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  • CLASSES

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

    DEA CLASS

    Rx

    DESCRIPTION

    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.

    COMMON BRAND NAMES

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

    HOW SUPPLIED

    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

    DOSAGE & INDICATIONS

    For the treatment of ischemic heart disease including variant angina (Prinzmetal's angina), unstable angina, and chronic stable angina.
    Oral dosage (regular-release tablets)
    Adults

    Initially, 80 to 120 mg PO every 8 hours. May increase up to 480 mg/day PO, administered in 3 to 4 divided doses.

    Patients with hepatic disease or small stature

    Initially, 40 mg PO every 8 hours.

    Geriatric

    In general, lower initial doses (e.g., 40 mg PO every 8 hours) of verapamil may be warranted. Adjust dosage based on clinical response, up to the maximum of 480 mg/day PO.

    Oral dosage (Covera-HS extended-release tablets, controlled onset)
    Adults

    Initially, 180 mg PO once daily at bedtime. If needed, dosage may be titrated stepwise in the following manner: 240 mg/day, 360 mg/day, and then 480 mg/day, with all doses given PO once daily at bedtime. Available dosage strengths include 180 and 240 mg tablets. Up to 540 mg PO once daily has been studied.

    Geriatric

    See adult dosage. In general, use lower initial adult dosage (e.g., initially, 180 mg/day PO, given once daily at bedtime). Adjust dosage based on clinical response.

    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

    5 to 10 mg (0.075 to 0.15 mg/kg) IV over at least 2 minutes. If no adequate response is seen in 30 minutes, may administer an additional 10 mg (0.15 mg/kg) IV. An optimal interval for subsequent doses has not been determined and should be individualized for each patient. Clinical practice guidelines recommend 2.5 to 5 mg IV over 2 minutes. If no therapeutic response or adverse reaction is seen, may administer repeated doses of 5 to 10 mg every 15 to 30 minutes up to a total dose of 20 mg. Alternative dosing is 5 mg IV every 15 minutes, up to a total dose of 30 mg. A nondihydropyridine calcium channel blocker is suggested for PSVT if adenosine or vagal maneuvers fail to convert, if PSVT recurs after these therapies, or if these therapies disclose another SVT.

    Children and Adolescents

    The most commonly used initial dose is 0.1 mg/kg (up to 5 mg maximum single dose) given as an IV bolus over at least 2 minutes. However, doses of 0.2 to 0.3 mg/kg up to a maximum of 5 mg IV have also been suggested. If no response, dose may be repeated in 30 minutes, up to a maximum of 10 mg. A continuous infusion of 1 to 7 mcg/kg/minute IV following the initial loading bolus dose has also been reported.

    Infants

    In general, the use of verapamil in infants less than 1 year of age is not recommended and has been associated with refractory hypotension and cardiac arrest. However, initial doses of 0.1 to 0.2 mg/kg IV bolus, given over at least 2 minutes under continuous ECG monitoring has been suggested by the manufacturer. If no response, dose may be repeated in 30 minutes.

    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 the 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

    5 to 10 mg (0.075 to 0.15 mg/kg) IV over at least 2 minutes. If no adequate response is seen in 30 minutes, may administer an additional 10 mg (0.15 mg/kg) IV and then initiate a 0.005 mg/kg/minute continuous IV infusion. An optimal interval for subsequent doses has not been determined and should be individualized for each patient. Clinical practice guidelines recommend an intravenous nondihydropyridine calcium channel blocker to slow the ventricular heart rate in patients with paroxysmal, persistent, or permanent atrial fibrillation in the acute setting in patients without pre-excitation. A nondihydropyridine calcium channel blocker is the preferred agent in patients with chronic obstructive pulmonary disease. Avoid use in patients with left ventricular systolic dysfunction or decompensated heart failure.

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

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

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

    180 to 480 mg PO once daily. Clinical practice guidelines recommend a nondihydropyridine calcium channel blocker to slow the ventricular heart rate in patients with paroxysmal, persistent, or permanent atrial fibrillation. A nondihydropyridine calcium channel blocker is the preferred agent in patients with chronic obstructive pulmonary disease. Avoid use in patients with pre-excitation, left ventricular systolic dysfunction, or decompensated heart failure.

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

    Initially, 80 mg PO 3 times daily. May increase at weekly intervals as needed up to 480 mg/day PO, given in divided doses. However, dosages greater than 360 mg/day have shown no additional benefit in the management of hypertension.

    Patients with hepatic disease or small stature

    Initially, 40 mg PO 3 times daily.

    Geriatric

    In general, lower initial doses (e.g., 40 mg PO 3 times daily) of verapamil may be warranted. Adjust dosage based on clinical response.

    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 (Calan SR caplets or Isoptin SR extended-release 12 hour tablets)
    Adults

    Initially, 180 mg PO once daily in the morning. Dosage may be increased to 240 mg PO twice daily.

    Patients with hepatic disease or small stature

    Initially, 120 mg PO once daily in the morning.

    Geriatric

    See adult dosage. In general, use lower initial adult dosage (e.g., 120 mg PO once daily in the morning). Adjust dosage based on clinical response.

    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 (Verelan extended-release 24 hour capsules)
    Adults

    Initially, 240 mg PO once daily in the morning. May increase, stepwise, to 360 mg and then 480 mg once daily, if needed. Upward titration should be based on therapeutic efficacy and safety evaluated approximately 24 hours after dosing. The antihypertensive effect is evident within the first week of therapy. The usual daily dose observed in clinical trials was 240 mg.

    Patients with hepatic disease or small stature

    Initially, 120 mg PO once daily in the morning.

    Geriatric and small adults

    120 mg PO once daily in the morning. May increase, stepwise, to 180 mg, 240 mg, 360 mg, and then 480 mg once daily, if needed. Upward titration should be based on therapeutic efficacy and safety evaluated approximately 24 hours after dosing. The antihypertensive effect is evident within the first week of therapy. The usual daily dose observed in clinical trials was 240 mg.

    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 (Verelan PM extended-release capsules, controlled onset)
    Adults

    Initially, 200 mg PO once daily at bedtime. Dosage may be increased, by 100 mg/day, up to 400 mg/day PO.

    Patients with hepatic disease or small stature

    Initially, 100 mg PO once daily at bedtime.

    Geriatric

    See adult dosage. In general, use lower initial adult dosage (e.g., 100 mg PO once daily at bedtime). Adjust dosage based on clinical response.

    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 (Covera-HS extended-release tablets, controlled onset)
    Adults

    Initially, 180 mg PO once daily at bedtime. If needed, dosage may be titrated stepwise in the following manner: 240 mg/day, 360 mg/day, and then 480 mg/day, with all doses given PO once daily at bedtime. Available dosage strengths include 180 and 240 mg tablets. Up to 540 mg PO once daily has been studied in pre-marketing trials.

    Geriatric

    See adult dosage. In general, use lower initial adult dosage (e.g., 180 mg PO once daily at bedtime). Adjust dosage based on clinical response.

    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 relief of ongoing ischemia after acute myocardial infarction† in the absence of congestive heart failure, left ventricular dysfunction, or AV block, when beta-blockers are ineffective or contraindicated.
    Oral dosage (regular-release tablets)
    Adults

    Initially, 80 to 120 mg PO every 8 hours. May increase up to 480 mg/day, administered in 3 to 4 divided doses.

    Geriatric

    In general, lower initial doses (e.g., 40 mg PO every 8 hours) of verapamil may be warranted. Adjust dosage based on clinical response.

    †Indicates off-label use

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    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.

    ADMINISTRATION

    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.

    STORAGE

    Calan:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Calan SR:
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Covera-HS:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Isoptin:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store at room temperature (between 59 to 86 degrees F)
    - Store in carton until time of use
    Isoptin SR:
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Verelan:
    - Avoid excessive heat (above 104 degrees F)
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Verelan PM:
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Verapamil is contraindicated in patients with a known hypersensitivity to the drug or any of its excipients.

