriate use of nitrates and beta-blockers or contraindication to beta-blockers in the absence of clinically significant left ventricular dysfunction, increased risk for cardiogenic shock, PR interval more than 0.24 second, or second- or third-degree AV block without a cardiac pacemaker.

Oral dosage (extended-release, once daily†) Adults

240 to 480 mg PO once daily. Guidelines for STEMI recommend a nondihydropyridine calcium channel blocker to relieve ischemia, lower blood pressure, or control the ventricular response rate in persons with atrial fibrillation who are intolerant of beta blockers. Guidelines for NSTEMI recommend a nondihydropyridine calcium channel blocker after appropriate use of nitrates and beta-blockers or contraindication to beta-blockers in the absence of clinically significant left ventricular dysfunction, increased risk for cardiogenic shock, PR interval more than 0.24 second, or second- or third-degree AV block without a cardiac pacemaker.

For the treatment of multifocal atrial tachycardia†. Oral dosage (immediate-release) Adults

80 mg PO every 6 hours. Usual maintenance dose: 180 to 480 mg/day for another supraventricular tachyarrhythmia. Guidelines recommend oral verapamil for patients with recurrent, symptomatic multifocal atrial tachycardia in the absence of heart failure with reduced ejection fraction.

Intravenous dosage Adults

2.5 to 5 mg IV every 5 minutes until response up to 15 mg.   Guidelines recommend intravenous verapamil for acute treatment in patients with multifocal atrial tachycardia.

For the treatment of premature ventricular contractions (PVCs)†. Oral dosage (extended-release, once daily) Adults

240 to 480 mg PO once daily.

Intravenous dosage Adults

2.5 to 5 mg IV every 15 to 30 minutes as needed.

†Indicates off-label use

Hepatic Impairment

Where possible (based on the dosage strengths available), reduce the initial verapamil dosage to about 33% of the usual starting dosage. Adjust dosage based on clinical goals. In patients with hepatic disease, verapamil clearance is reduced to 30% of normal.

Renal Impairment

No dosage adjustment is needed. However, the manufacturer recommends cautious monitoring in patients with renal impairment. About 70% of a verapamil dose is excreted renally as metabolites, including the major active metabolite (norverapamil).
 
Intermittent hemodialysis
Verapamil and norverapamil are not significantly removed by hemodialysis.

Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with verapamil is necessary; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. Abemaciclib is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration with verapamil is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6-fold.
Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with verapamil. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
Acebutolol: (Moderate) Use verapamil and acebutolol with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
Acetaminophen; Aspirin, ASA; Caffeine: (Minor) In a few reported cases, coadministration of verapamil with aspirin, ASA has led to increased bleeding times greater than observed with aspirin alone. The exact mechanism and clinical significance of this interaction is unknown. (Minor) Verapamil reduces the clearance of caffeine and increases serum caffeine concentrations, presumably via inhibition of hepatic metabolism. During concomitant therapy with verapamil, it may be prudent to advise patients to limit or minimize the intake of caffeinated products to minimize caffeine-related side effects.
Acetaminophen; Aspirin: (Minor) In a few reported cases, coadministration of verapamil with aspirin, ASA has led to increased bleeding times greater than observed with aspirin alone. The exact mechanism and clinical significance of this interaction is unknown.
Acetaminophen; Aspirin; Diphenhydramine: (Minor) In a few reported cases, coadministration of verapamil with aspirin, ASA has led to increased bleeding times greater than observed with aspirin alone. The exact mechanism and clinical significance of this interaction is unknown.
Acetaminophen; Caffeine: (Minor) Verapamil reduces the clearance of caffeine and increases serum caffeine concentrations, presumably via inhibition of hepatic metabolism. During concomitant therapy with verapamil, it may be prudent to advise patients to limit or minimize the intake of caffeinated products to minimize caffeine-related side effects.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with verapamil may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of verapamil could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If verapamil is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Verapamil is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Minor) Verapamil reduces the clearance of caffeine and increases serum caffeine concentrations, presumably via inhibition of hepatic metabolism. During concomitant therapy with verapamil, it may be prudent to advise patients to limit or minimize the intake of caffeinated products to minimize caffeine-related side effects.
Acetaminophen; Caffeine; Pyrilamine: (Minor) Verapamil reduces the clearance of caffeine and increases serum caffeine concentrations, presumably via inhibition of hepatic metabolism. During concomitant therapy with verapamil, it may be prudent to advise patients to limit or minimize the intake of caffeinated products to minimize caffeine-related side effects.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with verapamil may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of verapamil could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If verapamil is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Verapamil is a moderate inhibitor of CYP3A4.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Isometheptene has sympathomimetic properties. Patients taking antihypertensive agents may need to have their therapy modified. Careful blood pressure monitoring is recommended.
Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of verapamil is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like verapamil can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If verapamil is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Ibuprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of verapamil is necessary. If verapamil is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like verapamil can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If verapamil is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Acetaminophen; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Acetaminophen; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Acrivastine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Adagrasib: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with adagrasib. Coadministration may increase the exposure of verapamil. Adagrasib is a strong inhibitor of CYP3A; verapamil is a substrate of CYP3A.
Adenosine: (Moderate) Use adenosine with caution in the presence of calcium-channel blockers due to the potential for additive or synergistic depressant effects on the sinoatrial and atrioventricular nodes.
Afatinib: (Moderate) If the concomitant use of verapamil and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of verapamil. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and verapamil is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
Albuterol; Budesonide: (Moderate) Avoid coadministration of systemic budesonide with verapamil due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor.
Aldesleukin, IL-2: (Moderate) Calcium channel blockers may potentiate the hypotension seen with aldesleukin, IL 2.
Alemtuzumab: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of verapamil is necessary. If verapamil is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like verapamil can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If verapamil is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Alfuzosin: (Moderate) Monitor blood pressure if coadministration of alfuzosin and verapamil is necessary. This combination has the potential to cause hypotension in some patients. Coadministration may also result in increased alfuzosin serum concentrations. Alfuzosin is primarily metabolized by the CYP3A4 hepatic enzyme. In addition to potential for additive hypotension with alfuzosin, verapamil may also inhibit the metabolism of alfuzosin.
Aliskiren: (Moderate) Administration of 240 mg verapamil with 300 mg aliskiren resulted in an approximately 2-fold increase in AUC and Cmax of aliskiren; however, no dosage adjustment is necessary. Blood pressure should be closely monitored in patients taking both of these medications.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Administration of 240 mg verapamil with 300 mg aliskiren resulted in an approximately 2-fold increase in AUC and Cmax of aliskiren; however, no dosage adjustment is necessary. Blood pressure should be closely monitored in patients taking both of these medications.
Almotriptan: (Minor) Verapamil, a moderate CYP3A4 inhibitor, increases AUC and peak plasma concentrations of almotriptan by 20% and 24%, respectively; however, per the manufacturer, the changes are not clinically significant and no dosage adjustment of almotriptan is needed. Some patients might rarely have an increase in common side effects of almotriptan, such as dizziness, nausea or drowsiness.
Alprazolam: (Major) Avoid coadministration of alprazolam and verapamil due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with verapamil, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased alprazolam exposure by 1.6- to 1.98-fold.
Alprostadil: (Minor) The concomitant use of systemic alprostadil injection and antihypertensive agents, like calcium channel blockers, may cause additive hypotension. Caution is advised with this combination. Systemic drug interactions with the urethral suppository (MUSE) or alprostadil intracavernous injection are unlikely in most patients because low or undetectable amounts of the drug are found in the peripheral venous circulation following administration. In those men with significant corpora cavernosa venous leakage, hypotension might be more likely. Use caution with in-clinic dosing for erectile dysfunction (ED) and monitor for the effects on blood pressure. In addition, the presence of medications in the circulation that attenuate erectile function may influence the response to alprostadil. However, in clinical trials with alprostadil intracavernous injection, anti-hypertensive agents had no apparent effect on the safety and efficacy of alprostadil.
Alvimopan: (Moderate) Alvimopan is a substrate of P-glycoprotein (P-gp). Although the concomitant use of mild to moderate inhibitors of P-gp did not influence the pharmacokinetics of alvimopan, the concomitant use of strong P-gp inhibitors, such as verapamil has not been studied. Coadministration of verapamil and alvimopan may result in elevated concentrations of alvimopan. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect of alvimopan.
Amifostine: (Major) Patients receiving calcium-channel blockers should be closely monitored during amifostine infusions due to additive effects. Patients receiving amifostine at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of amifostine. If the antihypertensive cannot be stopped for 24 hours before chemotherapy doses of amifostine, patients should not receive amifostine.
Aminolevulinic Acid: (Minor) Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Amiodarone: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with amiodarone. Coadministration may increase the exposure of verapamil. Additive effects on cardiac contractility and/or AV conduction are also possible. Verapamil is a substrate of CYP3A4 and amiodarone is a moderate CYP3A4 inhibitor.
Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with verapamil is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Atorvastatin: (Moderate) Closely monitor for signs and symptoms of myopathy and rhabdomyolysis and consider atorvastatin dosage adjustment in patients also taking verapamil. Coadministration of verapamil, a P-gp inhibitor, with atorvastatin, a P-gp substrate, may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher statin doses. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with verapamil is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with verapamil is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Celecoxib: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with verapamil is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with verapamil is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with verapamil is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with verapamil is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amobarbital: (Major) Barbiturates have been shown to enhance the hepatic clearance of verapamil. The effect on oral verapamil is greater than for IV verapamil, but a significant increase in clearance has been noted for both verapamil dosage forms during concomitant administration of a barbiturate. Patients receiving verapamil should be monitored for loss of therapeutic effect if barbiturates are added.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of clarithromycin and verapamil, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving verapamil therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely. Verapamil is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). One case of a possible verapamil-clarithromycin interaction was reported, which was associated with hypotension.
Amphetamine; Dextroamphetamine Salts: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
Apalutamide: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with apalutamide is necessary. Concomitant use may decrease plasma concentrations of verapamil. Verapamil is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
Apomorphine: (Moderate) Use of calcium-channel blockers and apomorphine together can increase the hypotensive effects of apomorphine. Monitor blood pressure regularly during use of this combination.
Apraclonidine: (Minor) Apraclonidine had minimal effects on heart rate and blood pressure during clinical studies in patients with glaucoma. However, it is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with the use of antihypertensive agents. Use caution during concurrent use, especially in patients with severe, uncontrolled cardiovascular disease, including hypertension.
Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of verapamil with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant; increased verapamil exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in verapamil- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Verapamil is a moderate CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Verapamil is also a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may additionally increase plasma concentrations of verapamil. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Finally, aprepitant is a CYP2C9 inducer and verapamil is a CYP2C9 substrate. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant.
Aripiprazole: (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of verapamil. Patients receiving both a CYP2D6 inhibitor plus verapamil may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP3A and CYP2D6 substrate; verapamil is a moderate CYP3A inhibitor.
Articaine; Epinephrine: (Moderate) Antihypertensives, including calcium-channel blockers, antagonize the vasopressor effects of parenteral epinephrine.
Asenapine: (Moderate) Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of asenapine and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
Aspirin, ASA: (Minor) In a few reported cases, coadministration of verapamil with aspirin, ASA has led to increased bleeding times greater than observed with aspirin alone. The exact mechanism and clinical significance of this interaction is unknown.
Aspirin, ASA; Butalbital; Caffeine: (Major) Barbiturates have been shown to enhance the hepatic clearance of verapamil. The effect on oral verapamil is greater than for IV verapamil, but a significant increase in clearance has been noted for both verapamil dosage forms during concomitant administration of a barbiturate. Patients receiving verapamil should be monitored for loss of therapeutic effect if barbiturates are added. (Minor) In a few reported cases, coadministration of verapamil with aspirin, ASA has led to increased bleeding times greater than observed with aspirin alone. The exact mechanism and clinical significance of this interaction is unknown. (Minor) Verapamil reduces the clearance of caffeine and increases serum caffeine concentrations, presumably via inhibition of hepatic metabolism. During concomitant therapy with verapamil, it may be prudent to advise patients to limit or minimize the intake of caffeinated products to minimize caffeine-related side effects.
Aspirin, ASA; Caffeine: (Minor) In a few reported cases, coadministration of verapamil with aspirin, ASA has led to increased bleeding times greater than observed with aspirin alone. The exact mechanism and clinical significance of this interaction is unknown. (Minor) Verapamil reduces the clearance of caffeine and increases serum caffeine concentrations, presumably via inhibition of hepatic metabolism. During concomitant therapy with verapamil, it may be prudent to advise patients to limit or minimize the intake of caffeinated products to minimize caffeine-related side effects.
Aspirin, ASA; Caffeine; Orphenadrine: (Minor) In a few reported cases, coadministration of verapamil with aspirin, ASA has led to increased bleeding times greater than observed with aspirin alone. The exact mechanism and clinical significance of this interaction is unknown. (Minor) Verapamil reduces the clearance of caffeine and increases serum caffeine concentrations, presumably via inhibition of hepatic metabolism. During concomitant therapy with verapamil, it may be prudent to advise patients to limit or minimize the intake of caffeinated products to minimize caffeine-related side effects.
Aspirin, ASA; Carisoprodol: (Minor) In a few reported cases, coadministration of verapamil with aspirin, ASA has led to increased bleeding times greater than observed with aspirin alone. The exact mechanism and clinical significance of this interaction is unknown.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with verapamil may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of verapamil could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If verapamil is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Verapamil is a moderate inhibitor of CYP3A4. (Minor) In a few reported cases, coadministration of verapamil with aspirin, ASA has led to increased bleeding times greater than observed with aspirin alone. The exact mechanism and clinical significance of this interaction is unknown.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) In a few reported cases, coadministration of verapamil with aspirin, ASA has led to increased bleeding times greater than observed with aspirin alone. The exact mechanism and clinical significance of this interaction is unknown.
Aspirin, ASA; Dipyridamole: (Minor) In a few reported cases, coadministration of verapamil with aspirin, ASA has led to increased bleeding times greater than observed with aspirin alone. The exact mechanism and clinical significance of this interaction is unknown.
Aspirin, ASA; Omeprazole: (Minor) In a few reported cases, coadministration of verapamil with aspirin, ASA has led to increased bleeding times greater than observed with aspirin alone. The exact mechanism and clinical significance of this interaction is unknown.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of verapamil is necessary. If verapamil is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like verapamil can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If verapamil is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Minor) In a few reported cases, coadministration of verapamil with aspirin, ASA has led to increased bleeding times greater than observed with aspirin alone. The exact mechanism and clinical significance of this interaction is unknown.
Atazanavir: (Moderate) Coadministration of ritonavir with verapamil may increase the serum concentrations of verapamil, potentially resulting in verapamil toxicity. The manufacturer for ritonavir recommends caution when coadministering this combination. A similar effect could be expected with other anti-retroviral protease inhibitors, which are also inhibitors of CYP3A4.
Atazanavir; Cobicistat: (Moderate) Coadministration of cobicistat (a strong CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as verapamil, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate dose reductions are advised. (Moderate) Coadministration of ritonavir with verapamil may increase the serum concentrations of verapamil, potentially resulting in verapamil toxicity. The manufacturer for ritonavir recommends caution when coadministering this combination. A similar effect could be expected with other anti-retroviral protease inhibitors, which are also inhibitors of CYP3A4.
Atenolol: (Moderate) Use verapamil and atenolol with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
Atenolol; Chlorthalidone: (Moderate) Use verapamil and atenolol with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
Atorvastatin: (Moderate) Closely monitor for signs and symptoms of myopathy and rhabdomyolysis and consider atorvastatin dosage adjustment in patients also taking verapamil. Coadministration of verapamil, a P-gp inhibitor, with atorvastatin, a P-gp substrate, may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher statin doses.
Atorvastatin; Ezetimibe: (Moderate) Closely monitor for signs and symptoms of myopathy and rhabdomyolysis and consider atorvastatin dosage adjustment in patients also taking verapamil. Coadministration of verapamil, a P-gp inhibitor, with atorvastatin, a P-gp substrate, may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher statin doses.
Avanafil: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving verapamil. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Administration of another moderate CYP3A4 inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Avapritinib: (Major) Avoid coadministration of avapritinib with verapamil due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Baclofen: (Moderate) Baclofen has been associated with hypotension. Concurrent use with baclofen and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
Barbiturates: (Major) Barbiturates have been shown to enhance the hepatic clearance of verapamil. The effect on oral verapamil is greater than for IV verapamil, but a significant increase in clearance has been noted for both verapamil dosage forms during concomitant administration of a barbiturate. Patients receiving verapamil should be monitored for loss of therapeutic effect if barbiturates are added.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with verapamil may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of verapamil in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If verapamil is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Verapamil is an inhibitor of CYP3A4.
Benzphetamine: (Minor) Benzphetamine might increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking verapamil. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Additionally, monitor blood pressure and heart rate as concurrent use may also increase verapamil exposure. Berotralstat is a P-gp substrate and moderate CYP3A4 inhibitor; verapamil is a CYP3A4 substrate and P-gp inhibitor. Coadministration with another P-gp inhibitor increased berotralstat exposure by 69%.
Betaxolol: (Moderate) Use verapamil and betaxolol with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving verapamil. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving verapamil. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; verapamil inhibits P-gp.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with verapamil may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and verapamil is a P-gp inhibitor.
Bisoprolol: (Moderate) Use verapamil and bisoprolol with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Use verapamil and bisoprolol with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
Bortezomib: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Bosentan: (Moderate) Closely monitor blood pressure and for increased bosentan toxicity if coadministration of verapamil with bosentan is necessary; decreased verapamil and/or increased bosentan plasma concentrations may occur. Verapamil is a CYP3A4 substrate and inhibitor; bosentan is a CYP3A4 substrate and moderate CYP3A4 inducer.
Bosutinib: (Major) Avoid concomitant use of bosutinib and verapamil or as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Brexpiprazole: (Moderate) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, systemic exposure may be increased during use of a moderate CYP3A4 inhibitor such as verapamil and careful monitoring is advisable. In addition, the manufacturer recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. If verapamil is used in combination with brexpiprazole and a moderate to strong CYP2D6 inhibitor, the brexpiprazole dose should be adjusted and the patient should be carefully monitored for brexpiprazole-related adverse reactions.
Brigatinib: (Major) Avoid coadministration of brigatinib with verapamil if possible due to increased plasma exposure of brigatinib; increased verapamil concentrations may also occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of verapamil, resume the brigatinib dose that was tolerated prior to initiation of verapamil. Monitor blood pressure and heart rate. Brigatinib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%. Additionally, verapamil is a P-glycoprotein (P-gp) substrate. Brigatinib is a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates.
Brimonidine; Timolol: (Moderate) Use verapamil and timolol with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of verapamil. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; verapamil is a moderate inhibitor of CYP3A4. Administration of bromocriptine with a moderate inhibitor of CYP3A4 increased the bromocriptine mean AUC and Cmax by 3.7-fold and 4.6-fold, respectively.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Brompheniramine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Brompheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Budesonide: (Moderate) Avoid coadministration of systemic budesonide with verapamil due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor.
Budesonide; Formoterol: (Moderate) Avoid coadministration of systemic budesonide with verapamil due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Avoid coadministration of systemic budesonide with verapamil due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor.
Bupivacaine Liposomal: (Moderate) Verapamil may inhibit the CYP3A4-mediated metabolism of and bupivacaine. Use caution when administering these drugs concomitantly.
Bupivacaine: (Moderate) Verapamil may inhibit the CYP3A4-mediated metabolism of and bupivacaine. Use caution when administering these drugs concomitantly.
Bupivacaine; Epinephrine: (Moderate) Antihypertensives, including calcium-channel blockers, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Verapamil may inhibit the CYP3A4-mediated metabolism of and bupivacaine. Use caution when administering these drugs concomitantly.
Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and verapamil may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; verapamil inhibits both hepatic isoenzymes. (Moderate) Verapamil may inhibit the CYP3A4-mediated metabolism of and bupivacaine. Use caution when administering these drugs concomitantly.
Bupivacaine; Meloxicam: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. (Moderate) Verapamil may inhibit the CYP3A4-mediated metabolism of and bupivacaine. Use caution when administering these drugs concomitantly.
Buprenorphine: (Moderate) Concomitant use of buprenorphine and verapamil can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when verapamil is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping verapamil, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If verapamil is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and verapamil is a CYP3A4 inhibitor.
Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and verapamil can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when verapamil is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping verapamil, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If verapamil is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and verapamil is a CYP3A4 inhibitor.
Buspirone: (Moderate) Monitor for an increase in buspirone-related adverse reactions if coadministration with verapamil is necessary; the effect may be more pronounced if the patient has been titrated to a stable dose of buspirone and verapamil is added or removed from therapy. Buspirone is a sensitive CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with other moderate CYP3A inhibitors increased buspirone exposure by 3.4 to 6-fold and was accompanied by increased buspirone-related adverse reactions.
Butabarbital: (Major) Barbiturates have been shown to enhance the hepatic clearance of verapamil. The effect on oral verapamil is greater than for IV verapamil, but a significant increase in clearance has been noted for both verapamil dosage forms during concomitant administration of a barbiturate. Patients receiving verapamil should be monitored for loss of therapeutic effect if barbiturates are added.
Butalbital; Acetaminophen: (Major) Barbiturates have been shown to enhance the hepatic clearance of verapamil. The effect on oral verapamil is greater than for IV verapamil, but a significant increase in clearance has been noted for both verapamil dosage forms during concomitant administration of a barbiturate. Patients receiving verapamil should be monitored for loss of therapeutic effect if barbiturates are added.
Butalbital; Acetaminophen; Caffeine: (Major) Barbiturates have been shown to enhance the hepatic clearance of verapamil. The effect on oral verapamil is greater than for IV verapamil, but a significant increase in clearance has been noted for both verapamil dosage forms during concomitant administration of a barbiturate. Patients receiving verapamil should be monitored for loss of therapeutic effect if barbiturates are added. (Minor) Verapamil reduces the clearance of caffeine and increases serum caffeine concentrations, presumably via inhibition of hepatic metabolism. During concomitant therapy with verapamil, it may be prudent to advise patients to limit or minimize the intake of caffeinated products to minimize caffeine-related side effects.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Barbiturates have been shown to enhance the hepatic clearance of verapamil. The effect on oral verapamil is greater than for IV verapamil, but a significant increase in clearance has been noted for both verapamil dosage forms during concomitant administration of a barbiturate. Patients receiving verapamil should be monitored for loss of therapeutic effect if barbiturates are added. (Moderate) Concomitant use of codeine with verapamil may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of verapamil could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If verapamil is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Verapamil is a moderate inhibitor of CYP3A4. (Minor) Verapamil reduces the clearance of caffeine and increases serum caffeine concentrations, presumably via inhibition of hepatic metabolism. During concomitant therapy with verapamil, it may be prudent to advise patients to limit or minimize the intake of caffeinated products to minimize caffeine-related side effects.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Barbiturates have been shown to enhance the hepatic clearance of verapamil. The effect on oral verapamil is greater than for IV verapamil, but a significant increase in clearance has been noted for both verapamil dosage forms during concomitant administration of a barbiturate. Patients receiving verapamil should be monitored for loss of therapeutic effect if barbiturates are added. (Moderate) Concomitant use of codeine with verapamil may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of verapamil could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If verapamil is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Verapamil is a moderate inhibitor of CYP3A4. (Minor) In a few reported cases, coadministration of verapamil with aspirin, ASA has led to increased bleeding times greater than observed with aspirin alone. The exact mechanism and clinical significance of this interaction is unknown. (Minor) Verapamil reduces the clearance of caffeine and increases serum caffeine concentrations, presumably via inhibition of hepatic metabolism. During concomitant therapy with verapamil, it may be prudent to advise patients to limit or minimize the intake of caffeinated products to minimize caffeine-related side effects.
Cabergoline: (Moderate) Cabergoline should be used cautiously with antihypertensive agents, including verapamil. Cabergoline has been associated with hypotension. Initial doses of cabergoline higher than 1 mg may produce orthosta

tic hypotension. It may be advisable to monitor blood pressure. In addition, the prolactin-lowering effect of cabergoline may be diminished by medications that increase prolactin levels such as verapamil. Monitor for reduced response to cabergoline.
Cabotegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering verapamil with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Verapamil is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Cabozantinib: (Minor) Monitor for an increase in verapamil-related adverse reactions if coadministration with cabozantinib is necessary. Verapamil is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
Caffeine: (Minor) Verapamil reduces the clearance of caffeine and increases serum caffeine concentrations, presumably via inhibition of hepatic metabolism. During concomitant therapy with verapamil, it may be prudent to advise patients to limit or minimize the intake of caffeinated products to minimize caffeine-related side effects. (Minor) Verapamil reduces the clearance of caffeine and increases serum caffeine concentrations, presumably via inhibition of hepatic metabolism. During concomitant therapy with verapamil, it may be prudent to advise patients to limit or minimize the intake of caffeinated products to minimize caffeine-related side effects.
Caffeine; Sodium Benzoate: (Minor) Verapamil reduces the clearance of caffeine and increases serum caffeine concentrations, presumably via inhibition of hepatic metabolism. During concomitant therapy with verapamil, it may be prudent to advise patients to limit or minimize the intake of caffeinated products to minimize caffeine-related side effects.
Calcium: (Minor) Monitor blood pressure during concurrent use of calcium and calcium-channel blockers. Concomitant use may reduce the response to calcium-channel blockers.
Carbamazepine: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with carbamazepine is necessary. Additionally, monitor carbamazepine concentrations closely during coadministration; carbamazepine dose adjustments may be needed. Concomitant use may decrease exposure of verapamil and increase exposure of carbamazepine. Verapamil is a CYP3A substrate and moderate CYP3A inhibitor; carbamazepine is a CYP3A substrate and strong CYP3A inducer.
Carbidopa; Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Cariprazine: (Moderate) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Verapamil is a moderate inhibitor of CYP3A4 and may reduce the hepatic metabolism of CYP3A4 substrates, although the impact of moderate CYP3A4 inhibitors on cariprazine metabolism has not been studied. Monitoring for adverse effects, such as CNS effects and extrapyramidal symptoms, is advisable during coadministration. In addition, orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
Carteolol: (Moderate) Oral calcium-channel blockers and beta-blockers like carteolol are used together for their therapeutic benefits to reduce angina and improve exercise tolerance. However, concomitant administration of beta-adrenergic blocking agents and verapamil can lead to significant AV nodal blockade. This can manifest as heart block, bradycardia, cardiac conduction abnormalities and/or prolonged PR interval. Congestive heart failure or severe hypotension also can occur. The combination of beta-blockers and verapamil should be avoided in patients with poor ventricular function due to increased negative inotropic effects.
Carvedilol: (Moderate) Use verapamil and carvedilol with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. Monitor ECG and blood pressure if verapamil is coadministered with carvedilol. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
Celecoxib: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Celecoxib; Tramadol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Ceritinib: (Major) Avoid concomitant use of ceritinib with verapamil if possible due to the risk of additive bradycardia; verapamil exposure may also increase. Both ceritinib and verapamil can cause bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Monitor blood pressure and heart rate. Diltiazem is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
Cetirizine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Chlordiazepoxide: (Moderate) Verapamil is a CYP3A4 inhibitor and may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
Chlordiazepoxide; Amitriptyline: (Moderate) Verapamil is a CYP3A4 inhibitor and may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
Chlordiazepoxide; Clidinium: (Moderate) Verapamil is a CYP3A4 inhibitor and may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
Chloroprocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with verapamil may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of verapamil could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If verapamil is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Verapamil is a moderate inhibitor of CYP3A4.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with verapamil may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of verapamil could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If verapamil is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Verapamil is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of verapamil is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like verapamil can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If verapamil is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Chlorpheniramine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Chlorpheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Chlorthalidone; Clonidine: (Moderate) Avoid concomitant use of verapamil and extended-release clonidine tablets. Monitor heart rate during concomitant use of verapamil and other clonidine formulations. Concomitant use may potentiate bradycardia and risk of AV block. Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported during the use of verapamil and clonidine.
Cilostazol: (Major) Cilostazol clearance may be impaired by inhibitors of the CYP3A4 hepatic microsomal isoenzyme, including verapamil. When verapamil is coadministered with cilostazol, the manufacturer recommends that the cilostazol dosage be reduced by 50%.
Cimetidine: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with cimetidine. Coadministration may increase the exposure of verapamil.
Cisapride: (Contraindicated) Postmarketing surveillance reports have documented QT prolongation and ventricular arrhythmias, including torsade de pointes and death, when known and potent inhibitors of CYP3A4 are coadministered with cisapride. Verapamil may have the potential to inhibit the metabolism of cisapride through CYP3A4 and thus, should not be used with cisapride.
Cisplatin: (Minor) The absorption of verapamil can be reduced by the vindesine, doxorubicin, cisplatin (VAC) chemotherapeutic drug regimen.
Clarithromycin: (Major) Avoid coadministration of clarithromycin and verapamil, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving verapamil therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely. Verapamil is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). One case of a possible verapamil-clarithromycin interaction was reported, which was associated with hypotension.
Clofarabine: (Moderate) Concomitant use of clofarabine, a substrate of OCT1, and verapamil, an inhibitor of OCT1, may result in increased clofarabine levels. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g., hand and foot syndrome, rash, pruritus) in patients also receiving OCT1 inhibitors.
Clonazepam: (Moderate) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with verapamil; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in an increase in treatment-related adverse reactions. Clonazepam is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor.
Clonidine: (Moderate) Avoid concomitant use of verapamil and extended-release clonidine tablets. Monitor heart rate during concomitant use of verapamil and other clonidine formulations. Concomitant use may potentiate bradycardia and risk of AV block. Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported during the use of verapamil and clonidine.
Clorazepate: (Moderate) CYP3A4 inhibitors, such as verapamil, may reduce the metabolism of clorazepate and increase the potential for benzodiazepine toxicity.
Clozapine: (Moderate) Caution is advisable during concurrent use of verapamil and clozapine. Verapamil is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Cobicistat: (Moderate) Coadministration of cobicistat (a strong CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as verapamil, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate dose reductions are advised.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with chronic verapamil therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of verapamil is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of verapamil, resume cobimetinib at the previous dose. Use an alternative to verapamil in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; verapamil is a moderate inhibitor of both CYP3A and P-gp. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Cocaine: (Major) Use of cocaine with antihypertensive agents may increase the antihypertensive effects of the antihypertensive medications or may potentiate cocaine-induced sympathetic stimulation.
Codeine: (Moderate) Concomitant use of codeine with verapamil may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of verapamil could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If verapamil is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Verapamil is a moderate inhibitor of CYP3A4.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with verapamil may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of verapamil could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If verapamil is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Verapamil is a moderate inhibitor of CYP3A4.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with verapamil may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of verapamil could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If verapamil is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Verapamil is a moderate inhibitor of CYP3A4. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with verapamil may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of verapamil could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If verapamil is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Verapamil is a moderate inhibitor of CYP3A4. (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with verapamil may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of verapamil could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If verapamil is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Verapamil is a moderate inhibitor of CYP3A4.
Co-Enzyme Q10, Ubiquinone: (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10.
Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and verapamil in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Verapamil can inhibit colchicine's metabolism via P-glycoprotein (P-gp) and CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken a P-gp and moderate CYP3A4 inhibitor like verapamil in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
Colesevelam: (Moderate) Colesevelam may significantly decrease the Cmax and AUC of sustained-release verapamil. The clinical significance of this interaction is not known since verapamil bioavailability is highly variable.
Conivaptan: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with conivaptan. Coadministration may increase the exposure of verapamil. Conivaptan is a moderate inhibitor of CYP3A; verapamil is a substrate of CYP3A.
Conjugated Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as verapamil may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as verapamil may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as verapamil may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Crizotinib: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as verapamil, to the extent possible due to the risk of additive bradycardia; increased exposure to both drugs may also occur. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly, and watch for an increase in crizotinib-related adverse reactions. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs. Crizotinib and verapamil are both CYP3A substrates and moderate inhibitors.
Cyclobenzaprine: (Moderate) If concomitant treatment with cyclobenzaprine and verapamil is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases, due to the potential risk of serotonin syndrome. Discontinue all serotonergic agents and initiate supportive symptomatic treatment if serotonin syndrome occurs.
Cyclosporine: (Moderate) Coadministration of verapamil with cyclosporine can lead to increased cyclosporine concentrations and toxicity. Verapamil inhibits CYP3A4 metabolism and thereby can increase the serum concentrations of cyclosporine. Verapamil should be used cautiously in patients stabilized on cyclosporine; cyclosporine dosage reduction may be required.
Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with verapamil, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran while taking products containing verapamil including trandolapril; verapamil. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like verapamil in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with verapamil, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. Concomitant administration of verapamil and dabigatran results in an increased Cmax and AUC of dabigatran; the extent depends on the formulation of verapamil and timing of administration. The greatest increase in exposure of dabigatran occurs when verapamil is present in the gut when dabigatran is taken. In a pharmacokinetic study, immediate-release verapamil given 1 hour prior to dabigatran administration produced the greatest increase in exposure. If verapamil is administered 2 hours after dabigatran administration, the increase in AUC is negligible. Data from the RE-LY trial indicate no significant changes in dabigatran trough concentrations were seen in patients who received concomitant therapy with verapamil. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
Daclatasvir: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with verapamil, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. In addition, the therapeutic effects of verapamil, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as hypotension, headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
Danazol: (Minor) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates like calcium-channel blockers.
Dantrolene: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
Dapagliflozin; Saxagliptin: (Minor) Saxagliptin plasma concentrations are expected to increase in the presence of moderate CYP 3A4/5 inhibitors such as verapamil, but saxagliptin dose adjustment is not advised.
Daridorexant: (Major) Limit the daridorexant dose to 25 mg if coadministered with verapamil. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Darifenacin: (Moderate) Verapamil is an inhibitor of CYP3A4 isoenzymes. Co-administration with verapamil may lead to an increase in serum levels of drugs that are CYP3A4 substrates, including darifenacin.
Darunavir: (Moderate) As darunavir is a CYP3A substrate and inhibitor, interactions with calcium-channel blockers may occur. Complex interactions can be expected with coadministered with diltiazem or verapamil, as both are substrates and inhibitors of CYP3A4.
Darunavir; Cobicistat: (Moderate) As darunavir is a CYP3A substrate and inhibitor, interactions with calcium-channel blockers may occur. Complex interactions can be expected with coadministered with diltiazem or verapamil, as both are substrates and inhibitors of CYP3A4. (Moderate) Coadministration of cobicistat (a strong CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as verapamil, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate dose reductions are advised.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) As darunavir is a CYP3A substrate and inhibitor, interactions with calcium-channel blockers may occur. Complex interactions can be expected with coadministered with diltiazem or verapamil, as both are substrates and inhibitors of CYP3A4. (Moderate) Coadministration of cobicistat (a strong CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as verapamil, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate dose reductions are advised. (Moderate) Coadministration of tenofovir alafenamide with verapamil may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and verapamil is a P-gp inhibitor.
Deferasirox: (Moderate) Deferasirox inhibits CYP2C8. Verapamil is a substrate for CYP2C8. The concomitant administration of deferasirox and the CYP2C8 substrate repaglinide (single dose of 0.5 mg) resulted in an increase in repaglinide Cmax by 62% and an increase in AUC 2.3-fold. Although specific drug interaction studies of deferasirox and verapamil are not available, a similar interaction may occur. The dose of verapamil may need to be decreased if coadministered with deferasirox.
Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with verapamil. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; verapamil is a moderate inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
Degarelix: (Major) Avoid coadministration of degarelix with verapamil due to the risk of reduced efficacy of degarelix. Verapamil can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; degarelix is a GnRH analog.
Delavirdine: (Moderate) Delavirdine is a potent inhibitor of the CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as verapamil, should be expected with concurrent use of delavirdine.
Desloratadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Desogestrel; Ethinyl Estradiol: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Dexbrompheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Dexmedetomidine: (Moderate) Concomitant administration of dexmedetomidine and calcium-channel blockers could lead to additive hypotension and bradycardia; use together with caution. Dexmedetomidine can produce bradycardia or AV block and should be used cautiously in patients who are receiving antihypertensive drugs that may lower the heart rate such as calcium-channel blockers.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Dextromethorphan; Quinidine: (Major) Pharmacokinetic and pharmacodynamic interactions exist between quinidine and verapamil. Oral verapamil has been shown to reduce the clearance and metabolism of oral quinidine. Quinidine half-life increased and plasma concentrations were higher after verapamil. No changes in quinidine protein binding were observed. In addition to the pharmacokinetic interaction which may potentiate quinidine's clinical effects, both quinidine and verapamil can cause hypotension. When quinidine and verapamil are coadministered in doses that are each well tolerated as monotherapy, hypotension attributable to additive peripheral (alpha)-blockade is sometimes reported. Concurrent use of verapamil and quinidine in patients with hypertrophic cardiomyopathy or arrhythmias can cause significant hypotension. It is recommended to avoid combined therapy with verapamil and quinidine in patients with hypertrophic cardiomyopathy. Quinidine and verapamil may also have additive negative inotropic effects. Concurrent use of verapamil and quinidine should be monitored carefully for electrophysiologic and hemodynamic effects.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with verapamil is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and verapamil is a CYP3A4 inhibitor.