    Acute myocardial infarction, bradycardia, cardiogenic shock, heart failure, ventricular dysfunction

    Verapamil is contraindicated in patients with severe left ventricular dysfunction or cardiogenic shock. Intravenous verapamil is contraindicated in patients with severe congestive heart failure, unless secondary to a supraventricular tachyarrhythmia amenable to verapamil therapy, and in patients receiving intravenous beta adrenergic blocking drugs. Verapamil should be used cautiously in patients with other types of ventricular dysfunction, severe bradycardia, or congestive heart failure and/or in patients taking beta-adrenergic blocking agents because verapamil can precipitate or exacerbate heart failure in these patients, or cause excessive bradycardia or cardiac conduction abnormalities. Verapamil can be used for ventricular dysfunction due to a supraventricular tachyarrhythmia, which is amenable to verapamil therapy. It should be noted that verapamil's afterload-reducing effects can be beneficial in these patients and can counteract the drug's negative inotropic effects. If a patient is receiving digitalis, however, verapamil may further depress AV node conduction, possibly leading to varying degrees of conduction block (see Drug Interactions). Verapamil should not be used in patients with left ventricular dysfunction associated with acute myocardial infarction.

    Lown-Ganong-Levine syndrome, ventricular tachycardia, Wolff-Parkinson-White syndrome

    Verapamil is indicated for temporary control of heart rate in patients with atrial flutter or atrial fibrillation, in the absence of conduction over an accessory pathway. Verapamil is contraindicated in patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White syndrome and Lown-Ganong-Levine syndrome). In these patients, verapamil can paradoxically increase ventricular rate due to uninhibited antegrade conduction through the accessory bypass tract, resulting in potentially life-threatening conditions (ventricular fibrillation or cardiac arrest). Patients with these reentrant arrhythmias with a functioning artificial ventricular pacemaker may use still use a calcium channel blocker. Do not use intravenous verapamil in patients with ventricular tachycardia; proper differentiation between ventricular tachycardia and supraventricular tachycardia (SVT) is crucial when administering intravenous verapamil in the emergency room setting. Although verapamil may be effective in treating supraventricular tachycardia, administration to patients with ventricular tachycardia can cause ventricular fibrillation, severe hemodynamic deterioration, or death.

    Hypotension

    Verapamil decreases peripheral vascular resistance and may worsen hypotension. Verapamil is contraindicated in patients with a systolic blood pressures < 90 mmHg (i.e., severe hypotension). Verapamil should be used with caution in patients with mild to moderate hypotension. Blood pressure should be monitored in patients receiving verapamil. If moderate hypotension is a result of supraventricular tachycardia (SVT), verapamil may improve blood pressure by correcting the arrhythmia.

    AV block, sick sinus syndrome

    Verapamil is contraindicated in patients with sick sinus syndrome or advanced heart block (second- or third-degree AV block) who do not have a functioning artificial pacemaker in place. Use of verapamil in patients with these conditions may lead to severe hypotension, bradycardia, or asystole.

    Hepatic disease, renal disease, renal failure, renal impairment

    Patients with renal disease or hepatic disease (such as cirrhosis or hepatic failure) can experience a delayed clearance of verapamil and its metabolites; drug accumulation may increase the risk of adverse effects. About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Until further data are available, verapamil should be administered cautiously to patients with renal impairment or renal failure; these patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of excessive dosage. The half-life of verapamil may be increased up to 14—16 hours in patients with hepatic impairment; plasma clearance may be reduced by 30%. Dosage adjustments may be necessary in patients with hepatic impairment.

    Cardiomyopathy

    Verapamil should be used with great caution in patients with hypertrophic cardiomyopathy or idiopathic hypertrophic subaortic stenosis (IHSS). In 120 patients with hypertrophic cardiomyopathy, verapamil was administered at doses up to 720 mg/day PO. Three patients with severe left ventricular outflow obstruction and a history of left ventricular dysfunction died in pulmonary edema. Eight other patients had pulmonary edema and/or severe hypotension; most of these patients had abnormally high (over 20 mm Hg) pulmonary capillary wedge pressure and a marked left ventricular outflow obstruction. Three of the 8 patients received concomitant quinidine therapy (see Drug Interactions). Sinus bradycardia (11%), second-degree AV block (4%) and sinus arrest (2%) were also reported. Most adverse effects responded well to dose reduction and only rarely did verapamil have to be discontinued.

    Aortic stenosis

    Verapamil should not be used in patients with advanced aortic stenosis because it can worsen the abnormal pressure gradient associated with this condition.

    Myasthenia gravis, neuromuscular disease

    Verapamil should be used with caution in patients with neuromuscular disease. Verapamil has been reported to decrease neuromuscular transmission in patients with Duchenne's muscular dystrophy and causes a worsening of myasthenia gravis. Verapamil also may prolong recovery from neuromuscular blockade with neuromuscular blockers such as vecuronium (see Drug Interactions).

    Constipation, fecal impaction, gastroesophageal reflux disease (GERD), GI obstruction, hiatal hernia, ileus

    Verapamil frequently causes constipation. Verapamil should be used cautiously in patients with GI obstruction or ileus, fecal impaction, or pre-existing constipation. Calcium channel blockers should also be used cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Calcium-channel blockers act to relax the lower esophageal sphincter.

    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.

    Breast-feeding

    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.

    Children, infants, neonates

    Use of verapamil in neonates and infants should generally be avoided. Severe adverse hemodynamic effects have occurred rarely following IV administration of verapamil in neonates and infants; if verapamil is used in this population, extreme caution should be exercised. Children are also more likely than adults to be susceptible to the hemodynamic effects of verapamil. Safe and effective use of conventional and extended-release verapamil tablets in children younger than 18 years of age has not been established.

    Geriatric

    Geriatric patients may exhibit a delayed clearance of verapamil and its metabolites; the elimination half-life of verapamil may be prolonged in the elderly. In general, lower initial doses of verapamil may be warranted in geriatric patients. According to the Beers Criteria, non-dihydropyridine calcium channel blockers including verapamil are considered potentially inappropriate medications (PIMs) for use in geriatric patients with heart failure due to the potential for fluid retention and exacerbation of the condition; however, avoidance is only recommended in heart failure patients with a reduced ejection fraction. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, antihypertensive regimens should be individualized to achieve the desired outcome while minimizing adverse effects. Antihypertensives may cause dizziness, postural hypotension, fatigue, and there is an increased risk for falls. In addition, calcium channel blockers may cause peripheral edema and clinically significant constipation; some agents may cause generalized aching, headache, and muscle pain. There are many drug interactions that can potentiate the effects of antihypertensives. Some antihypertensives require a gradual taper to avoid adverse consequences caused by abrupt discontinuation. The OBRA guidelines also caution that antiarrhythmic agents can have serious adverse effects (e.g., impairment of mental function, appetite, behavior, heart function, or falls) in older individuals.

    ADVERSE REACTIONS

    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 (unspecified) / Early / 0-2.0
    flushing / Rapid / 0.6-0.8
    vertigo / Early / Incidence not known