Diazoxide: (Moderate) Additive hypotensive effects can occur with the concomitant administration of diazoxide with other antihypertensive agents. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly. The manufacturer advises that IV diazoxide should not be administered to patients within 6 hours of receiving other antihypertensive agents.
Diclofenac: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Diclofenac; Misoprostol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Dienogest; Estradiol valerate: (Minor) Verapamil inhibits CYP3A4 activity. Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when verapamil is coadministered with either estrogens or combined hormonal contraceptives.
Diethylpropion: (Major) Diethylpropion has vasopressor effects and may limit the benefit of calcium-channel blockers. Although leading drug interaction texts differ in the potential for an interaction between diethylpropion and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications.
Diflunisal: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Digoxin: (Major) Consider an empiric digoxin dosage reduction when used with verapamil. Follow digoxin concentrations closely and monitor for signs and symptoms of digoxin toxicity. Concomitant use may increase digoxin exposure and the risk for digoxin related adverse effects. The risk for bradycardia and hypotension may also increase. Chronic verapamil treatment has been observed to increase digoxin levels by 50% to 75% during the first week of digoxin therapy. Digoxin is a P-gp substrate and verapamil is a P-gp inhibitor.
Diphenhydramine; Ibuprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Diphenhydramine; Naproxen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Diphenhydramine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Disopyramide: (Contraindicated) Disopyramide and verapamil should not be used concomitantly due to potential for additive negative inotropic effects which could result in left ventricular impairment. Avoid disopyramide administration within 48 hours before or 24 hours after verapamil administration. In addition, verapamil can theoretically inhibit the CYP3A4 metabolism of disopyramide.
Dofetilide: (Contraindicated) The concomitant use of verapamil (CYP3A4 inhibitor) and dofetilide is contraindicated. Coadministration of dofetilide with verapamil increased dofetilide peak plasma concentrations by 42%, although the overall exposure to dofetilide was not significantly increased. Concurrent use of verapamil and dofetilide was also associated with a higher occurrence of torsade de pointes in dofetilide clinical trials.
Dolasetron: (Major) Use caution and monitor ECG if a drug known to prolong the PR interval (e.g., verapamil) is combined with dolasetron. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Concurrent use may result in additive effects.
Dolutegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering verapamil with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Verapamil is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Donepezil: (Minor) Verapamil may inhibit the metabolism of donepezil by inhibiting CYP3A4. The clinical effect of this interaction on the response to donepezil has not been determined.
Donepezil; Memantine: (Minor) Verapamil may inhibit the metabolism of donepezil by inhibiting CYP3A4. The clinical effect of this interaction on the response to donepezil has not been determined.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with verapamil may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and verapamil is a P-gp inhibitor.
Dorzolamide; Timolol: (Moderate) Use verapamil and timolol with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
Doxazosin: (Moderate) Monitor blood pressure if verapamil is used with other antihypertensive agents; an additive blood pressure lowering effect may occur. Using verapamil with agents that attenuate alpha-adrenergic function, such as doxazosin, may result in blood pressure reductions that are excessive in some patients.
Doxercalciferol: (Moderate) Cytochrome P450 enzyme inhibitors, such as verapamil, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy.
Doxorubicin Liposomal: (Major) Avoid the concomitant use of doxorubicin and verapamil; use of these drugs together may increase doxorubicin concentrations and increase the risk of doxorubicin-induced toxicity. Doxorubicin is a substrate of CYP3A4 and P-glycoprotein (P-gp); verapamil is a substrate and inhibitor of CYP3A4 and P-gp.
Doxorubicin: (Major) Avoid the concomitant use of doxorubicin and verapamil; use of these drugs together may increase doxorubicin concentrations and increase the risk of doxorubicin-induced toxicity. Doxorubicin is a substrate of CYP3A4 and P-glycoprotein (P-gp); verapamil is a substrate and inhibitor of CYP3A4 and P-gp.
Dronabinol: (Moderate) Use caution if coadministration of dronabinol with verapamil is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; verapamil is a moderate inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
Dronedarone: (Major) If coadministered with dronedarone, initiate verapamil at a low dose and increase only after ECG verification of good tolerability. Both verapamil and dronedarone are substrates and moderate CYP3A4 inhibitors; increased exposure to both drugs may occur. Additionally, the conduction effects of dronedarone may be potentiated by concurrent use of calcium channel blockers with depressant effects on the sinus and AV nodes.
Drospirenone; Estradiol: (Minor) Verapamil inhibits CYP3A4 activity. Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when verapamil is coadministered with either estrogens or combined hormonal contraceptives.
Drospirenone; Ethinyl Estradiol: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Duloxetine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Dutasteride; Tamsulosin: (Moderate) The concomitant administration of tamsulosin with other antihypertensive agents can cause additive hypotensive effects. In addition, diltiazem, nicardipine, and verapamil may increase tamsulosin plasma concentrations via CYP3A4 inhibition. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.
Duvelisib: (Moderate) Monitor for increased toxicity of duvelisib and verapamil during coadministration. Coadministration may increase the exposure of both drugs. Duvelisib is a substrate and moderate inhibitor of CYP3A; verapamil is also a substrate and moderate inhibitor of CYP3A.
Edoxaban: (Major) Reduce the dose of edoxaban to 30 mg/day PO in patients being treated for deep venous thrombosis (DVT) or pulmonary embolism and receiving concomitant therapy with verapamil. No dosage adjustment is required in patients with atrial fibrillation. Edoxaban is a P-glycoprotein (P-gp) substrate and verapamil is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of verapamil; monitor for increased adverse effects of edoxaban.
Efavirenz: (Moderate) Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with verapamil may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and verapamil is a P-gp inhibitor. (Moderate) Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with verapamil may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and verapamil is a P-gp inhibitor. (Moderate) Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
Elacestrant: (Major) Avoid concomitant use of elacestrant and verapamil due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased elacestrant overall exposure by 2.3-fold.
Elagolix; Estradiol; Norethindrone acetate: (Minor) Verapamil inhibits CYP3A4 activity. Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when verapamil is coadministered with either estrogens or combined hormonal contraceptives.
Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with verapamil may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Verapamil is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Eletriptan: (Moderate) Monitor for increased eletriptan-related adverse effects if coadministered with verapamil. Systemic concentrations of eletriptan may be increased. Eletriptan is a substrate for CYP3A, and verapamil is a moderate CYP3A inhibitor. Coadministration of other moderate CYP3A inhibitors increased the eletriptan AUC by 2 to 4-fold.
Elexacaftor; tezacaftor; ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with verapamil; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); verapamil is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If verapamil and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to every other day in the morning when coadministered with verapamil; omit the ivacaftor evening dose and administer in the morning every other day alternating with elexacaftor; tezacaftor; ivacaftor (i.e., recommended dose of elexacaftor; tezacaftor; ivacaftor on day 1 in the morning and recommended dose of ivacaftor on day 2 in the morning). Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; verapamil is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure by 2.9-fold. Simulation suggests a moderate inhibitor may increase elexacaftor and tezacaftor exposure by 2.3-fold and 2.1-fold, respectively.
Eliglustat: (Major) In intermediate or poor CYP2D6 metabolizers (IMs or PM), coadministration of verapamil (including trandolapril; verapamil) and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EMs), coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with both verapamil and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Verapamil is a moderate CYP3A inhibitor and P-glycoprotein (P-gp) substrate; eliglustat is a CYP3A and CYP2D6 substrate and P-gp inhibitor. Coadministration of eliglustat with CYP3A inhibitors, such as verapamil, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A. In addition, coadministration of eliglustat with P-gp substrates (e.g., verapamil) may result in increased concentrations of the concomitant drug; monitor patients closely for adverse events, and consider reducing the dosage of verapamil and titrating to clinical effect.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of cobicistat (a strong CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as verapamil, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate dose reductions are advised. (Moderate) Coadministration of tenofovir alafenamide with verapamil may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and verapamil is a P-gp inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of cobicistat (a strong CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as verapamil, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate dose reductions are advised. (Moderate) Coadministration of tenofovir disoproxil fumarate with verapamil may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and verapamil is a P-gp inhibitor.
Empagliflozin: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
Empagliflozin; Linagliptin: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
Empagliflozin; Linagliptin; Metformin: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
Empagliflozin; Metformin: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering verapamil with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Verapamil is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. (Moderate) Coadministration of tenofovir alafenamide with verapamil may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and verapamil is a P-gp inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Close clinical monitoring is advised when administering verapamil with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Verapamil is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. (Moderate) Coadministration of tenofovir disoproxil fumarate with verapamil may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and verapamil is a P-gp inhibitor.
Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with verapamil may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and verapamil is a P-gp inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with verapamil may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and verapamil is a P-gp inhibitor.
Encorafenib: (Major) Avoid coadministration of encorafenib and verapamil due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of verapamil. If verapamil is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of verapamil. Encorafenib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Entrectinib: (Major) Avoid coadministration of entrectinib with verapamil due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If verapamil is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of verapamil. Entrectinib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
Enzalutamide: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with enzalutamide is necessary. Concomitant use may decrease plasma concentrations of verapamil. Verapamil is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
Ephedrine: (Major) The cardiovascular effects of sympathomimetics, such as ephedrine, may reduce the antihypertensive effects produced by calcium-channel blockers. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
Ephedrine; Guaifenesin: (Major) The cardiovascular effects of sympathomimetics, such as ephedrine, may reduce the antihypertensive effects produced by calcium-channel blockers. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
Epinephrine: (Moderate) Antihypertensives, including calcium-channel blockers, antagonize the vasopressor effects of parenteral epinephrine.
Epirubicin: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Verapamil is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
Epoprostenol: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Ergot alkaloids: (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of verapamil is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and verapamil is a moderate CYP3A inhibitor.
Ergotamine; Caffeine: (Minor) Verapamil reduces the clearance of caffeine and increases serum caffeine concentrations, presumably via inhibition of hepatic metabolism. During concomitant therapy with verapamil, it may be prudent to advise patients to limit or minimize the intake of caffeinated products to minimize caffeine-related side effects.
Erlotinib: (Major) Avoid coadministration of erlotinib with verapamil if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP1A2. Verapamil is a CYP3A4 and CYP1A2 inhibitor. Coadministration with another moderate CYP3A4/CYP1A2 inhibitor increased erlotinib exposure by 39% and increased the erlotinib Cmax by 17%.
Erythromycin: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with erythromycin. Coadministration may increase the exposure of verapamil. Erythromycin is a moderate inhibitor of CYP3A4; verapamil is a substrate of CYP3A4.
Esmolol: (Major) Esmolol is contraindicated with intravenous verapamil use in close proximity (within a few hours). Fatal cardiac arrests have occurred in patients receiving esmolol and intravenous verapamil. Use esmolol and oral verapamil with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
Estazolam: (Moderate) Verapamil is a CYP3A4 inhibitor and may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity.
Esterified Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as verapamil may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Esterified Estrogens; Methyltestosterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as verapamil may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Estradiol: (Minor) Verapamil inhibits CYP3A4 activity. Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when verapamil is coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Levonorgestrel: (Minor) Verapamil inhibits CYP3A4 activity. Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when verapamil is coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Norethindrone: (Minor) Verapamil inhibits CYP3A4 activity. Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when verapamil is coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Norgestimate: (Minor) Verapamil inhibits CYP3A4 activity. Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when verapamil is coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Progesterone: (Minor) The metabolism of progesterone may be inhibited by verapamil, an inhibitor of cytochrome P450 3A4 hepatic enzymes. (Minor) Verapamil inhibits CYP3A4 activity. Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when verapamil is coadministered with either estrogens or combined hormonal contraceptives.
Estropipate: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as verapamil may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Ethanol: (Major) Advise patients to avoid alcohol and alcohol-containing products while taking verapamil. Verapamil has been found to significantly inhibit alcohol elimination resulting in elevated blood alcohol concentrations that may prolong the intoxicating effects of alcohol. The patient may experience an increase in sedation, dizziness, hypotension, and CNS depression. (Major) Verapamil has been found to significantly inhibit alcohol elimination resulting in elevated blood alcohol concentrations that may prolong the intoxicating effects of alcohol. The patient may experience an increase in sedation, dizziness, hypotension, and CNS depression. Advise the patient to limit alcohol ingestion during verapamil therapy.
Ethinyl Estradiol; Norelgestromin: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Ethinyl Estradiol; Norethindrone Acetate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Ethinyl Estradiol; Norgestrel: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Ethosuximide: (Moderate) Verapamil is an inhibitor of CYP3A4 isoenzymes. Co-administration with verapamil may lead to an increase in serum levels of drugs that are CYP3A4 substrates including ethosuximide.
Ethynodiol Diacetate; Ethinyl Estradiol: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Etodolac: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Etomidate: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
Etonogestrel: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as verapamil may increase the serum concentration of etonogestrel.
Etonogestrel; Ethinyl Estradiol: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as verapamil may increase the serum concentration of etonogestrel. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Etravirine: (Moderate) Monitor for an increase in etravirine-related adverse reactions and decreased verapamil efficacy if concomitant use is necessary. The exposure of both drugs may be altered. Etravirine is a CYP3A substrate and moderate CYP3A inducer and verapamil is a CYP3A substrate and moderate CYP3A inhibitor.
Everolimus: (Major) Coadministration of everolimus with verapamil requires a dose reduction for some indications and close monitoring for others. For patients with oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, reduce the initial dose of everolimus to 2.5 mg PO once daily; the dose may be increased to 5 mg PO once daily if the 2.5 mg dose is tolerated. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, reduce the daily dose of everolimus by 50%, changing to every-other-day dosing if the reduced dose is lower than the lowest available strength; assess the everolimus whole blood trough concentration 2 weeks after initiation of verapamil and adjust the dose as necessary to remain in the recommended therapeutic range. Also monitor everolimus whole blood trough concentrations for patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Verapamil is a moderate CYP3A4 and P-gp inhibitor. Coadministration with verapamil increased the Cmax and AUC of everolimus by 2.3-fold and 3.5-fold, respectively.
Ezetimibe; Simvastatin: (Major) Do not exceed a simvastatin dose of 10 mg/day in patients taking verapamil due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on verapamil, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of verapamil and simvastatin against the potential risks. Verapamil increases the simvastatin exposure by approximately 2-fold. The interaction is presumed due to increased simvastatin bioavailability via inhibition of CYP3A metabolism and reduction of first-pass metabolism by verapamil.
Fedratinib: (Moderate) Monitor for increased toxicity of verapamil during coadministration as fedratinib may increase verapamil exposure. Fedratinib is a moderate inhibitor of CYP3A; verapamil is a substrate of CYP3A.
Fenoprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of verapamil is necessary. If verapamil is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like verapamil can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If verapamil is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Fexofenadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Fezolinetant: (Contraindicated) Concomitant use of fezolinetant and verapamil is contraindicated due to the risk of increased fezolinetant exposure which may increase the risk of fezolinetant-related adverse effects. Fezolinetant is a CYP1A2 substrate; verapamil is a weak CYP1A2 inhibitor. Concomitant use with another weak CYP1A2 inhibitor increased fezolinetant overall exposure by 100%.
Finasteride; Tadalafil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with verapamil is necessary. Tadalafil is a CYP3A4 substrate and verapamil is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or verapamil; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased overall exposure to finerenone by 248%.
Fingolimod: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as verapamil. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
Flecainide: (Moderate) Limit use of flecainide and verapamil when possible, and do not exceed maximum daily doses. Coadministration of flecainide with verapamil increases the risk of bradycardia, AV block, and hypotension.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and moderate CYP3A4 inhibitors, such as verapamil, is contraindicated. Moderate CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a moderate CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a moderate CYP3A4 inhibitor following flibanserin use, start the moderate CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
Fluconazole: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with fluconazole. Coadministration may increase the exposure of verapamil. Verapamil is a substrate of CYP3A and fluconazole is a moderate CYP3A inhibitor.
Flurazepam: (Moderate) CYP3A4 inhibitors, such as verapamil, may reduce the metabolism of flurazepam and increase the potential for benzodiazepine toxicity.
Flurbiprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Fluticasone; Umeclidinium; Vilanterol: (Moderate) Umeclidinium is a P-gp substrate. When verapamil, a moderate P-gp transporter inhibitor, was given to healthy adult subjects at a dose of 240 mg once daily in combination with umeclidinium, no effect on umeclidinium Cmax was observed. However, an approximately 1.4-fold increase in umeclidinium AUC was observed.
Fluvoxamine: (Moderate) Certain SSRIs, including fluvoxamine, are inhibitors of CYP3A4, and may theoretically increase verapamil serum concentrations.
Fosamprenavir: (Moderate) Monitor blood pressure, heart rate, and for increased fosamprenavir-related adverse reactions during coadministration of verapamil with fosamprenavir. Concomitant use may increase the exposure of both drugs. Verapamil and fosamprenavir are both CYP3A substrates and moderate CYP3A inhibitors.
General anesthetics: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
Ginger, Zingiber officinale: (Minor) In vitro studies have demonstrated the positive inotropic effects of ginger, Zingiber officinale. It is theoretically possible that ginger could affect the action of antiarrhythmics, however, no clinical data are available.
Ginkgo, Ginkgo biloba: (Moderate) Ginkgo biloba appears to inhibit the metabolism of calcium-channel blockers, perhaps by inhibiting the CYP3A4 isoenzyme. A non-controlled pharmacokinetic study in healthy volunteers found that the concurrent administration of ginkgo with nifedipine resulted in a 53% increase in nifedipine peak concentrations. More study is needed regarding ginkgo's effects on CYP3A4 and whether clinically significant drug interactions result.
Ginseng, Panax ginseng: (Moderate) Ginseng appears to inhibit the metabolism of calcium-channel blockers, perhaps by inhibiting the CYP3A4 isoenzyme. A non-controlled pharmacokinetic study in healthy volunteers found that the concurrent administration of ginseng with nifedipine resulted in a 30% increase in nifedipine peak concentrations. More study is needed regarding ginseng's effects on CYP3A4 and whether clinically significant drug interactions result.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and verapamil as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Glecaprevir and verapamil are both substrates and inhibitors of P-glycoprotein (P-gp). (Moderate) Caution is advised with the coadministration of pibrentasvir and verapamil as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Pibrentasvir and verapamil are both substrates and inhibitors of P-glycoprotein (P-gp).
Goserelin: (Major) Avoid coadministration of goserelin with verapamil due to the risk of reduced efficacy of goserelin. Verapamil can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; goserelin is a GnRH analog.
Grapefruit juice: (Major) Grapefruit juice contains an unknown compound that can inhibit the cytochrome P-450 CYP3A4 isozyme in the gut wall. Grapefruit juice can increase the serum concentrations and oral bioavailability of verapamil. Co-administration of oral verapamil with grapefruit juice significantly increases the AUC and peak plasma concentrations of verapamil. It is generally recommended to avoid grapefruit juice during verapamil therapy.
Green Tea: (Minor) Verapamil reduces the clearance of caffeine and increases serum caffeine concentrations, presumably via inhibition of hepatic metabolism. During concomitant therapy with verapamil, it may be prudent to advise patients to limit or minimize the intake of caffeinated products such as green tea.
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of verapamil is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like verapamil can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If verapamil is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Guanfacine: (Major) Verapamil may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon verapamil discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and verapamil is a moderate CYP3A4 inhibitor.
Haloperidol: (Moderate) In general, antipsychotics like haloperidol should be used cautiously with antihypertensive agents due to the possibility of additive hypotension. Verapamil is a substrate and inhibitor of CYP3A4. Mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and substrates or inhibitors of CYP3A4 or CYP2D6. Elevated haloperidol concentrations occurring through inhibition of CYP2D6 or CYP3A4 may increase the risk of adverse effects, including QT prolongation.
Histrelin: (Major) Avoid coadministration of histrelin with verapamil due to the risk of reduced efficacy of histrelin. Verapamil can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of verapamil is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like verapamil can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If verapamil is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydantoins: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with hydantoins is necessary. Concomitant use may decrease plasma concentrations of verapamil. Verapamil is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers.
Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of verapamil is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like verapamil can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If verapamil is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of verapamil is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like verapamil can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If verapamil is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of verapamil is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like verapamil can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If verapamil is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Ibrutinib: (Major) If ibrutinib is coadministered with verapamil, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if verapamil is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Ibuprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Ibuprofen; Famotidine: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of verapamil is necessary. If verapamil is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like verapamil can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If verapamil is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Ibuprofen; Pseudoephedrine: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with verapamil, a CYP3A substrate, as verapamil toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with verapamil is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Verapamil is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Iloperidone: (Moderate) Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
Iloprost: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Imatinib: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including verapamil.
Imipramine: (Moderate) Verapamil inhibits the CYP3A4 metabolism of imipramine and decreases imipramine clearance by 25%. Imipramine serum concentrations are suggested to monitor imipramine therapy when adding verapamil therapy or changing verapamil dosage.
Indacaterol: (Minor) Although no dosage adjustment of the 75 mcg indacaterol daily dose is needed, use caution if indacaterol and verapamil are used concurrently. By inhibiting CYP3A4 and P-gp, verapamil alters indacaterol metabolism. In drug interaction studies, coadministration of indacaterol 300 mcg (single dose) with verapamil (80 mcg 3 times daily for 4 days) resulted in a 2-fold increase in indacaterol AUC (0-24), and 1.5-fold increase in indacaterol Cmax.
Indacaterol; Glycopyrrolate: (Minor) Although no dosage adjustment of the 75 mcg indacaterol daily dose is needed, use caution if indacaterol and verapamil are used concurrently. By inhibiting CYP3A4 and P-gp, verapamil alters indacaterol metabolism. In drug interaction studies, coadministration of indacaterol 300 mcg (single dose) with verapamil (80 mcg 3 times daily for 4 days) resulted in a 2-fold increase in indacaterol AUC (0-24), and 1.5-fold increase in indacaterol Cmax.
Indinavir: (Moderate) Coadministration of ritonavir with verapamil may increase the serum concentrations of verapamil, potentially resulting in verapamil toxicity. The manufacturer for ritonavir recommends caution when coadministering this combination. A similar effect could be expected with other anti-retroviral protease inhibitors, which are also inhibitors of CYP3A4.
Indomethacin: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Infigratinib: (Major) Avoid concomitant use of infigratinib and verapamil. Coadministration may increase infigratinib exposure, increasing the risk of adverse effects. Infigratinib is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor.
Intravenous Lipid Emulsions: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with verapamil may result in increased serum concentrations of both drugs. Verapamil is a substrate and inhibitor of the hepatic isoenzyme CYP3A4 and a substrate of the drug transporter P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of CYP3A4 and an inhibitor of P-gp. Caution and close monitoring are advised if these drugs are used together.
Isocarboxazid: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
Isoflurane: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of verapamil. Dosages of verapamil may need to be adjusted while the patient is receiving rifampin.
Isoniazid, INH; Rifampin: (Major) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of verapamil. Dosages of verapamil may need to be adjusted while the patient is receiving rifampin.
Isoproterenol: (Moderate) The pharmacologic effects of isoproterenol may cause an increase in blood pressure. If isoproterenol is used concomitantly with antihypertensives, the blood pressure should be monitored as the administration of isoproterenol can compromise the effectiveness of antihypertensive agents.
Isosorbide Dinitrate, ISDN: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
Isosorbide Mononitrate: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
Itraconazole: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase verapamil serum concentrations via inhibition of CYP3A4 with the potential for verapamil toxicity. Edema has been reported in patients receiving concomitantly itraconazole and dihydropyridine calcium-channel blockers; therefore, caution is recommended when administering these medications in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Ivabradine: (Major) Avoid coadministration of ivabradine and verapamil. Both ivabradine and verapamil may cause bradycardia. In addition, ivabradine is primarily metabolized by CYP3A4; verapamil inhibits CYP3A4. Coadministration may increase the plasma concentrations of ivabradine further increasing the risk for bradycardia exacerbation and conduction disturbances.
Ivacaftor: (Major) If verapamil and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with verapamil due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of verapamil is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor.
Ketamine: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
Ketoconazole: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with ketoconazole. Coadministration may increase the exposure of verapamil. Verapamil is a CYP3A substrate and ketoconazole is a strong CYP3A4 inhibitor. Clinically significant interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil. Hypotension, bradyarrhythmias, and other side effects have been observed with some combinations.
Ketoprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Ketorolac: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Labetalol: (Major) Intravenous labetalol is contraindicated with intravenous verapamil use in close proximity (within a few hours). Fatal cardiac arrests have occurred in patients receiving intravenous beta-blockers and intravenous calcium channel blockers. Use oral labetalol and oral verapamil with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction, such as calcium-channel blockers, because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with verapamil may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and verapamil is a P-gp inhibitor.
Lanreotide: (Moderate) Concomitant administration of bradycardia-inducing drugs (e.g., calcium-channel blockers) may have an additive effect on the reduction of heart rate associated with lanreotide. Adjust the calcium-channel blocker dose if necessary.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of clarithromycin and verapamil, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving verapamil therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely. Verapamil is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). One case of a possible verapamil-clarithromycin interaction was reported, which was associated with hypotension.
Lapatinib: (Major) Monitor blood pressure, heart rate, and monitor for an increase in lapatinib-related adverse reactions if coadministration of verapamil with lapatinib is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Increased plasma concentrations of lapatinib are likely. Concomitant use may also increase verapamil exposure.
Larotrectinib: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with verapamil is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Lasmiditan: (Moderate) Monitor heart rate if lasmiditan is coadministered with calcium-channel blockers as concurrent use may increase the risk for bradycardia. Lasmiditan has been associated with lowering of heart rate. In a drug interaction study, addition of a single 200 mg dose of lasmiditan to another heart rate lowering drug decreased heart rate by an additional 5 beats per minute.
Lefamulin: (Moderate) Monitor for increased toxicity of verapamil as well as lefamulin-related adverse effects if oral lefamulin is administered with verapamil as concurrent use may increase exposure from both drugs; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and moderate CYP3A4 inhibitor; verapamil is a CYP3A4 substrate and P-gp and moderate CYP3A4 inhibitor.
Lemborexant: (Major) Avoid coadministration of lemborexant and verapamil as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration of lemborexant with another moderate CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Lenacapavir: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with lenacapavir. Coadministration may increase the exposure of verapamil. Verapamil is a CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor.
Letermovir: (Moderate) Plasma concentrations of verapamil are expected to be elevated when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If these drugs are given together, closely monitor for verapamil-related adverse events. Verapamil is a CYP3A4 substrate. Letermovir is a moderate inhibitor of CYP3A4. However, when given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Clinically significant interactions with verapamil have been reported with other moderate and strong inhibitors of CYP3A4.
Leuprolide: (Major) Avoid coadministration of leuprolide with verapamil due to the risk of reduced efficacy of leuprolide. Verapamil can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog.
Leuprolide; Norethindrone: (Major) Avoid coadministration of leuprolide with verapamil due to the risk of reduced efficacy of leuprolide. Verapamil can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog.
Levamlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with verapamil is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Levoketoconazole: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with ketoconazole. Coadministration may increase the exposure of verapamil. Verapamil is a CYP3A substrate and ketoconazole is a strong CYP3A4 inhibitor. Clinically significant interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil. Hypotension, bradyarrhythmias, and other side effects have been observed with some combinations.
Levonorgestrel; Ethinyl Estradiol: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Lidocaine: (Moderate) Concomitant use of systemic lidocaine and verapamil may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; verapamil inhibits both hepatic isoenzymes.
Lidocaine; Epinephrine: (Moderate) Antihypertensives, including calcium-channel blockers, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Concomitant use of systemic lidocaine and verapamil may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; verapamil inhibits both hepatic isoenzymes.
Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and verapamil may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; verapamil inhibits both hepatic isoenzymes.
Lisdexamfetamine: (Minor) Lisdexamfetamine might increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
Lithium: (Moderate) Monitor for neurologic adverse reactions during concomitant use of lithium and calcium channel blockers. Concomitant use may increase the risk of neurologic adverse reactions, such as ataxia, tremors, nausea, vomiting, diarrhea, and/or tinnitus.