    DRUG INTERACTIONS

    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) Oral calcium-channel blockers and beta-blockers like acebutolol 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.
    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; Butalbital: (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.
    Acetaminophen; 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) 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; Butalbital; 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. (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: (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; Magnesium Salicylate; Phenyltoloxamine: (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; Phenyltoloxamine; Salicylamide: (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; Phenyltoloxamine: (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; 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; 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: (Major) Monitor for respiratory depression and sedation if hydrocodone and verapamil are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as verapamil, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of oxycodone with verapamil may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of verapamil could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If verapamil is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and verapamil is a CYP3A4 inhibitor.
    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.
    Afatinib: (Major) If the concomitant use of verapamil and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of verapamil. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and verapamil is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir 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 ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. 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.
    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) Alfentanil may cause bradycardia. The risk of significant hypotension and/or bradycardia during therapy with alfentanil is increased in patients receiving calcium-channel blockers. In addition to additive hypotensive effects, calcium-channel blockers that are CYP3A4 inhibitors (e.g., diltiazem, nicardipine, and verapamil) can theoretically decrease hepatic metabolism of some opiates (CYP3A4 substrates), such as alfentanil. Diltiazem increases the half-life of alfentanil by 50% via inhibition of cytochrome P450 (CYP) 3A4 metabolism and may delay tracheal extubation after anesthesia. Reduced clearance of alfentanil should be considered when recovery from alfentanil infusions for anesthesia is evaluated in patients receiving concurrent diltiazem therapy.
    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; Amlodipine: (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. (Moderate) When verapamil (non-dihydropyridine calcium channel blocker) and amlodipine (dihydropyridine calcium-channel blocker) are given, hypotension and impaired cardiac performance may occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Also, amlodipine is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration of diltiazem (moderate CYP3A4 inhibitor) with amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. A similar pharmacokinetic effect may occur with verapamil. While concomitant use may be beneficial for carefully selected patients, caution is warranted; blood pressure, heart rate, and therapeutic response should be closely monitored.
    Aliskiren; Amlodipine; 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. (Moderate) When verapamil (non-dihydropyridine calcium channel blocker) and amlodipine (dihydropyridine calcium-channel blocker) are given, hypotension and impaired cardiac performance may occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Also, amlodipine is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration of diltiazem (moderate CYP3A4 inhibitor) with amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. A similar pharmacokinetic effect may occur with verapamil. While concomitant use may be beneficial for carefully selected patients, caution is warranted; blood pressure, heart rate, and therapeutic response should be closely monitored.
    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.
    Aliskiren; Valsartan: (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: (Moderate) Consider a reduced dose of alprazolam is concurrent use of verapamil is necessary. Coadministration of alprazolam, a CYP3A4 substrate, with verapamil, a moderate CYP3A4 inhibitor, may result in increased alprazolam exposure.
    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.
    Amiodarone: (Major) Based on the pharmacology of amiodarone and verapamil, additive effects on cardiac contractility and/or AV conduction are possible. Concurrent use of amiodarone and verapamil may result in bradycardia, AV block, and/or depressed cardiac output; monitor clinical response. In addition, amiodarone is both a substrate and inhibitor of CYP3A4 metabolism, and may potentially interact with verapamil via CYP3A4 metabolic pathways.
    Amitriptyline; Chlordiazepoxide: (Moderate) Verapamil is a CYP3A4 inhibitor and may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
    Amlodipine: (Moderate) When verapamil (non-dihydropyridine calcium channel blocker) and amlodipine (dihydropyridine calcium-channel blocker) are given, hypotension and impaired cardiac performance may occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Also, amlodipine is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration of diltiazem (moderate CYP3A4 inhibitor) with amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. A similar pharmacokinetic effect may occur with verapamil. While concomitant use may be beneficial for carefully selected patients, caution is warranted; blood pressure, heart rate, and therapeutic response should be closely monitored.
    Amlodipine; Atorvastatin: (Major) Verapamil may increase the serum concentrations of atorvastatin. Verapamil is a CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. (Moderate) When verapamil (non-dihydropyridine calcium channel blocker) and amlodipine (dihydropyridine calcium-channel blocker) are given, hypotension and impaired cardiac performance may occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Also, amlodipine is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration of diltiazem (moderate CYP3A4 inhibitor) with amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. A similar pharmacokinetic effect may occur with verapamil. While concomitant use may be beneficial for carefully selected patients, caution is warranted; blood pressure, heart rate, and therapeutic response should be closely monitored.
    Amlodipine; Benazepril: (Moderate) When verapamil (non-dihydropyridine calcium channel blocker) and amlodipine (dihydropyridine calcium-channel blocker) are given, hypotension and impaired cardiac performance may occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Also, amlodipine is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration of diltiazem (moderate CYP3A4 inhibitor) with amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. A similar pharmacokinetic effect may occur with verapamil. While concomitant use may be beneficial for carefully selected patients, caution is warranted; blood pressure, heart rate, and therapeutic response should be closely monitored.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) When verapamil (non-dihydropyridine calcium channel blocker) and amlodipine (dihydropyridine calcium-channel blocker) are given, hypotension and impaired cardiac performance may occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Also, amlodipine is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration of diltiazem (moderate CYP3A4 inhibitor) with amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. A similar pharmacokinetic effect may occur with verapamil. While concomitant use may be beneficial for carefully selected patients, caution is warranted; blood pressure, heart rate, and therapeutic response should be closely monitored.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) When verapamil (non-dihydropyridine calcium channel blocker) and amlodipine (dihydropyridine calcium-channel blocker) are given, hypotension and impaired cardiac performance may occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Also, amlodipine is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration of diltiazem (moderate CYP3A4 inhibitor) with amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. A similar pharmacokinetic effect may occur with verapamil. While concomitant use may be beneficial for carefully selected patients, caution is warranted; blood pressure, heart rate, and therapeutic response should be closely monitored.
    Amlodipine; Olmesartan: (Moderate) When verapamil (non-dihydropyridine calcium channel blocker) and amlodipine (dihydropyridine calcium-channel blocker) are given, hypotension and impaired cardiac performance may occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Also, amlodipine is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration of diltiazem (moderate CYP3A4 inhibitor) with amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. A similar pharmacokinetic effect may occur with verapamil. While concomitant use may be beneficial for carefully selected patients, caution is warranted; blood pressure, heart rate, and therapeutic response should be closely monitored.
    Amlodipine; Telmisartan: (Moderate) When verapamil (non-dihydropyridine calcium channel blocker) and amlodipine (dihydropyridine calcium-channel blocker) are given, hypotension and impaired cardiac performance may occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Also, amlodipine is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration of diltiazem (moderate CYP3A4 inhibitor) with amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. A similar pharmacokinetic effect may occur with verapamil. While concomitant use may be beneficial for carefully selected patients, caution is warranted; blood pressure, heart rate, and therapeutic response should be closely monitored.
    Amlodipine; Valsartan: (Moderate) When verapamil (non-dihydropyridine calcium channel blocker) and amlodipine (dihydropyridine calcium-channel blocker) are given, hypotension and impaired cardiac performance may occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Also, amlodipine is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration of diltiazem (moderate CYP3A4 inhibitor) with amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. A similar pharmacokinetic effect may occur with verapamil. While concomitant use may be beneficial for carefully selected patients, caution is warranted; blood pressure, heart rate, and therapeutic response should be closely monitored.
    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; Lansoprazole: (Major) Coadministration of clarithromycin and calcium-channel blockers should be avoided if possible, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. Most reports of acute kidney injury were with the combination of clarithromycin with calcium channel blockers metabolized by CYP3A4 and involved elderly patients at least 65 years of age. Clarithromycin may decrease the clearance of calcium-channel blockers (e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil) via inhibition of CYP3A4 metabolism. 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. If the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy, azithromycin is the preferred agent.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Coadministration of clarithromycin and calcium-channel blockers should be avoided if possible, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. Most reports of acute kidney injury were with the combination of clarithromycin with calcium channel blockers metabolized by CYP3A4 and involved elderly patients at least 65 years of age. Clarithromycin may decrease the clearance of calcium-channel blockers (e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil) via inhibition of CYP3A4 metabolism. 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. If the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy, azithromycin is the preferred agent.
    Amphetamine; Dextroamphetamine Salts: (Major) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as calcium-channel blockers. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Amprenavir: (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.
    Amyl Nitrite: (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.
    Apixaban: (Moderate) Use apixaban and verapamil together with caution in patients with significant renal dysfunction as risk of bleeding may be increased. Verapamil is a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor. Apixaban is a substrate of CYP3A4 and P-gp. In a pharmacokinetic study, apixaban Cmax and AUC increased by 31% and 40%, respectively, when given with another moderate CYP3A4 and P-gp inhibitor. Although serum concentrations of non-vitamin K oral anticoagulants have been increased in the presence of moderate inhibitors, one cohort study found that the risk of bleeding was not increased.
    Apomorphine: (Moderate) Patients receiving apomorphine may experience orthostatic hypotension, hypotension, and/or syncope. Extreme caution should be exercised if apomorphine is used concurrently with antihypertensive agents, or vasodilators such as nitrates.
    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) Increased aripiprazole blood levels are expected when aripiprazole is coadministered with inhibitors of CYP3A4, such as verapamil. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. In addition, because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 inhibitor.
    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; Butalbital; 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. (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; Dihydrocodeine: (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: (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) Concomitant use of oxycodone with verapamil may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of verapamil could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If verapamil is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and verapamil is a CYP3A4 inhibitor. (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; Pravastatin: (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 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) Oral calcium-channel blockers and beta-blockers like atenolol 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.
    Atenolol; Chlorthalidone: (Moderate) Oral calcium-channel blockers and beta-blockers like atenolol 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.
    Atorvastatin: (Major) Verapamil may increase the serum concentrations of atorvastatin. Verapamil is a CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate.
    Atorvastatin; Ezetimibe: (Major) Verapamil may increase the serum concentrations of atorvastatin. Verapamil is a CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate.
    Atropine; Hyoscyamine; Phenobarbital; 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.
    Avanafil: (Moderate) Avanafil is a primary substrate of CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Particular caution should be used when prescribing avanafil to patients receiving concomitant moderate CYP3A4 inhibitors including verapamil. For example, erythromycin increased avanafil Cmax and AUC equal to approximately 2-fold and 3-fold, respectively, and prolonged the half-life of avanafil to approximately 8 hours. Therefore, during coadministration, the maximum recommended dose of avanafil is 50 mg, not to exceed once every 24 hours.
    Axitinib: (Moderate) Use caution if coadministration of axitinib with verapamil is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1.Verapamil is a moderate CYP3A4 inhibitor as well as a weak inhibitor of CYP1A2. Verapamil increased exposure to simvastatin, another CYP3A4 substrate, by 2.5-fold. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (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. (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents.
    Azithromycin: (Moderate) Both verapamil and azithromycin are P-glycoprotein (PGP) inhibitors and substrates, so coadministration may lead to increased concentrations of either agent. Monitor patients for increased side effects if these drugs are given together.
    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.
    Belladonna Alkaloids; Ergotamine; 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. (Major) Because of the potential to cause coronary vasospasm , ergotamine theoretically could antagonize the therapeutic effects of calcium-channel blockers. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of ergotamine and increase the risk of ergot toxicity.
    Bendroflumethiazide; Nadolol: (Moderate) Oral calcium-channel blockers and beta-blockers like nadolol 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.
    Benzonatate: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Benzphetamine: (Major) Benzphetamine can increase both systolic and diastolic blood pressure and may counteract the activity of calcium-channel blockers. This represents a pharmacodynamic, and not a pharmacokinetic, interaction. Close monitoring of blood pressure, especially in patients who are taking antihypertensive agents, may be needed
    Betaxolol: (Moderate) Oral calcium-channel blockers and beta-blockers like betaxolol 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.
    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.
    Bisoprolol: (Moderate) Oral calcium-channel blockers and beta-blockers like bisoprolol 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.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Oral calcium-channel blockers and beta-blockers like bisoprolol 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.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering verapamil with boceprevir due to an increased potential for verapamil-related adverse events. If verapamil dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Predictions about the interaction can be made based on the metabolic pathways of verapamil and boceprevir. Both verapamil and boceprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4 and the drug efflux transporter, P-glycoprotein (PGP). When used in combination, the plasma concentrations of both medications may be elevated.
    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) Although no specific interactions have been documented, bosentan has vasodilatory effects and may contribute additive hypotensive effects when given with calcium-channel blockers. In addition, bosentan may induce hepatic metabolism of calcium-channel blockers metabolized by CYP3A4 isoenzymes. Diltiazem and verapamil have potential to inhibit CYP3A4 metabolism of bosentan. Bosentan has been shown to have no pharmacokinetic interactions with nimodipine.
    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.
    Bretylium: (Major) Concomitant use of bretylium with other antiarrhythmics, such as verapamil, can have additive, antagonistic, or synergistic electrophysiologic, pharmacodynamic, or toxic effects, including hypotension. Combined antiarrhythmic therapy may necessitate a reduction in antiarrhythmic drug dosages, to decrease the potential for toxicity.
    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: (Moderate) Monitor for decreased efficacy of verapamil if coadministration with brigatinib is necessary. Verapamil is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of verapamil may decrease.
    Brimonidine; Timolol: (Moderate) Oral calcium-channel blockers and beta-blockers like timolol 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.
    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. Additionally, bromocriptine should be used cautiously with other medications known to lower blood pressure such as verapamil. Monitoring of blood pressure should be considered, especially during the initial weeks of therapy or during dose increases. 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; Carbetapentane; 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; Guaifenesin; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and verapamil are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as verapamil, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and verapamil are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as verapamil, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Brompheniramine; Pseudoephedrine: (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 oral budesonide and verapamil due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; verapamil a weak CYP3A4 inhibitor and the active metabolite norverapamil is a moderate CYP3A4 inhibitor. In the presence of a strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
    Budesonide; Formoterol: (Moderate) Avoid coadministration of oral budesonide and verapamil due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; verapamil a weak CYP3A4 inhibitor and the active metabolite norverapamil is a moderate CYP3A4 inhibitor. In the presence of a strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
    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; 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.
    Buprenorphine: (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, such as buprenorphine.
    Buprenorphine; Naloxone: (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, such as buprenorphine.
    Buspirone: (Moderate) Coadministration of buspirone with verapamil substantially increases the plasma concentrations of buspirone by about three-fold. The mechanism is probably related to the inhibition of CYP3A4 by verapamil. Buspirone dose adjustment may be necessary and should be based on clinical assessment.
    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.
    Cabazitaxel: (Minor) Cabazitaxel is a CYP3A4 and P-glycoprotein (P-gp) substrate; verapamil is a moderate inhibitor of CYP3A4 as well as a P-gp inhibitor. A drug interaction study with repeated administration of aprepitant, another moderate CYP3A4 inhibitor, did not modify the exposure to cabazitaxel; however, formal drug interaction studies have not been conducted with P-gp inhibitors. Use caution when cabazitaxel is administered concomitantly with P-gp inhibitors.
    Cabergoline: (Major) Cabergoline has been associated with hypotension in some instances. Cabergoline should be used cautiously in those receiving antihypertensive agents. Also, Verapamil is an inhibitor of CYP3A4 isoenzymes and may decrease the metabolism of ergot alkaloids.
    Cabozantinib: (Moderate) Monitor for an increase in cabozantinib- and verapamil-related adverse events if concomitant use of cabozantinib and verapamil is necessary. Cabozantinib is primarily metabolized by CYP3A4 and verapamil is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and verapamil is a substrate of P-gp; plasma concentrations of verapamil may be increased. 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.
    Caffeine; Ergotamine: (Major) Because of the potential to cause coronary vasospasm , ergotamine theoretically could antagonize the therapeutic effects of calcium-channel blockers. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of ergotamine and increase the risk of ergot toxicity. (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.
    Carbamazepine: (Moderate) Carbamazepine and verapamil are metabolized by hepatic isozyme CYP3A4. Verapamil, a CYP3A4 inhibitor, may decrease the metabolism of carbamazepine. Consider dose reduction of carbamazepine if verapamil is added. In theory, carbamazepine can reduce verapamil oral bioavailability by accelerating its CYP3A4 metabolism.
    Carbetapentane; 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.
    Carbetapentane; 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.
    Carbetapentane; 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.
    Carbetapentane; 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.
    Carbetapentane; Phenylephrine; Pyrilamine: (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.
    Carbetapentane; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    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.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and verapamil are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as verapamil, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. (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.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and verapamil are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as verapamil, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Carbinoxamine; 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.
    Carbinoxamine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    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) Oral calcium-channel blockers and beta-blockers like carvedilol 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.
    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.