Lofexidine: (Moderate) Because both lofexidine and verapamil can cause hypotension and bradycardia, concurrent use should be avoided if possible. Patients being given lofexidine in an outpatient setting should be capable of and instructed on self-monitoring for hypotension, orthostasis, bradycardia, and associated symptoms. If clinically significant or symptomatic hypotension and/or bradycardia occur, the next dose of lofexidine should be reduced in amount, delayed, or skipped.
Lomitapide: (Contraindicated) Concomitant use of verapamil and lomitapide is contraindicated. If treatment with verapamil is unavoidable, lomitapide should be stopped during the course of treatment. Verapamil is a moderate CYP3A4 inhibitor. The exposure to lomitapide was increased 27-fold in the presence of ketoconazole, a strong CYP3A4 inhibitor. Although concomitant use of moderate CYP3A4 inhibitors with lomitapide has not been studied, a significant increase in lomitapide exposure is likely during concurrent use.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and verapamil is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; verapamil is a CYP3A4 substrate and moderate CYP3A4 inhibitor.
Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with verapamil. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and verapamil is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with verapamil. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and verapamil is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Lopinavir; Ritonavir: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil and ritonavir. Coadministration may increase the exposure of verapamil. Verapamil is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor.
Loratadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Lovastatin: (Major) Coadministration of verapamil and lovastatin increases the risk for myopathy/rhabdomyolysis, particularly with higher doses of lovastatin. In patients taking verapamil, the initial lovastatin dose should not exceed 10 mg/day PO. While the FDA-approved product labeling for lovastatin products recommends a maximum lovastatin dosage of 20 mg/day when these agents are used together, the product labeling for verapamil suggests a maximum lovastatin dosage of 40 mg/day. The benefits of the use of lovastatin in patients taking verapamil should be carefully weighed against the risks of this combination. Specific dosage recommendations for pediatric patients receiving this combination are not available.
Lumacaftor; Ivacaftor: (Major) If verapamil and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Lumacaftor; Ivacaftor: (Moderate) Concomitant use of verapamil and lumacaftor; ivacaftor may decrease the therapeutic effects of verapamil; caution and close monitoring of blood pressure are advised if these drugs are used together. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C8, CYP2C9, and the P-glycoprotein (P-gp) drug transporter. Verapamil is a substrate of CYP3A4, CYP2C8, CYP2C9, and P-gp. Clinically significant interactions have been reported with inducers of CYP3A4; rifampin, a strong CYP3A inducer markedly reduces oral verapamil bioavailability. Of note, verapamil is also a moderate CYP3A inhibitor. Although lumacaftor; ivacaftor is a primary substrate of CYP3A, dosage adjustment of lumacaftor; ivacaftor is not required.
Lumateperone: (Major) Reduce the dose of lumateperone to 21 mg once daily if concomitant use of verapamil is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased lumateperone exposure by approximately 2-fold.
Lurasidone: (Major) Verapamil is a moderate inhibitor of CYP3A4 and has the potential for interactions with substrates of CYP3A4 such as lurasidone. Concurrent use of these medications may lead to an increased risk of lurasidone-related adverse reactions. If a moderate inhibitor of CYP3A4 is being prescribed and lurasidone is added in an adult patient, the recommended starting dose of lurasidone is 20 mg/day and the maximum recommended daily dose of lurasidone is 80 mg/day. If a moderate CYP3A4 inhibitor is added to an existing lurasidone regimen, reduce the lurasidone dose to one-half of the original dose. Patients should be monitored for efficacy and toxicity. In addition, due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of antihypertensive agents. If coadministration is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and verapamil due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. If concomitant use is unavoidable, consider reducing the dose of lurbinectedin if clinically indicated. Lurbinectedin is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor.
Maraviroc: (Moderate) Use caution if coadministration of maraviroc with verapamil is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A4/P-glycoprotein (P-gp) substrate and verapamil is a CYP3A4/P-gp inhibitor. Monitor for an increase in adverse effects with concomitant use.
Mavacamten: (Major) Reduce the mavacamten dose by 1 level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients receiving mavacamten and starting verapamil therapy. Avoid initiation of verapamil in patients who are on stable treatment with mavacamten 2.5 mg per day because a lower dose of mavacamten is not available. Initiate mavacamten at the recommended starting dose of 5 mg PO once daily in patients who are on stable verapamil therapy. Expect additive negative inotropic effects during concomitant use of mavacamten and verapamil. If concomitant therapy with verapamil is initiated, or if the dose is increased, monitor left ventricular ejection fraction closely until stable doses and clinical response have been achieved. Avoid concomitant use of mavacamten with verapamil plus a beta-blocker due to association with left ventricular systolic dysfunction and heart failure symptoms. Concomitant use increases mavacamten exposure, which may increase the risk of adverse drug reactions. Mavacamten is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. The impact that a CYP3A inhibitor may have on mavacamten overall exposure varies based on the patient's CYP2C19 metabolizer status. Concomitant use of mavacamten 25 mg with verapamil sustained-release 240 mg increased mavacamten exposure by 15% in CYP2C19 normal and intermediate metabolizers.
Meclofenamate Sodium: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Mefenamic Acid: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Mefloquine: (Moderate) Mefloquine is metabolized by CYP3A4. Verapamil is an inhibitor of this enzyme and may decrease the clearance of mefloquine and increase mefloquine systemic exposure.
Melatonin: (Moderate) Monitor blood pressure during concomitant calcium-channel blocker and melatonin use. Melatonin may impair the efficacy of calcium-channel blockers. In a placebo-controlled study, melatonin evening ingestion led to significant increases in blood pressure (6.5 mmHg systolic and 4.9 mmHg diastolic) and heart rate (3.9 bpm) throughout the day in patients taking a calcium channel blocker Melatonin appeared to antagonize the antihypertensive effects of the calcium channel blocker.
Meloxicam: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Metformin; Repaglinide: (Moderate) Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Verapamil has been shown to be an inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
Metformin; Saxagliptin: (Minor) Saxagliptin plasma concentrations are expected to increase in the presence of moderate CYP 3A4/5 inhibitors such as verapamil, but saxagliptin dose adjustment is not advised.
Methadone: (Moderate) Verapamil may increase methadone serum concentrations via inhibition of CYP3A4 metabolism of methadone. Inhibition of methadone metabolism can lead to toxicity including CNS adverse effects and potential for QT prolongation and torsades de pointes when high doses of methadone are used.
Methamphetamine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
Methohexital: (Major) Barbiturates have been shown to enhance the hepatic clearance of verapamil. The effect on oral verapamil is greater than for IV verapamil, but a significant increase in clearance has been noted for both verapamil dosage forms during concomitant administration of a barbiturate. Patients receiving verapamil should be monitored for loss of therapeutic effect if barbiturates are added.
Methoxsalen: (Minor) Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Methylphenidate Derivatives: (Moderate) Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate derivatives and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate derivatives. Methylphenidate derivatives can reduce the hypotensive effect of antihypertensive agents, including calcium-channel blockers.
Metoprolol: (Major) Intravenous metoprolol is contraindicated with intravenous verapamil use in close proximity (within a few hours). Fatal cardiac arrests have occurred in patients receiving intravenous beta-blockers and intravenous calcium channel blockers. Use oral metoprolol and oral verapamil with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
Metoprolol; Hydrochlorothiazide, HCTZ: (Major) Intravenous metoprolol is contraindicated with intravenous verapamil use in close proximity (within a few hours). Fatal cardiac arrests have occurred in patients receiving intravenous beta-blockers and intravenous calcium channel blockers. Use oral metoprolol and oral verapamil with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
Midazolam: (Major) A clinically significant interaction has occurred with verapamil, a CYP3A4 inhibitor and oral midazolam, a CYP3A4 substrate. When verapamil and midazolam are coadministered, the AUC and half-life of midazolam are increased and the associated sedation is more pronounced. The significance of an interaction between verapamil and IV midazolam is uncertain, however, but may be less significant due to absence of an effect by verapamil on presystemic midazolam clearance.
Mifepristone: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil and mifepristone. Coadministration may increase the exposure of verapamil. Verapamil is a CYP3A4 substrate and mifepristone is a strong inhibitor of CYP3A4.
Milrinone: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.
Mitapivat: (Moderate) Do not exceed mitapivat 20 mg PO twice daily during coadministration with verapamil and monitor hemoglobin and for adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased mitapivat overall exposure by 2.6-fold.
Mitotane: (Moderate) Use caution if mitotane and verapamil are used concomitantly, and monitor for decreased efficacy of verapamil and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and verapamil is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of verapamil.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and verapamil; reduce the dose of mobocertinib by approximately 50% and monitor the QT interval more frequently if use is necessary. Concomitant use may increase mobocertinib exposure and the risk for adverse reactions. Mobocertinib is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Use of a moderate CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 100% to 200%.
Nabumetone: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Nadolol: (Moderate) Use verapamil and nadolol with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with verapamil. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; verapamil is a moderate P-gp inhibitor and a moderate CYP3A4 inhibitor.
Naloxegol: (Major) Avoid concomitant administration of naloxegol and verapamil due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with verapamil is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and verapamil. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and verapamil is a moderate CYP3A and P-gp inhibitor.
Naproxen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Naproxen; Esomeprazole: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Naproxen; Pseudoephedrine: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Nebivolol: (Moderate) Use verapamil and nebivolol with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
Nebivolol; Valsartan: (Moderate) Use verapamil and nebivolol with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
Nefazodone: (Moderate) Nefazodone is an inhibitor of CYP3A4, and may theoretically increase verapamil serum concentrations.
Neratinib: (Major) Avoid concomitant use of verapamil with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and verapamil is a dual moderate CYP3A4/P-glycoprotein (P-gp) inhibitor. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that verapamil may increase neratinib exposure by 299%.
Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with antihypertensive agents.
Neuromuscular blockers: (Moderate) Concomitant use of neuromuscular blockers and calcium-channel blockers may prolong neuromuscular blockade.
Niacin, Niacinamide: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents, especially calcium-channel blockers. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Niacin; Simvastatin: (Major) Do not exceed a simvastatin dose of 10 mg/day in patients taking verapamil due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on verapamil, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of verapamil and simvastatin against the potential risks. Verapamil increases the simvastatin exposure by approximately 2-fold. The interaction is presumed due to increased simvastatin bioavailability via inhibition of CYP3A metabolism and reduction of first-pass metabolism by verapamil. (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents, especially calcium-channel blockers. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Nifedipine: (Moderate) Diltiazem has been reported to increase the plasma level and hypotensive effects of nifedipine via CYP3A4 inhibition. Verapamil may also inhibit CYP3A4 metabolism of nifedipine.
Nilotinib: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with nilotinib is necessary; also monitor for nilotinib-related side effects. Nilotinib and verapamil are both substrates of and inhibitors of CYP3A4. Elevations of verapamil plasma levels resulting in clinically significant interactions have been reported with other moderate CYP3A4 inhibitors. Increased nilotinib concentrations may increase the risk for treatment-related side effects.
Nintedanib: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as verapamil, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Verapamil is a moderate inhibitor of both P-gp and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
Nirmatrelvir; Ritonavir: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil and ritonavir. Coadministration may increase the exposure of verapamil. Verapamil is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor.
Nitrates: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
Nitroglycerin: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
Nitroprusside: (Moderate) Additive hypotensive effects may occur when nitroprusside is used concomitantly with other antihypertensive agents. Dosages should be adjusted carefully, according to blood pressure.
Nonsteroidal antiinflammatory drugs: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Norethindrone; Ethinyl Estradiol: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Norgestimate; Ethinyl Estradiol: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Octreotide: (Moderate) Monitor for bradycardia during concomitant use of verapamil and octreotide and adjust drug dosage based on response as appropriate. Both medications may cause bradycardia and concomitant use may increase bradycardia risk.
Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Olanzapine; Fluoxetine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Olanzapine; Samidorphan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Olaparib: (Major) Avoid coadministration of olaparib with verapamil due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 150 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after verapamil is discontinued. Olaparib is a CYP3A substrate and verapamil is a moderate CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with a moderate CYP3A inhibitor is predicted to increase the olaparib Cmax by 14% and the AUC by 121%.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and verapamil is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and verapamil may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If verapamil is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with verapamil is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and verapamil. If concomitant use is necessary, decrease omaveloxolone dose to 100 mg once daily; additional dosage reductions may be necessary. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Concomitant use increased omaveloxolone overall exposure by 1.25-fold.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as verapamil and thereby reduce their oral bioavailability. The dosage requirements of verapamil may be increased in patients receiving concurrent enzyme inducers.
Oritavancin: (Moderate) Coadministration of oritavancin and verapamil may result in increases or decreases in verapamil exposure and may increase side effects or decrease efficacy of verapamil. Verapamil is metabolized by CYP3A4 and CYP2C9. Oritavancin weakly induces CYP3A4, while weakly inhibiting CYP2C9. If these drugs are administered concurrently, monitor the patient for signs of toxicity or lack of efficacy.
Osimertinib: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with osimertinib is necessary. Verapamil is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Concomitant use may increase verapamil exposure.
Oxaprozin: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Oxcarbazepine: (Moderate) Monitor for decreased plasma levels of MHD, the active metabolite of oxcarbazepine, if coadministered with verapamil. The oxcarbazepine dose may require adjustment after initiation, dosage modification, or discontinuation of verapamil. Verapamil has been shown to decrease MHD exposure by approximately 20%. The mechanism of interaction is unknown.
Oxybutynin: (Moderate) Monitor for oxybutynin-related adverse reactions if coadministration with verapamil is necessary. Oxybutynin is a CYP3A4 substrate and verapamil is a moderate CYP3A inhibitor. Concomitant use with moderate CYP3A4 inhibitors may alter the mean pharmacokinetic parameters of oxybutynin, although the clinical relevance of these potential interactions is unknown.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of verapamil is necessary. If verapamil is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like verapamil can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If verapamil is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Oxymetazoline: (Major) The vasoconstricting actions of oxymetazoline, an alpha adrenergic agonist, may reduce the antihypertensive effects produced by calcium-channel blockers. If these drugs are used together, closely monitor for changes in blood pressure.
Ozanimod: (Major) Treatment with ozanimod should generally not be initiated in patients who are concurrently treated with both a heart rate lowering calcium channel blocker (e.g., verapamil) and a beta blocker. If treatment initiation with ozanimod is considered in patients on both a heart rate lowering calcium channel blocker and beta blocker, advice from a cardiologist should be sought.