    Ceritinib: (Major) Avoid coadministration of ceritinib with verapamil due to the risk of additive bradycardia and increased verapamil exposure. If unavoidable, monitor heart rate and blood pressure regularly. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary. Ceritinib is a CYP3A4 inhibitor and verapamil is primarily metabolized by CYP3A4.
    Cerivastatin: (Severe) Verapamil may increase the serum concentrations of cerivastatin which is a CYP3A4 substrate. The interaction is presumed due to increased cerivastatin bioavailability via inhibition of CYP3A4 metabolism and reduction of first-pass metabolism.
    Cetirizine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Cevimeline: (Moderate) Cevimeline is metabolized by cytochrome P450 CYP3A4 and CYP2D6. In theory, concurrent administration of inhibitors of CYP3A4, such as verapamil, may lead to increased cevimeline plasma concentrations.
    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.
    Chlophedianol; 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.
    Chlordiazepoxide: (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; 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; Dihydrocodeine; 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; Dihydrocodeine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and verapamil are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as verapamil, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Chlorpheniramine; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and verapamil are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as verapamil, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and verapamil are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as verapamil, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. (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; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and verapamil are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as verapamil, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. (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) Complete AV block resulting in a nodal rhythm and sinus bradycardia resulting in hospitalization and pacemaker insertion have been reported during combination therapy of clonidine with diltiazem or verapamil. Monitor heart rate in patients receiving concomitant clonidine and verapamil which is known to affect sinus node function or AV nodal conduction.
    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) Cimetidine is a potent inhibitor of many of the isoenzymes of the hepatic CYP450 oxidative enzyme system. The metabolism of calcium-channel blockers like verapamil is inhibited by cimetidine.
    Cinacalcet: (Major) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Subjects being treated with 200 mg ketoconazole twice daily for 7 days received a single 90 mg cinacalcet dose on day 5 of therapy. The AUC and Cmax for cinacalcet increased 2.3 to 2.2 times, respectively, compared to 90 mg cinacalcet given alone. Therefore, caution is recommended when co-administering cinacalcet with other CYP3A4 enzyme inhibitors. These agents may include verapamil. If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor during cinacalcet therapy, the manufacturer recommends that dosage adjustment may be needed with close monitoring of PTH and serum calcium concentrations.
    Cisapride: (Severe) 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.
    Citalopram: (Moderate) During concurrent use of citalopram and verapamil, clinicians should monitor patients for a potential increase in side effects or toxicity. In theory, verapamil may inhibit the metabolism of citalopram through inhibition of CYP3A4. It should be noted that because citalopram is metabolized by multiple enzyme systems, inhibition of one pathway may not appreciably decrease citalopram clearance.
    Clarithromycin: (Major) Coadministration of clarithromycin and calcium-channel blockers should be avoided if possible, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. Most reports of acute kidney injury were with the combination of clarithromycin with calcium channel blockers metabolized by CYP3A4 and involved elderly patients at least 65 years of age. Clarithromycin may decrease the clearance of calcium-channel blockers (e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil) via inhibition of CYP3A4 metabolism. 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. If the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy, azithromycin is the preferred agent.
    Clindamycin: (Moderate) Concomitant use of clindamycin and verapamil may decrease clindamycin clearance and increase the risk of adverse reactions. Clindamycin is a CYP3A4 substrate; verapamil is a moderate inhibitor of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
    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) CYP3A4 inhibitors, such as verapamil, may reduce the metabolism of clonazepam and increase the potential for benzodiazepine toxicity.
    Clonidine: (Moderate) Complete AV block resulting in a nodal rhythm and sinus bradycardia resulting in hospitalization and pacemaker insertion have been reported during combination therapy of clonidine with diltiazem or verapamil. Monitor heart rate in patients receiving concomitant clonidine and verapamil which is known to affect sinus node function or AV nodal conduction.
    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 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.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of cobicistat (a 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 verapamil and tenofovir alafenamide may result in elevated tenofovir concentrations. Verapamil is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as verapamil. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Moderate) Coadministration of cobicistat (a 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).
    Cod Liver Oil: (Moderate) Fish oil supplements may cause mild, dose-dependent reductions in systolic or diastolic blood pressure in untreated hypertensive patients. Relatively high doses of fish oil are required to produce any blood pressure lowering effect. Additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents. (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.
    Codeine; Phenylephrine; Promethazine: (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.
    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 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 twice daily or 0.6 mg once daily or if the original dose is 0.6 mg once daily, decrease the dose to 0.3 mg once daily; for treatment of gout flares, give 1.2 mg as a single dose and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed 1.2 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: (Major) Avoid concomitant use of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and CYP3A4 substrate, and verapamil, a CYP3A4/P-gp substrate and CYP3A4 inhibitor. Coadministration may result in elevated concentrations of both conivaptan and verapamil. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as verapamil, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion.
    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: (Moderate) Monitor blood pressure and heart rate, as well as monitoring for an increase in crizotinib-related adverse reactions, if coadministration of verapamil with crizotinib is necessary. Both verapamil and crizotinib are CYP3A4 substrates and moderate CYP3A4 inhibitors.
    Cyclobenzaprine: (Major) Concurrent use of cyclobenzaprine with verapamil increases the possibility of developing serotonin syndrome. If these drugs must be used together, closely monitor the patient for signs and symptoms of serotonin syndrome. If such a reaction develops, immediately discontinue both drugs. Additionally, based on in vitro data the CYP3A4 enzyme and CYP1A2 enzyme are primarily responsible for the hepatic metabolism of cyclobenzaprine. Concentrations of cyclobenzaprine could increase if used in combination with CYP3A4 inhibitors such as verapamil. Observe the patient for enhanced side effects, such as CNS depression, if these drugs are coadministered.
    Cyclophosphamide: (Moderate) Use caution if cyclophosphamide is used concomitantly with verapamil, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide or a loss of blood pressure control. The clinical significance of this interaction is unknown. The absorption of verapamil can be reduced by the cyclophosphamide, vincristine, procarbazine, prednisone (COPP) chemotherapeutic drug regimen. Also, cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Verapamil is a moderate CYP3A4 inhibitor; conversion of cyclophosphamide to its active metabolites may be affected. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    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.
    Dalfopristin; Quinupristin: (Moderate) Dalfopristin; quinupristin is a major inhibitor of cytochrome P450 3A4 and may decrease the elimination of drugs metabolized by this enzyme including verapamil.
    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.
    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 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.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of verapamil with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of all 5 drugs. A verapamil dose reduction and close monitoring for adverse events (i.e., hypotension and edema) are advised during coadministration. If adverse events are observed, consider further verapamil dose reductions or an alternative to the calcium channel blocker. Both verapamil and ritonavir are substrates and inhibitors of CYP3A4; paritaprevir and dasabuvir (minor) are partially metabolized by CYP3A4. Verapamil also inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. (Moderate) Concurrent administration of verapamil with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of both drugs. A verapamil dose reduction and close monitoring for adverse events (i.e., hypotension and edema) are advised during coadministration. If adverse events are observed, consider further verapamil dose reductions or an alternative to the calcium channel blocker. Both verapamil and ritonavir are substrates and inhibitors of CYP3A4; paritaprevir and dasabuvir (minor) are partially metabolized by CYP3A4. Verapamil also inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. (Moderate) Concurrent administration of verapamil with ritonavir may result in elevated plasma concentrations of both drugs. Both verapamil and ritonavir are substrates and inhibitors of CYP3A4. Verapamil also inhibits the drug transporter P-glycoprotein (P-gp); ritonavir is a substrate of P-gp. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Dasatinib: (Moderate) Dasatinib inhibits CYP3A4. Therefore, caution is warranted when drugs that are metabolized by this enzyme, such as calcium-channel blockers, are administered concurrently with dasatinib as increased adverse reactions may occur. Diltiazem, nicardipine and verapamil may also inhibit the metabolism of dasatinib.
    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.
    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.
    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.
    Dexmethylphenidate: (Moderate) Dexmethylphenidate can reduce the hypotensive effect of antihypertensive agents, including calcium-channel blockers. Periodic evaluation of blood pressure is advisable during concurrent use of dexmethylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of dexmethylphenidate.
    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) Verapamil inhibits CYP3A4 metabolism, and therefore may inhibit the metabolism of oxidized benzodiazepines, including diazepam.
    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) Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively; serum concentrations of orally administered digoxin can increase by 50 to 75% during the first week of combination therapy, possibly resulting in digitalis toxicity. When verapamil is coadministered with intravenous (IV) digoxin, the digoxin AUC is increased by 24%. Measure serum digoxin concentrations before initiating verapamil. Reduce digoxin concentrations by decreasing the oral digoxin dose by approximately 30 to 50%, decreasing the IV digoxin dose by 15 to 30%, or by modifying the dosing frequency and continue monitoring. In addition to serum concentration information, the manufacturer of verapamil recommends adjusting the digoxin dosage according to clinical response, since digoxin serum concentrations may not accurately reflect response. Digoxin is a substrate for P-glycoprotein (P-gp). Verapamil inhibits P-gp, an energy-dependent cellular drug efflux pump. The inhibition of P-gp in the intestinal cell wall may lead to increased oral absorption of digoxin. It also has been shown that verapamil inhibits the secretion of digoxin by P-gp transporters in the kidney leading to decreased renal tubular elimination of digoxin and increased serum concentrations. Both drugs slow conduction through the AV node, and for this reason, these drugs are sometimes used together for ventricular control in patients with atrial fibrillation or flutter. In clinical trials in patients with atrial fibrillation or atrial flutter on both verapamil and digoxin, ventricular rates below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients. Additionally, the effect of verapamil on the pharmacokinetics of digoxin is magnified in patients with hepatic cirrhosis.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Dihydroergotamine: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and verapamil are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as verapamil, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. (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.
    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: (Severe) 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: (Severe) 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.
    Dorzolamide; Timolol: (Moderate) Oral calcium-channel blockers and beta-blockers like timolol 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.
    Doxazosin: (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.
    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: (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, THC: (Major) 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) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Diltiazem and verapamil are inhibitors of CYP3A4 and substrates of CYP3A and P-gp; nifedipine and amlodipine are substrates for CYP3A4. In clinical trials, the coadministration of dronedarone and calcium-channel blockers (diltiazem, verapamil, and nifedipine) resulted in an increase in exposure of calcium channel blockers by 1.4 to 1.5 fold and an increase in dronedarone exposure by 1.4 to1.7 fold. Furthermore, calcium channel blockers may potentiate the electrophysiologic effects of dronedarone (e.g., decreased AV and sinus node conduction). If coadministration of calcium channel blockers and dronedarone cannot be avoided, administer low doses of the calcium channel blocker and increase dosage only after ECG verification of tolerability.
    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: (Moderate) Dutasteride is metabolized by CYP3A4 enzyme. The clearance of dutasteride may be reduced when co-administered with the CYP3A4 inhibitor verapamil.
    Dutasteride; Tamsulosin: (Moderate) Dutasteride is metabolized by CYP3A4 enzyme. The clearance of dutasteride may be reduced when co-administered with the CYP3A4 inhibitor verapamil. (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.
    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: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as verapamil. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (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.
    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.
    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.
    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; 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 verapamil and tenofovir alafenamide may result in elevated tenofovir concentrations. Verapamil is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as verapamil. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (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.
    Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of verapamil and tenofovir alafenamide may result in elevated tenofovir concentrations. Verapamil is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as verapamil. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Enflurane: (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.
    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.
    Epirubicin: (Major) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant treatment with epirubicin and calcium-channel blockers. Individuals receiving these medications concurrently are at increased risk of developing heart failure.
    Eplerenone: (Major) Eplerenone is metabolized by the CYP3A4 pathway. Coadministration of eplerenone with verapamil has resulted in 2- to 2.9-fold increases in eplerenone AUC. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension. If these medications are given concurrently in post-myocardial infarction patients with heart failure, do not exceed an eplerenone dose of 25 mg PO once daily. If these medications are given concurrently, and eplerenone is used for hypertension, 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.
    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.
    Ergoloid Mesylates: (Major) 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, such as ergoloid mesylates.
    Ergonovine: (Major) Because of its potential to cause coronary vasospasm, ergonovine could theoretically antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. In addition, calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of ergonovine and increase the risk of ergot toxicity.
    Ergotamine: (Major) Because of the potential to cause coronary vasospasm , ergotamine theoretically could antagonize the therapeutic effects of calcium-channel blockers. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of ergotamine and increase the risk of ergot toxicity.
    Erlotinib: (Major) Avoid the coadministration of erlotinib with verapamil due to the risk of increased 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 moderate CYP3A4 inhibitor and a weak inhibitor of 1A2. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%; coadministration with verapamil may also increase erlotinib exposure.
    Erythromycin: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Erythromycin; Sulfisoxazole: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Esmolol: (Moderate) Oral calcium-channel blockers and beta-blockers like esmolol 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.
    Esomeprazole; 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.
    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 Cypionate; Medroxyprogesterone: (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: (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.
    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.
    Eszopiclone: (Moderate) Patients should be advised of the potential for next-day psychomotor and/or memory impairment during coadministration of eszopiclone and CYP3A4 inhibitors, such as verapamil. CYP3A4 is a primary metabolic pathway for eszopiclone, and increased systemic exposure to eszopiclone increases the risk of next-day impairment, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Ethanol: (Major) Verapamil has been found to significantly inhibit ethanol elimination resulting in elevated blood ethanol 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: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Desogestrel: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Etonogestrel: (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.
    Ethinyl Estradiol; Levonorgestrel: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    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; Norethindrone Acetate; Ferrous fumarate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norgestimate: (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.
    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.
    Etoposide, VP-16: (Major) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with verapamil. Verapamil is an inhibitor of CYP3A4 and P-glycoprotein (P-gp); etoposide, VP-16 is a CYP3A4 and P-gp substrate. Coadministration may cause accumulation of etoposide and decreased metabolism, resulting in increased etoposide concentrations.
    Etravirine: (Moderate) Etravirine is a CYP3A4 inducer/substrate, a CYP2C9 inhibitor/substrate, a CYP2C19 inhibitor/substrate, and a P-glycoprotein (P-gp) inhibitor. Verapamil is a CYP3A4 substrate/inhibitor, a CYP2C9 substrate, a CYP2C19 substrate, and P-gp substrate/inhibitor. Caution is warranted if these drugs are coadministered.
    Everolimus: (Major) A dose adjustment of everolimus is necessary when prescribed with verapamil due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. For patients with subependymal giant cell astrocytoma (SEGA) with TSC, the recommended starting dose of Afinitor/Afinitor Disperz is 2.5 mg/m2 once daily, rounded to the nearest tablet strength; subsequent dosing should be guided by therapeutic drug monitoring (TDM), with administration every other day if dose reduction is required for patients receiving the lowest available tablet strength. If verapamil is discontinued, increase everolimus to its original dose after a washout period of 2 to 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); verapamil is a moderate CYP3A4 and P-gp inhibitor. Coadministration with verapamil increased everolimus exposure by 3.5-fold.
    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 CYP3A4 metabolism and reduction of first-pass metabolism by verapamil.
    Famotidine; 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.
    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: (Major) 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, such as fentanyl. Also, the risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving calcium-channel blockers.
    Fesoterodine: (Moderate) Fesoterodine is rapidly hydrolyzed to its active metabolite, 5-hydroxymethyltolterodine, which is metabolized via hepatic CYP3A4. In theory, the CYP3A4 inhibitory effects of verapamil may result in an increase in plasma concentrations of 5-hydroxymethyltolterodine. The need for fesoterodine doses greater than 4 mg/day should be carefully evaluated prior to increasing the dose during concurrent use of mild to moderate 3A4 inhibitors.
    Fexofenadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    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) 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. (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: (Major) Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction. A study in healthy volunteers has shown that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization.
    Flibanserin: (Severe) 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) Fluconazole may decrease the clearance of calcium-channel blockers, including verapamil, via inhibition of CYP3A4 metabolism.
    Fluoxetine: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers, including verapamil, via inhibition of CYP3A4 metabolism.
    Fluoxetine; Olanzapine: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers, including verapamil, via inhibition of CYP3A4 metabolism. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    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.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with verapamil. Verapamil is an inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with verapamil, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Fosamprenavir: (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.
    Fospropofol: (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.
    Gefitinib: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and verapamil are used concomitantly; this also applies to trandolapril; verapamil. Gefitinib is metabolized significantly by CYP3A4 and verapamil is a moderate CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    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).
    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: (Major) Monitor for respiratory depression and sedation if hydrocodone and verapamil are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as verapamil, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and verapamil are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as verapamil, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    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.
    Guarana: (Minor) Caffeine is an active component of guarana. 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 guarana and beverages including coffee, teas, or colas in an effort to minimize caffeine-related side effects.
    Halofantrine: (Moderate) Drugs which significantly inhibit cytochrome CYP3A4, such as verapamil, may lead to an inhibition of halofantrine metabolism, placing the patient at risk for halofantrine cardiac toxicity. If concurrent use of halofantrine and a CYP3A4 inhibitor is warranted, it would be prudent to use caution and monitor the ECG periodically.
    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.
    Halothane: (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.