Paclitaxel: (Minor) Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as certain calcium-channel blockers. In vitro, the metabolism of paclitaxel via CYP3A4 was inhibited by verapamil, a moderate CYP3A4 inhibitor. However, the verapamil concentrations used exceeded those found in vivo following normal therapeutic doses. Verapamil also blocks the multidrug resistance (MDR) P-glycoprotein, which is a mechanism of resistance to naturally occurring (non-synthetic) chemotherapy agents. Verapamil could enhance paclitaxel's activity and toxicity through this mechanism as well. Small clinical trials have indicated that the coadministration of r-verapamil, an isomer of verapamil, and paclitaxel results in a significant decrease in paclitaxel clearance and an increase in paclitaxel toxicity. Some experts state that pharmacokinetic interactions between paclitaxel and verapamil do not appear to be clinically significant in vivo. However, combining the drugs in clinical practice may require close monitoring; monitor for paclitaxel induced side effects such as myelosuppression, infection, or peripheral neuropathy.
Pacritinib: (Major) Avoid concurrent use of pacritinib with verapamil due to the risk of increased pacritinib exposure which increases the risk of adverse reactions. Pacritinib is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor.
Paliperidone: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and calcium-channel blockers who are susceptible to hypotension.
Palovarotene: (Major) Avoid concomitant use of palovarotene and verapamil due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. If concomitant use is necessary, decrease the palovarotene dose by half. Palovarotene is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased palovarotene overall exposure by 2.5-fold.
Paricalcitol: (Moderate) Paricalcitol is partially metabolized by CYP3A4. Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as verapamil. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
Pasireotide: (Major) Pasireotide may cause a decrease in heart rate. Closely monitor patients who are also taking drugs associated with bradycardia such as calcium-channel blockers. Dose adjustments of calcium-channel blockers may be necessary.
Pazopanib: (Moderate) Pazopanib is a weak inhibitor of and substrate for CYP3A4 and P-glycoprotein (P-gp). Verapamil is a substrate for and an inhibitor of CYP3A4 and P-gp. Concurrent administration may result in increased pazopanib concentrations and/or increased verapamil concentrations. Dose reduction of pazopanib should be considered when coadministration of pazopanib and verapamil is necessary.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and verapamil due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If verapamil is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of verapamil. Pemigatinib is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase pemigatinib exposure by approximately 50% to 80%.
Pentobarbital: (Major) Barbiturates have been shown to enhance the hepatic clearance of verapamil. The effect on oral verapamil is greater than for IV verapamil, but a significant increase in clearance has been noted for both verapamil dosage forms during concomitant administration of a barbiturate. Patients receiving verapamil should be monitored for loss of therapeutic effect if barbiturates are added.
Pentoxifylline: (Moderate) Pentoxifylline has been used concurrently with antihypertensive drugs (beta blockers, diuretics) without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensives. If indicated, dosage of the antihypertensive agents should be reduced.
Perindopril; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with verapamil is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and verapamil due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If verapamil is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of verapamil. Pexidartinib is a CYP3A substrate; verapamil is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased pexidartinib overall exposure by 67%.
Phenelzine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
Phenobarbital: (Major) Barbiturates have been shown to enhance the hepatic clearance of verapamil. The effect on oral verapamil is greater than for IV verapamil, but a significant increase in clearance has been noted for both verapamil dosage forms during concomitant administration of a barbiturate. Patients receiving verapamil should be monitored for loss of therapeutic effect if barbiturates are added.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Barbiturates have been shown to enhance the hepatic clearance of verapamil. The effect on oral verapamil is greater than for IV verapamil, but a significant increase in clearance has been noted for both verapamil dosage forms during concomitant administration of a barbiturate. Patients receiving verapamil should be monitored for loss of therapeutic effect if barbiturates are added.
Phenoxybenzamine: (Moderate) Additive pharmacodynamic effects are especially prominent when verapamil is co-administered with alpha-blockers or beta-blockers. The use of alpha-blockers with verapamil can lead to excessive hypotension.
Phentolamine: (Moderate) Additive pharmacodynamic effects are especially prominent when verapamil is co-administered with alpha-blockers. The use of alpha-blockers with verapamil can lead to excessive hypotension.
Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Photosensitizing agents (topical): (Minor) Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Pimozide: (Major) Concurrent use of pimozide and verapamil should be avoided. Pimozide is metabolized primarily through CYP3A4, and verapamil is a CYP3A4 inhibitor. Elevated pimozide concentrations occurring through inhibition of CYP3A4 can lead to QT prolongation, ventricular arrhythmias, and sudden death.
Pindolol: (Moderate) Use verapamil and pindolol with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
Piroxicam: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Ponesimod: (Major) Avoid concomitant use of ponesimod and medications that may decrease heart rate such as verapamil due to the risk for severe bradycardia and heart block. Consider consultation from a cardiologist if concomitant use is necessary.
Posaconazole: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with posaconazole is necessary. Concurrent use may result in elevated verapamil concentrations. Verapamil is a CYP3A4 substrate and posaconazole is a strong CYP3A4 inhibitor.
Pralsetinib: (Major) Avoid concomitant use of verapamil with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a CYP3A and P-gp substrate and verapamil is a combined moderate CYP3A and P-gp inhibitor. Coadministration increased the overall exposure of pralsetinib by 108%.
Prazosin: (Moderate) Prazosin is well-known to produce a 'first-dose' phenomenon. Some patients develop significant hypotension shortly after administration of the first dose. The first dose response (acute postural hypotension) of prazosin may be exaggerated in patients who are receiving beta-adrenergic blockers, diuretics, or other antihypertensive agents. Concomitant administration of prazosin with other antihypertensive agents is not prohibited, however. This can be therapeutically advantageous, but lower dosages of each agent should be used. The use of alpha-blockers with verapamil can lead to excessive hypotension; In addition, verapamil has been reported to increase the AUC and Cmax of prazosin.
Prednisone: (Minor) The absorption of verapamil can also be reduced by the cyclophosphamide, vincristine, procarbazine, prednisone (COPP) chemotherapeutic drug regimen.
Prilocaine; Epinephrine: (Moderate) Antihypertensives, including calcium-channel blockers, antagonize the vasopressor effects of parenteral epinephrine.
Primidone: (Major) Barbiturates have been shown to enhance the hepatic clearance of verapamil. The effect on oral verapamil is greater than for IV verapamil, but a significant increase in clearance has been noted for both verapamil dosage forms during concomitant administration of a barbiturate. Patients receiving verapamil should be monitored for loss of therapeutic effect if barbiturates are added.
Probenecid; Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and verapamil in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Verapamil can inhibit colchicine's metabolism via P-glycoprotein (P-gp) and CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken a P-gp and moderate CYP3A4 inhibitor like verapamil in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
Procainamide: (Moderate) Procainamide can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents. Intravenous administration of procainamide is more likely to cause hypotensive effects.
Procarbazine: (Minor) The absorption of verapamil can also be reduced by the cyclophosphamide, vincristine, procarbazine, prednisone (COPP) chemotherapeutic drug regimen.
Progesterone: (Minor) The metabolism of progesterone may be inhibited by verapamil, an inhibitor of cytochrome P450 3A4 hepatic enzymes.
Promethazine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Propafenone: (Moderate) Coadministration of propafenone with verapamil has the potential to cause additive decreases in AV conduction and/or negative inotropic effects. In addition, concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and verapamil with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A4 and CYP2D6 substrate and verapamil is a moderate CYP3A4 inhibitor.
Propofol: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
Propranolol: (Major) Intravenous propranolol is contraindicated with intravenous verapamil use in close proximity (within a few hours). Fatal cardiac arrests have occurred in patients receiving intravenous beta-blockers and intravenous calcium channel blockers. Use oral propranolol and oral verapamil with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension. A decrease in propranolol clearance has been observed when administered concomitantly with verapamil.
Propranolol; Hydrochlorothiazide, HCTZ: (Major) Intravenous propranolol is contraindicated with intravenous verapamil use in close proximity (within a few hours). Fatal cardiac arrests have occurred in patients receiving intravenous beta-blockers and intravenous calcium channel blockers. Use oral propranolol and oral verapamil with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension. A decrease in propranolol clearance has been observed when administered concomitantly with verapamil.
Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Pseudoephedrine; Triprolidine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Quazepam: (Moderate) CYP3A4 inhibitors, including verapamil, may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity.
Quetiapine: (Minor) Verapamil may inhibit the CYP3A4-mediated metabolism of quetiapine, leading to increased serum concentrations of quetiapine. The manufacturer of quetiapine recommends a reduced dosage during concurrent administration of CYP3A4 inhibitors.
Quinidine: (Major) Pharmacokinetic and pharmacodynamic interactions exist between quinidine and verapamil. Oral verapamil has been shown to reduce the clearance and metabolism of oral quinidine. Quinidine half-life increased and plasma concentrations were higher after verapamil. No changes in quinidine protein binding were observed. In addition to the pharmacokinetic interaction which may potentiate quinidine's clinical effects, both quinidine and verapamil can cause hypotension. When quinidine and verapamil are coadministered in doses that are each well tolerated as monotherapy, hypotension attributable to additive peripheral (alpha)-blockade is sometimes reported. Concurrent use of verapamil and quinidine in patients with hypertrophic cardiomyopathy or arrhythmias can cause significant hypotension. It is recommended to avoid combined therapy with verapamil and quinidine in patients with hypertrophic cardiomyopathy. Quinidine and verapamil may also have additive negative inotropic effects. Concurrent use of verapamil and quinidine should be monitored carefully for electrophysiologic and hemodynamic effects.
Quinine: (Moderate) Quinine is a substrate of P-glycoprotein (PGP) and CYP3A4 and verapamil is a PGP and CYP3A4 inhibitor; therefore, quinine concentrations could be increased with coadministration. Additionally, verapamil is a CYP3A4 substrate and quinine can inhibit CYP3A4; therefore, verapamil concentrations could also be increased with coadministration. Monitor patients for increased side effects of quinine and verapamil if these drugs are given together.
Ramelteon: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as verapamil, may lead to increases in the serum concentrations of ramelteon.
Ranolazine: (Major) The dose of ranolazine, a CYP3A4 and P-glycoprotein substrate, should be limited to 500 mg PO twice daily when coadministered with verapamil, a moderate CYP3A inhibitor. Verapamil (120 mg three times daily) causes dose-dependent increases in the average steady-state concentrations of ranolazine by about 2-fold.
Rasagiline: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider during concurrent use of an MAOI and a calcium-channel blocker.
Red Yeast Rice: (Major) Red yeast rice is best avoided by patients taking CYP3A4 inhibitors, such as verapamil. Since certain red yeast rice products contain lovastatin, clinicians should use red yeast rice cautiously in combination with drugs known to interact with lovastatin. CYP3A4 inhibitors have been shown to increase HMG-CoA reductase activity and potential for myopathy/rhabdomyolysis when coadministered with lovastatin, particularly with higher doses of lovastatin. The benefits of the use of lovastatin in patients taking verapamil should be carefully weighed against the risks of this combination.
Regadenoson: (Major) Because of the potential for additive or synergistic depressant effects on SA and AV nodes, regadenoson should be used with caution in the presence of agents that slow cardiac conduction, such as verapamil.
Relugolix: (Major) Avoid concomitant use of relugolix and oral verapamil. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer verapamil at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and verapamil is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral verapamil. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer verapamil at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and verapamil is a P-gp inhibitor. (Minor) Verapamil inhibits CYP3A4 activity. Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when verapamil is coadministered with either estrogens or combined hormonal contraceptives.
Remifentanil: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving calcium-channel blockers due to additive hypotensive effects.
Repaglinide: (Moderate) Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Verapamil has been shown to be an inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
Ribociclib: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with ribociclib is necessary. Verapamil is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
Ribociclib; Letrozole: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with ribociclib is necessary. Verapamil is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
Rifabutin: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as verapamil and thereby reduce their oral bioavailability. The dosage requirements of verapamil may be increased in patients receiving concurrent enzyme inducers.
Rifampin: (Major) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of verapamil. Dosages of verapamil may need to be adjusted while the patient is receiving rifampin.
Rifapentine: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with rifapentine is necessary. Concomitant use may decrease plasma concentrations of verapamil. Verapamil is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with verapamil is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and verapamil is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rilpivirine: (Moderate) Close clinical monitoring is advised when administering verapamil with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Verapamil is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with verapamil; concurrent use may increase rimegepant exposure. Rimegepant is a CYP3A4 and P-gp substrate; verapamil is a moderate CYP3A4 inhibitor and a P-gp inhibitor.
Risperidone: (Moderate) Risperidone has been associated with orthostatic hypotension and may enhance the hypotensive effects of antihypertensive agents. Clinically significant hypotension has been observed with concomitant use of risperidone and antihypertensive medications. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving antihypertensive agents concomitantly.
Ritlecitinib: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with ritlecitinib. Coadministration may increase the exposure of verapamil. Verapamil is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor.
Ritonavir: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil and ritonavir. Coadministration may increase the exposure of verapamil. Verapamil is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor.
Rivaroxaban: (Moderate) Avoid coadministration of rivaroxaban and verapamil in patients with renal impairment (CrCL 15 to 79 mL/minute) unless the potential benefit justifies the potential risk. Rivaroxaban is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and verapamil is a P-gp and moderate CYP3A4 inhibitor. In a pharmacokinetic trial, coadministration with another combined moderate CYP3A4/P-gp inhibitor increased the AUC of rivaroxaban by 76% in patients with mild renal impairment (CrCL 50 to 79 mL/minute) and by 99% in patients with moderate renal impairment (CrCL 30 to 49 mL/minute) compared to patients with normal renal function (CrCL greater than 80 mL/minute); similar trends in pharmacodynamic effects were also observed.
Romidepsin: (Moderate) Romidepsin is a substrate for CYP3A4 and P-glycoprotein (P-gp). Verapamil is an inhibitor of CYP3A4 and P-gp. Concurrent administration of romidepsin with an inhibitor of CYP3A4 and P-gp may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
Ruxolitinib: (Minor) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as verapamil, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
Saxagliptin: (Minor) Saxagliptin plasma concentrations are expected to increase in the presence of moderate CYP 3A4/5 inhibitors such as verapamil, but saxagliptin dose adjustment is not advised.
Secobarbital: (Major) Barbiturates have been shown to enhance the hepatic clearance of verapamil. The effect on oral verapamil is greater than for IV verapamil, but a significant increase in clearance has been noted for both verapamil dosage forms during concomitant administration of a barbiturate. Patients receiving verapamil should be monitored for loss of therapeutic effect if barbiturates are added.
Segesterone Acetate; Ethinyl Estradiol: (Minor) Coadministration of segesterone, a CYP3A4 substrate and verapamil, a moderate CYP3A4 inhibitor may increase the serum concentration of segesterone. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and verapamil due to the risk of increased selpercatinib exposure which may increase the risk of adverse reactions, including QT prolongation. If coadministration is unavoidable, reduce the dose of selpercatinib to 80 mg PO twice daily if original dose was 120 mg twice daily, and to 120 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If verapamil is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of verapamil. Selpercatinib is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration with verapamil is predicted to increase selpercatinib exposure by 60% to 99%.
Selumetinib: (Major) Avoid coadministration of selumetinib and verapamil due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If verapamil is discontinued, resume the original selumetinib dose after 3 elimination half-lives of verapamil. Selumetinib is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Sevoflurane: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