    Hawthorn, Crataegus laevigata: (Moderate) Hawthorn, Crataegus laevigata (also known as C. oxyacantha) may potentially interact with antihypertensive, heart failure, or arrhythmia medications such as the calcium-channel blockers. Following hawthorn administration, the cardiac action potential duration is increased and the refractory period is prolonged. Hawthorn may also lower peripheral vascular resistance. Patients with hypertension or heart failure should be advised to only use hawthorn with their prescribed medications after discussion with their prescriber. Patients who choose to take hawthorn should receive periodic blood pressure and heart rate monitoring.
    Homatropine; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and verapamil are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as verapamil, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydantoins: (Moderate) Hydantoin anticonvulsants (i.e., phenytoin, fosphenytoin, or ethotoin) may reduce verapamil serum concentrations via enzyme induction. Patients receiving verapamil should be monitored for loss of therapeutic effect if any hepatic enzyme inducing drugs are added to their treatment regimen.
    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.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Verapamil can inhibit the metabolism of some beta-blockers (e.g., metoprolol), and can cause additive effects on slowing of AV conduction and depression of blood pressure. Oral calcium-channel blockers and beta-blockers 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.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Verapamil can inhibit the metabolism of some beta-blockers (e.g., propranolol), and can cause additive effects on slowing of AV conduction and depression of blood pressure. Oral calcium-channel blockers and beta-blockers 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.
    Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and verapamil are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as verapamil, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Ibuprofen: (Major) Monitor for respiratory depression and sedation if hydrocodone and verapamil are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as verapamil, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. (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; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and verapamil are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as verapamil, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. (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.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Monitor for respiratory depression and sedation if hydrocodone and verapamil are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as verapamil, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and verapamil are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as verapamil, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and verapamil are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as verapamil, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Hydroxyprogesterone: (Minor) In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes. Theoretically, the metabolism of hydroxyprogesterone may also be inhibited by ketoconazole. It has not been determined whether other drugs which inhibit CYP3A4 hepatic enzymes, like verapamil, would have a similar effect.
    Ibrutinib: (Major) If coadministered with verapamil, initiate ibrutinib therapy at a reduced dose of 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease; monitor patients more frequently for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    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; Oxycodone: (Moderate) Concomitant use of oxycodone with verapamil may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of verapamil could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If verapamil is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and verapamil is a CYP3A4 inhibitor. (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.
    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.
    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.
    Irinotecan Liposomal: (Moderate) Use caution if irinotecan liposomal is coadministered with verapamil, a CYP3A4 inhibitor, due to increased risk of irinotecan-related toxicity. The metabolism of liposomal irinotecan has not been evaluated; however, coadministration of ketoconazole, a strong CYP3A4 and UGT1A1 inhibitor, with non-liposomal irinotecan HCl resulted in increased exposure to both irinotecan and its active metabolite, SN-38.
    Irinotecan: (Moderate) Verapamil is a moderate inhibitor of both CYP3A4 and P-glycoprotein (P-gp); irinotecan is a CYP3A4 and P-gp substrate. Coadministration may result in increased irinotecan exposure. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    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) Use caution when administering ivacaftor and verapamil concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and verapamil is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A, CYP2C9, and P-glycoprotein (P-gp); verapamil is partially metabolized by CYP3A, CYP2C9, and is a substrate of P-gp. Coadministration may increase verapamil exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ixabepilone: (Moderate) Ixabepilone is a CYP3A4 substrate, and concomitant use with mild or moderate CYP3A4 inhibitors such as verapamil has not been studied. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. Caution is recommended if ixabepilone is coadministered with verapamil; closely monitor patients for ixabepilone-related toxicities.
    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) Ketoconazole may decrease the clearance of calcium-channel blockers, such as verapamil, via inhibition of CYP3A4 metabolism.
    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: (Moderate) Oral calcium-channel blockers and beta-blockers like labetalol 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.
    Lacosamide: (Moderate) Lacosamide causes PR interval prolongation in some patients. Caution is advised during coadministration of lacosamide with other drugs that cause PR prolongation, such as calcium-channel blockers, since further PR prolongation is possible. If concurrent use is necessary, an ECG is recommended prior to initiation of lacosamide and after the drug is titrated to the maintenance dose. Patients receiving intravenous lacosamide should be closely monitored due to the potential for profound bradycardia and AV block during coadministration.
    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; 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.
    Lapatinib: (Major) Lapatinib is a CYP3A4 substrate, and concomitant use of verapamil may decrease the metabolism and increase the serum concentrations of lapatinib. Further, verapamil is also a P-glycoprotein inhibitor; concurrent administration of lapatinib with a P-glycoprotein inhibitor is likely to cause elevated serum lapatinib concentrations, and caution is recommended.
    Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Levomethadyl: (Major) Agents that inhibit hepatic cytochrome P450 3A4, such as verapamil, may decrease the metabolism of levomethadyl, increase levomethadyl levels, and may precipitate severe arrhythmias including torsade de pointes.
    Levomilnacipran: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of verapamil may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    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.
    Lisdexamfetamine: (Major) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Lithium: (Major) Lithium neurotoxicity has been reported during co-administration of lithium and verapamil or diltiazem, and is possible during concurrent use of other calcium-channel blockers with lithium. Symptoms of toxicity have included ataxia, tremors, nausea, vomiting, diarrhea, and tinnitus. The interaction between verapamil and lithium is variable and unpredictable. Both decreased lithium concentrations and lithium toxicity have been reported after the addition of verapamil. The possibility of a loss of lithium's therapeutic effect due to lower serum lithium concentrations may be offset somewhat by the fact that calcium-channel blocking agents share some neuropharmacological actions with lithium; limited data suggest that oral verapamil is effective in controlling an acute manic episode either as a single agent or in combination with lithium. Regarding diltiazem, although neurotoxicity was reported after the addition of diltiazem, other drugs were administered concomitantly. Worsened psychosis has been reported with the combination of diltiazem and lithium. Until more data are available, diltiazem and verapamil should be used cautiously in patients receiving lithium.
    Lomitapide: (Severe) 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.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP3A4 and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with verapamil, a CYP3A4 and P-gp inhibitor. If these drugs are used together, 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).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP3A4 and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with verapamil, a CYP3A4 and P-gp inhibitor. If these drugs are used together, 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).
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of verapamil with ritonavir may result in elevated plasma concentrations of both drugs. Both verapamil and ritonavir are substrates and inhibitors of CYP3A4. Verapamil also inhibits the drug transporter P-glycoprotein (P-gp); ritonavir is a substrate of P-gp. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    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.
    Lovastatin; Niacin: (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. (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.
    Lumacaftor; Ivacaftor: (Major) Use caution when administering ivacaftor and verapamil concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and verapamil is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A, CYP2C9, and P-glycoprotein (P-gp); verapamil is partially metabolized by CYP3A, CYP2C9, and is a substrate of P-gp. Coadministration may increase verapamil exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    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.
    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.
    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) Melatonin may impair the efficacy of some calcium-channel blockers, and caution is advised with concurrent use. In one 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 nifedipine (GITS formulation). Melatonin appeared to antagonize the antihypertensive effects of nifedipine. The mechanism of this interaction is unclear. It may be prudent to avoid melatonin use during calcium-channel blocker therapy.
    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.
    Mephobarbital: (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.
    Mestranol; Norethindrone: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients; monitor patients receiving concurrent therapy to confirm that the desired antihypertensive effect is being obtained.
    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: (Major) 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 or the selection of alternative therapeutic agents may be needed.
    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.
    Methylergonovine: (Major) Because of its potential to cause coronary vasospasm, methylergonovine could theoretically antagonize the therapeutic effects of calcium-channel blockers. In addition, calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of methylergonovine and increase the risk of ergot toxicity.
    Methylphenidate: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents, including calcium-channel blockers. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Methylprednisolone: (Moderate) Verapamil may decrease the metabolism of methylprednisolone via inhibition of the CYP3A4 isoenzyme, with the potential for increased corticosteroid effects. Verapamil is a moderate CYP3A4 inhibitor and methylprednisolone is a CYP3A4 substrate. Oral coadministration of another moderate CYP3A4 inhibitor and methylprednisolone has been shown to increase the AUC of methylprednisolone by about 2.6-fold and increase the half-life 1.9-fold.
    Methysergide: (Major) Because of the potential to cause coronary vasospasm , methysergide theoretically could antagonize the therapeutic effects of calcium-channel blockers. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, verapamil, may also reduce the hepatic metabolism of selected ergot alkaloids and increase the risk of ergot toxicity.