Sildenafil: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with verapamil is necessary; consider a starting dose of 25 mg of sildenafil when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. In a drug interaction study, coadministration with a moderate CYP3A4 inhibitor increased the Cmax and AUC of sildenafil by 160% and 182%, respectively. Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A4 inhibitors will be less for sildenafil injection than those observed after oral sildenafil administration.
Silodosin: (Moderate) Monitor for silodosin-related adverse effects if coadministered with verapamil; silodosin exposure may be increased. In addition the incidence of dizziness and orthostatic hypotension were increased in patients also receiving antihypertensive medications in clinical trials. Verapamil is a moderate CYP3A4 inhibitor and P-gp inhibitor; silodosin is a CYP3A4 and P-gp substrate. Although the effect of moderate CYP3A4 inhibitors on silodosin exposure has not been studied, coadministration of a combined P-gp/strong CYP3A4 inhibitor increased the silodosin AUC by 2.9-fold to 3.2-fold.
Simvastatin: (Major) Do not exceed a simvastatin dose of 10 mg/day in patients taking verapamil due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on verapamil, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of verapamil and simvastatin against the potential risks. Verapamil increases the simvastatin exposure by approximately 2-fold. The interaction is presumed due to increased simvastatin bioavailability via inhibition of CYP3A metabolism and reduction of first-pass metabolism by verapamil.
Sincalide: (Moderate) Sincalide-induced gallbladder ejection fraction may be affected by calcium-channel blockers. False study results are possible in patients with drug-induced hyper- or hypo-responsiveness; thorough patient history is important in the interpretation of results.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving verapamil due to the potential for additive effects on heart rate. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Additionally, concomitant use of siponimod and verapamil may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of verapamil. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and verapamil is a moderate CYP3A and P-gp inhibitor. Concomitant use increased sirolimus overall exposure by 2.2-fold in a drug interaction study.
Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with verapamil. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). In addition, verapamil is an inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of verapamil, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for changes in blood pressure and increased side effects if these drugs are administered concurrently. (Moderate) Use caution when administering velpatasvir with verapamil. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). In addition, verapamil is an inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and verapamil as sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Sorafenib: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with sorafenib is necessary. Verapamil is a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
Sotalol: (Moderate) Monitor blood pressure and heart rate if concomitant use of verapamil and sotalol is necessary. Concomitant use can increase the risk of bradycardia or hypotension.
Sparsentan: (Moderate) Monitor for an increase in sparsentan-related adverse effects if concomitant use with verapamil is necessary. Concomitant use may increase sparsentan exposure. Sparsentan is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sparsentan overall exposure by 70%.
St. John's Wort, Hypericum perforatum: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with St. John's Wort is necessary. Concomitant use may decrease plasma concentrations of verapamil. Verapamil is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if verapamil must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of verapamil is necessary. If verapamil is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a moderate CYP3A4 inhibitor like verapamil can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If verapamil is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sulindac: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Sumatriptan; Naproxen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Suvorexant: (Major) A dose reduction to 5 mg of suvorexant is recommended during concurrent use with verapamil. The suvorexant dose may be increased to 10 mg if needed for efficacy. Suvorexant is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased the suvorexant AUC by 2-fold.
Tacrolimus: (Moderate) Verapamil, a CYP3A4 substrate, may inhibit tacrolimus metabolism by inhibiting CYP3A4 intestinal metabolism. If verapamil is added to tacrolimus therapy, blood trough concentrations of tacrolimus should be monitored and dose adjustments may be necessary.
Tadalafil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with verapamil is necessary. Tadalafil is a CYP3A4 substrate and verapamil is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Talazoparib: (Major) Avoid coadministration of verapamil with talazoparib when used for the treatment of breast cancer due to increased talazoparib exposure. If concomitant use is unavoidable, reduce the dose of talazoparib to 0.75 mg PO once daily. If verapamil is discontinued, wait at least 3 to 5 half-lives of verapamil before increasing the dose of talazoparib to the prior dose used before verapamil therapy. A talazoparib dose reduction is not necessary for patients with prostate cancer; monitor for an increase in talazoparib-related adverse reactions. Talazoparib is a P-gp substrate and verapamil is a P-gp inhibitor. In clinical trials, coadministration with verapamil increased talazoparib exposure by 45%.
Tamsulosin: (Moderate) The concomitant administration of tamsulosin with other antihypertensive agents can cause additive hypotensive effects. In addition, diltiazem, nicardipine, and verapamil may increase tamsulosin plasma concentrations via CYP3A4 inhibition. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.
Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and verapamil. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as verapamil, may increase exposure to tasimelteon with the potential for adverse reactions.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with verapamil as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. If concomitant use is unavoidable, decrease current tazemetostat daily dosage by 50% (e.g., decrease 800 mg PO twice daily to 400 mg PO twice daily; 600 mg PO twice daily to 400 mg PO for first dose and 200 mg PO for second dose; 400 mg PO twice daily to 200 mg PO twice daily). If verapamil is discontinued, wait at least 3 half-lives of verapamil before increasing the dose of tazemetostat to the previous tolerated dose. Tazemetostat is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Telmisartan; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with verapamil is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Temsirolimus: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with verapamil; an increase in treatment-related adverse reactions may also occur. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another calcium channel blocker. Both drugs are also P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use is likely to lead to increased concentrations of both temsirolimus and diltiazem.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with verapamil may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and verapamil is a P-gp inhibitor.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with verapamil may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and verapamil is a P-gp inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with verapamil may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and verapamil is a P-gp inhibitor.
Terazosin: (Moderate) The first-dose response (acute postural hypotension) of terazosin can be potentiated by coadministration with beta-blockers. The use of alpha-blockers with verapamil can lead to excessive hypotension; In addition, verapamil has been reported to increase the AUC and Cmax of prazosin and terazosin.
Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering verapamil. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenzymes, with major contributions coming from CYP3A4; verapamil is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
Tetrabenazine: (Moderate) Tetrabenazine may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of tetrabenazine may be necessary in patients receiving antihypertensive agents concomitantly.
Tetracaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of tetracaine and antihypertensive agents.
Tezacaftor; Ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with verapamil; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); verapamil is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If verapamil and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Thalidomide: (Moderate) Thalidomide and other agents that slow cardiac conduction such as calcium-channel blockers should be used cautiously due to the potential for additive bradycardia.
Theophylline, Aminophylline: (Moderate) Verapamil has been reported to decrease theophylline clearance. The mechanism is most likely reduced cytochrome P-450 metabolism of theophylline. Since the therapeutic range is narrow for theophylline, monitor theophylline serum concentrations during verapamil therapy. (Moderate) Verapamil may decrease aminophylline clearance due to reduced cytochrome P-450 metabolism of aminophylline. Since the therapeutic range is narrow for aminophylline, monitor serum concentrations during verapamil therapy.
Thiothixene: (Moderate) Thiothixene should be used cautiously in patients receiving antihypertensive agents. Additive hypotensive effects are possible.
Ticagrelor: (Moderate) Coadministration of ticagrelor and verapamil may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and verapamil is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
Timolol: (Moderate) Use verapamil and timolol with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
Tipranavir: (Moderate) Verapamil is a substrate and inhibitor of CYP3A4, is a substrate of Pgp, and can prolong the PR interval; both pharmacokinetic and pharmacodynamic interactions may occur with tipranavir. Cautious dose titration of verapamil should be considered.
Tizanidine: (Major) Avoid concomitant use of tizanidine and verapamil as increased tizanidine exposure may occur. If use together is necessary, initiate tizanidine at 2 mg and increase by 2 to 4 mg/day based on clinical response. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occurs. Tizanidine is a CYP1A2 substrate and verapamil is a weak CYP1A2 inhibitor.
Tolmetin: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Tolterodine: (Moderate) In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. Verapamil is a CYP3A4 inhibitor. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed. Because it is difficult to assess which patients will be poor metabolizers of tolterodine via CYP2D6, those patients receiving CYP3A4 inhibitors should not receive more than 2 mg/day of tolterodine.
Tolvaptan: (Major) Avoid coadministration of verapamil when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with verapamil. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
Topotecan: (Major) Avoid coadministration of verapamil with oral topotecan due to increased topotecan exposure; verapamil may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and verapamil is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Tranylcypromine: (Major) Avoid concomitant use of calcium-channel blockers and tranylcypromine due to the risk of additive hypotension. Potential for this interaction persists for up to 10 days after discontinuation of tranylcypromine (or 4 to 5 half-lives after discontinuation of the calcium-channel blocker). If a medication-free interval is not feasible, initiate therapy at the lowest appropriate dose and monitor blood pressure closely.
Trazodone: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
Treprostinil: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with verapamil and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and verapamil is a moderate CYP3A inhibitor.
Triptorelin: (Major) Avoid coadministration of triptorelin with verapamil due to the risk of reduced efficacy of triptorelin. Verapamil can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; triptorelin is a GnRH analog.
Tucatinib: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with tucatinib. Coadministration may increase the exposure of verapamil. Tucatinib is a strong inhibitor of CYP3A4; verapamil is a substrate of CYP3A4.
Ubrogepant: (Major) Limit the initial dose of ubrogepant to 50 mg and avoid a second dose within 24 hours if coadministered with verapamil. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 and P-gp substrate; verapamil is a moderate CYP3A4 inhibitor and a P-gp inhibitor. Coadministration with verapamil resulted in a 3.5-fold increase in the exposure of ubrogepant.
Umeclidinium: (Moderate) Umeclidinium is a P-gp substrate. When verapamil, a moderate P-gp transporter inhibitor, was given to healthy adult subjects at a dose of 240 mg once daily in combination with umeclidinium, no effect on umeclidinium Cmax was observed. However, an approximately 1.4-fold increase in umeclidinium AUC was observed.
Umeclidinium; Vilanterol: (Moderate) Umeclidinium is a P-gp substrate. When verapamil, a moderate P-gp transporter inhibitor, was given to healthy adult subjects at a dose of 240 mg once daily in combination with umeclidinium, no effect on umeclidinium Cmax was observed. However, an approximately 1.4-fold increase in umeclidinium AUC was observed.
Valdecoxib: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Vardenafil: (Major) Do not use vardenafil orally disintegrating tablets with verapamil due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Additive hypotensive effects are also possible. Vardenafil is primarily metabolized by CYP3A and verapamil is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased the AUC of vardenafil by 4-fold.
Vemurafenib: (Moderate) Concomitant use of vemurafenib and verapamil may result in altered concentrations of verapamil and increased concentrations of vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4, a substrate/inhibitor of P-glycoprotein (PGP), and an inhibitor of CYP1A2 and CYP2C9. Verapamil is a substrate/inhibitor of CYP3A4 and PGP and a substrate of CYP1A2 and CYP2C9. Use caution and monitor patients for toxicity and efficacy.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with verapamil due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of verapamil. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; verapamil is a CYP3A4 (moderate) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with calcium channel blockers is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use with calcium channel blockers could enhance the rate of verteporfin uptake by the vascular endothelium, resulting in enhanced photosensitivity.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with verapamil is necessary. Vinblastine is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Enhanced vinblastine toxicity was reported with coadministration of another moderate CYP3A4 inhibitor.
Vincristine Liposomal: (Major) Verapamil inhibits CYP3A4 and P-glycoprotein (P-gp); vincristine is a CYP3A and P-gp substrate. Coadministration could increase exposure to vincristine; however, verapamil must be given in toxic doses to achieve this effect. An in vitro study has shown that verapamil competes with vincristine for protein binding sites, specifically 1-acid glycoprotein. Verapamil reduced the binding of vincristine to various proteins by 27 to 60%. The clinical significance of this interaction is not known. The absorption of verapamil may also be reduced by coadministration with the cyclophosphamide, vincristine, procarbazine, prednisone (COPP) chemotherapeutic drug regimen. Monitor for increased side effects of vincristine and loss of blood pressure control during coadministration.
Vincristine: (Major) Verapamil inhibits CYP3A4 and P-glycoprotein (P-gp); vincristine is a CYP3A and P-gp substrate. Coadministration could increase exposure to vincristine; however, verapamil must be given in toxic doses to achieve this effect. An in vitro study has shown that verapamil competes with vincristine for protein binding sites, specifically 1-acid glycoprotein. Verapamil reduced the binding of vincristine to various proteins by 27 to 60%. The clinical significance of this interaction is not known. The absorption of verapamil may also be reduced by coadministration with the cyclophosphamide, vincristine, procarbazine, prednisone (COPP) chemotherapeutic drug regimen. Monitor for increased side effects of vincristine and loss of blood pressure control during coadministration.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with verapamil is necessary. Vinorelbine is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor.
Voclosporin: (Major) Reduce the voclosporin dosage to 15.8 mg PO in the morning and 7.9 mg PO in the evening if coadministered with verapamil. Concomitant use may increase voclosporin exposure and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Voclosporin is a sensitive CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration with verapamil increased voclosporin exposure by 2.7-fold.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of clarithromycin and verapamil, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving verapamil therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely. Verapamil is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). One case of a possible verapamil-clarithromycin interaction was reported, which was associated with hypotension.
Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and verapamil. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with verapamil, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
Voriconazole: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with voriconazole is necessary. Concurrent use may result in elevated verapamil concentrations. Verapamil is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
Voxelotor: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with voxelotor. Coadministration may increase the exposure of verapamil. Voxelotor is a moderate inhibitor of CYP3A; verapamil is a substrate of CYP3A.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with verapamil is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Verapamil is a CYP1A2 and moderate CYP3A4 inhibitor and warfarin is a CYP1A2/CYP3A4 substrate.
Zafirlukast: (Minor) Caution should be used when CYP3A4 inhibitors are co-administered with verapamil, a CYP3A4 substrate and inhibitor. This combination may cause reduced metabolism and increased effect of verapamil.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO twice daily if coadministered with verapamil. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Further decrease the zanubrutinib dose as recommended if adverse reactions occur. After discontinuation of verapamil, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. The AUC of zanubrutinib is predicted to increase by 157% to 317% when coadministered with other moderate CYP3A4 inhibitors.
Ziprasidone: (Major) Verapamil may reduce ziprasidone metabolism via inhibition of CYP3A4 isoenzymes.
Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and verapamil is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs that are P-gp substrates.

Calan SR/Isoptin/Isoptin SR/Verapamil/Verapamil Hydrochloride Oral Tab ER: 120mg, 180mg, 240mg
Calan/Verapamil/Verapamil Hydrochloride Oral Tab: 40mg, 80mg, 120mg
Isoptin/Verapamil/Verapamil Hydrochloride Intravenous Inj Sol: 1mL, 2.5mg
Verapamil/Verapamil Hydrochloride/Verelan Oral Cap DR Pellets: 120mg, 180mg, 240mg
Verapamil/Verapamil Hydrochloride/Verelan/Verelan PM Oral Cap ER: 100mg, 120mg, 180mg, 200mg, 240mg, 300mg, 360mg

Adults

480 mg/day PO for Calan, Calan SR, Isoptin, Isoptin SR, Verelan, or generic equivalents; 400 mg/day PO for Verelan PM; 540 mg/day PO for Covera-HS; for most approved indications.

Elderly

480 mg/day PO for Calan, Calan SR, Isoptin, Isoptin SR, Verelan; 400 mg/day PO for Verelan PM; 540 mg/day PO for Covera-HS; for most approved indications.

Adolescents

Safety and efficacy have not been established; however, doses up to 8 mg/kg/day PO have been reported in pediatric patients. Do not exceed the adult maximum dose for a given dosage form.

Children

Safety and efficacy have not been established; however, doses up to 8 mg/kg/day PO have been reported in pediatric patients. Do not exceed the adult maximum dose for a given dosage form.

Mechanism of Action: Verapamil inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes. It exerts its activity at the membrane surface of arterial smooth muscle cells and within conductile and contractile tissue in the myocardium. Serum calcium levels remain unchanged. Calcium channels in myocardial and vascular smooth muscle cell membranes are selective and allow a slow inward flow of calcium, which contributes to excitation-contraction coupling and electrical discharge of conduction cells (plateau phase of the action potential) in the heart and vasculature. Verapamil inhibits this influx, possibly by deforming the channel, or inhibiting ion-control gating mechanisms. Intracellularly, it also may interfere with the release of calcium from the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, resulting in dilation of the coronary and systemic arteries. These actions increase oxygen delivery to the myocardial tissue and decrease total peripheral resistance, systemic blood pressure, and afterload. This reduction in myocardial oxygen demand, cardiac workload, and vascular tone is believed to be responsible for the drug's beneficial effects in angina and its antihypertensive activities. Inhibition of calcium-mediated smooth muscle contraction is thought to also be the explanation of verapamil's action in the prevention and treatment of migraine. Verapamil exerts equipotent effects on calcium channels in SA and AV nodes, and on the peripheral vasculature, however, verapamil is less potent as a peripheral vasodilator than nifedipine and related dihydropyridine analogs.The electrophysiologic effects of verapamil make it a favorable agent for controlling and/or converting certain supraventricular arrhythmias. In the myocardium, membrane 'pores' are termed 'slow channels' if they are selective for calcium influx and 'fast channels' if they are selective for sodium influx. Nodal tissue (e.g., sinus node and AV node) possesses only calcium channels, which explains why verapamil is effective in treating arrhythmias dependent on nodal conduction. The inherent rhythm of nodal tissue is a function of the 'slow' inward flow of calcium through gated channels in the membrane. By slowing conduction through the AV node, verapamil affects the ventricular response rate in tachyarrhythmias that originate above the AV node. Verapamil is ineffective for treating ventricular arrhythmias since ectopic foci arising in this region of the myocardium are primarily dependent on alterations of sodium influx and are more readily suppressed with sodium influx-inhibiting drugs such as lidocaine and related analogs. Verapamil's inhibitory effects on conduction through the atrioventricular (AV) node is stronger than nifedipine's and similar to diltiazem's, which is reflected on the ECG as a prolonged PR interval. Second- or third-degree heart block is possible, especially if verapamil is given to patients receiving beta-blockers. Verapamil may decrease resting heart rate, particularly in patients with sick sinus syndrome. Clinical arrhythmias for which verapamil is effective include paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation/flutter, and other atrial-based tachycardias. Verapamil is more effective than digoxin for controlling ventricular rate in atrial fibrillation since the effects of verapamil on the AV node persist during sympathetic stimulation.In general, calcium-channel blockers exert favorable effects on LVH, and do not worsen insulin resistance or exert detrimental effects on the lipid profile. Finally, animal data has shown that CCBs including verapamil may interfere with the atherogenic process. Interestingly, human data have also shown a beneficial effect but clinical studies are limited. The mechanism of this effect may be related to prevention of accumulation of intracellular calcium in vascular smooth muscle cells.

Verapamil is administered orally and intravenously. The first-pass effect explains the large discrepancy between oral and parenteral doses. Verapamil and its active and primary metabolite norverapamil are well distributed throughout the body including the CNS. The drug is excreted into breast milk, reaching concentrations approaching those in maternal serum and posing potential problems for infants of nursing mothers. Verapamil also readily crosses the placenta. Approximately 90% is bound to plasma proteins. 
 
About 70% of a dose is excreted renally as metabolites. Although it is extensively metabolized in the liver to more than 12 metabolites, only norverapamil is detectable in the serum to any great extent. Norverapamil possesses approximately 20% of the pharmacologic activity of the parent compound. Norverapamil is a vasodilator, which lacks effects on the heart rate or P-R interval. The first-pass metabolism of verapamil is stereoselective, with preferential metabolism of the l-isomer. The elimination half-life averages 2—5 hours following single doses of the drug and increases with chronic dosing to 5—12 hours. The half-life of norverapamil ranges 4—10 hours.
 
Elimination of verapamil occurs primarily via renal pathways (70%), and 16% of the drug is eliminated in the feces within 5 days. Less than 5% of the drug is excreted in the urine as the parent compound.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP1A2, CYP2C8, CYP2C9, and CYP2C18, P-gp
In vitro metabolic studies indicate that verapamil is metabolized by CYP3A4, CYP1A2, CYP2C8, CYP2C9, and CYP2C18. Clinically significant interactions have been reported with inducers or inhibitors of CYP3A4; therefore, patients receiving verapamil should be monitored closely for drug interactions. In addition, verapamil inhibits CYP3A4 isoenzymes. It is also a substrate and inhibitor of P-glycoprotein.

Oral Route

Oral verapamil is a racemic mixture. Verapamil is marketed in several oral dosage forms that are not completely interchangeable. Following oral administration, verapamil undergoes extensive first-pass metabolism, resulting in a bioavailability of 20—35%. A nonlinear correlation exists between verapamil dose and plasma concentrations. Co-administration with grapefruit juice increases the bioavailability and plasma concentrations of verapamil. Food has a variable effect on oral verapamil, depending on the product formulation. Hepatic enzyme-inducing drugs (see Drug Interactions) or hepatic disease can significantly alter the bioavailability of oral verapamil.
 
The onset of action occurs within 1—2 hours following oral administration. Peak pharmacodynamic effects are observed in 1—2 hours and 5 hours for the immediate- and sustained-release oral preparations of the drug, respectively. In general, the duration of activity for verapamil averages 8—10 hours for standard-release preparations and 24 hours for extended-release formulations. The extended-release preparation Covera-HS delivers verapamil via a unique delivery system known as COER-24 (Controlled-Onset-Extended-Release). Instead of immediately releasing the drug, the COER-24 system delays release for 4—5 hours. Since Covera-HS is administered at bedtime, this system provides peak verapamil concentrations during the early waking hours when blood pressure and heart rate are rising at their highest rate.

Intravenous Route

The onset of action occurs within 1—5 minutes following intravenous dosing. The hemodynamic effects of verapamil after intravenous administration peak within 5 minutes and persist for 10—20 minutes, although they can be much longer in some patients. The effects of IV verapamil on AV nodal conduction occur within 1—2 minutes, peak within 10—15 minutes, and persist for 30—60 minutes, although prolonged effects on conduction have been reported.

Pregnancy

There are no adequate or well-controlled studies of verapamil in pregnant women. Use verapamil during pregnancy only if clearly needed. Verapamil crosses the placenta and can be detected in umbilical vein blood at delivery. Reproduction studies in rabbits and rats at doses up to 1.5 and 6 times the human oral daily dose, respectively, resulted in embryocidal and retarded fetal growth and development. No teratogenic results were observed.

Verapamil distributes into breast milk. Due to the potential for adverse effects in nursing infants, discontinue breast-feeding during verapamil administration. The neonatal myocardium is very sensitive to changes in calcium status, and the therapeutic dose for a neonate is unknown. However, given limited data that the nursing infant may not ingest a significant dosage via the milk (reported infant exposure ranged from less than 0.01% to 0.1% of the maternally ingested verapamil dose ) and due to the lack of reported adverse effects, previous American Academy of Pediatrics (AAP) recommendations considered verapamil usually compatible with breast-feeding.