    Metoprolol: (Moderate) Verapamil can inhibit the metabolism of some beta-blockers (e.g., metoprolol), and can cause additive effects on slowing of AV conduction and depression of blood pressure. Oral calcium-channel blockers and beta-blockers 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.
    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, RU-486: (Moderate) Mifepristone inhibits CYP3A4 and coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP3A4 substrates, including many of the calcium-channel blockers. Drugs in which CYP3A is the primary route of metabolism should be used with caution if co-administered with mifepristone. The lowest possible dose and/or a decreased frequency of dosing must be used with therapeutic drug monitoring when possible. For calcium channel blockers, monitor blood pressure, heart rate, fluid retention and for shortness of breath as potential side effects. Avoiding calcium channel blockers by using other classes of antihypertensive agents that are not substrates for CYP3A4 may be appropriate in some patients requiring long-term administration of inhibitory drugs.
    Milnacipran: (Moderate) Milnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents may be diminished during concurrent use of milnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Milrinone: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.
    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.
    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) Oral calcium-channel blockers and beta-blockers like nadolol 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.
    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) Concomitant use of naloxegol with moderate CYP3A4 inhibitors should be avoided. Naloxegol is metabolized primarily by the CYP3A enzyme system. Moderate CYP3A4 inhibitors, such as verapamil, may increase the risk of naloxegol related adverse reactions. If concomitant use is unavoidable, decrease the dosage of naloxegol to 12.5 mg PO once daily and monitor for adverse reactions.
    Nanoparticle Albumin-Bound Paclitaxel: (Minor) Coadministration of verapamil and paclitaxel may result in a significant decrease in paclitaxel clearance and an increase in paclitaxel toxicity. Paclitaxel metabolism was reduced in an in vitro study with supratherapeutic verapamil concentrations. Further studies are needed to clarify the actual clinical significance of these results. Combining these drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    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; 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.
    Naproxen; Sumatriptan: (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.
    Nebivolol: (Moderate) Oral calcium-channel blockers and beta-blockers like nebivolol 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.
    Nebivolol; Valsartan: (Moderate) Oral calcium-channel blockers and beta-blockers like nebivolol 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.
    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 moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with antihypertensive agents.
    Neuromuscular blockers: (Moderate) Prolongation of the effects of neuromuscular blockers is possible when they are given in combination with calcium-channel blockers, particularly verapamil and diltiazem. It may be necessary to decrease the dosage of verapamil when it is administered to patients receiving non-depolarizing or polarizing neuromuscular blockers.
    Nevirapine: (Minor) Nevirapine is an inducer of the cytochrome P4503A enzyme. Concomitant administration of nevirapine with drugs that are extensively metabolized by this enzyme, including calcium-channel blockers may require dosage adjustments.
    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 CYP3A4 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) The concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), and verapamil, a substrate and inhibitor of CYP3A4 and a P-gp inhibitor, may result in increased nilotinib and/or verapamil levels. A nilotinib and/or verapamil dose reduction may be necessary if these drugs are used together. Monitor patients for nilotinib and/or verapamil toxicity (e.g., QT interval prolongation, hypotension) if these drugs are used together.
    Nintedanib: (Moderate) Verapamil is a moderate inhibitor of both P-glycoprotein (P-gp) and CYP3A4; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of verapamil and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    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.
    Octreotide: (Moderate) Dose adjustments in drugs such as beta-blockers and calcium-channel blockers which cause bradycardia and/or affect cardiac conduction may be necessary during octreotide therapy due to additive effects.
    Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Olaparib: (Major) Avoid coadministration of olaparib with verapamil and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and verapamil is a moderate CYP3A4 inhibitor.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of verapamil with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of both drugs. A verapamil dose reduction and close monitoring for adverse events (i.e., hypotension and edema) are advised during coadministration. If adverse events are observed, consider further verapamil dose reductions or an alternative to the calcium channel blocker. Both verapamil and ritonavir are substrates and inhibitors of CYP3A4; paritaprevir and dasabuvir (minor) are partially metabolized by CYP3A4. Verapamil also inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. (Moderate) Concurrent administration of verapamil with ritonavir may result in elevated plasma concentrations of both drugs. Both verapamil and ritonavir are substrates and inhibitors of CYP3A4. Verapamil also inhibits the drug transporter P-glycoprotein (P-gp); ritonavir is a substrate of P-gp. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    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.
    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: (Minor) Verapamil may decrease the plasma levels of MHD, the active metabolite of oxcarbazepine. The mechanism is not clear since it is contrary to the typical interactions seen with verapamil which are the result of its hepatic CYP3A4 inhibition.
    Oxybutynin: (Moderate) Oxybutynin is metabolized by CYP3A4. Inhibitors of the CYP3A4 enzyme, such as verapamil, may increase the serum concentrations of oxybutynin. The manufacturer recommends caution when oxybutynin is co-administered with CYP3A4 inhibitors.
    Oxycodone: (Moderate) Concomitant use of oxycodone with verapamil may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of verapamil could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If verapamil is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and verapamil is a CYP3A4 inhibitor.
    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.
    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.
    Paliperidone: (Moderate) Paliperidone may cause orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses of paliperidone may be necessary in patients receiving antihypertensive agents concomitantly.
    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.
    Penbutolol: (Moderate) Oral calcium-channel blockers and beta-blockers like penbutolol 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.
    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) When verapamil (non-dihydropyridine calcium channel blocker) and amlodipine (dihydropyridine calcium-channel blocker) are given, hypotension and impaired cardiac performance may occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Also, amlodipine is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration of diltiazem (moderate CYP3A4 inhibitor) with amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. A similar pharmacokinetic effect may occur with verapamil. While concomitant use may be beneficial for carefully selected patients, caution is warranted; blood pressure, heart rate, and therapeutic response should be closely monitored.
    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.
    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.
    Phenylephrine; Promethazine: (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: (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) Oral calcium-channel blockers and beta-blockers like pindolol 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.
    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.
    Posaconazole: (Moderate) Theoretically, posaconazole may inhibit the metabolism of many calcium-channel blockers via inhibition of CYP3A4. Use caution when coadministering posaconazole and any calcium-channel blocker.
    Pramipexole: (Moderate) Population pharmacokinetics suggest that coadministration of drugs secreted by the cationic transport system, such as verapamil, decreases the clearance of pramipexole by about 20 percent. An increase in pramipexole levels secondary to the use of verapamil, may result in an increased risk of somnolence, postural hypotension, or other clinically significant events.
    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.
    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.
    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.
    Procaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    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.
    Propafenone: (Major) Coadministration of propafenone with verapamil has the potential to cause additive decreases in AV conduction and/or negative inotropic effects. In addition, certain calcium-channel blockers, such as verapamil, inhibit CYP3A4, a partial pathway for propafenone metabolism.
    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: (Moderate) Verapamil can inhibit the metabolism of some beta-blockers (e.g., propranolol), and can cause additive effects on slowing of AV conduction and depression of blood pressure. Oral calcium-channel blockers and beta-blockers 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.
    Pseudoephedrine: (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, especially verapamil.
    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) Use caution if ribociclib is coadministered with verapamil, as the systemic exposure of both ribociclib and verapamil may increase resulting in increased adverse reactions (e.g., hypotension, neutropenia, QT prolongation). Ribociclib is extensively metabolized by CYP3A4 and is a moderate CYP3A4 inhibitor; Verapamil is both a CYP3A4 substrate and moderate inhibitor.
    Ribociclib; Letrozole: (Moderate) Use caution if ribociclib is coadministered with verapamil, as the systemic exposure of both ribociclib and verapamil may increase resulting in increased adverse reactions (e.g., hypotension, neutropenia, QT prolongation). Ribociclib is extensively metabolized by CYP3A4 and is a moderate CYP3A4 inhibitor; Verapamil is both a CYP3A4 substrate and moderate 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) Rifampin, a potent hepatic enzyme inducer, significantly reduces the oral bioavailability of verapamil, presumably by increasing first-pass metabolism. Rifapentine, an enzyme inducer, may have a similar effect. Patients receiving verapamil should be monitored for loss of therapeutic effect if any hepatic enzyme inducing drugs are added to their treatment regimen.
    Rifaximin: (Moderate) Rifaximin is a P-glycoprotein (P-gp) substrate. An in vitro study with the P-gp inhibitor verapamil showed that the efflux ratio of rifaximin was reduced more than 50%. Due to the potential for substantially increased systemic exposure to rifaximin, caution is advised when concurrent use of these drugs is required. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin. The clinical significance of this interaction is unknown.
    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.
    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.
    Ritonavir: (Moderate) Concurrent administration of verapamil with ritonavir may result in elevated plasma concentrations of both drugs. Both verapamil and ritonavir are substrates and inhibitors of CYP3A4. Verapamil also inhibits the drug transporter P-glycoprotein (P-gp); ritonavir is a substrate of P-gp. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Rivaroxaban: (Moderate) Avoid concomitant administration of rivaroxaban and verapamil in patients with CrCl 15 to 80 ml/min unless the potential benefit justifies the potential risk. Verapamil is a moderate CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Pharmacokinetic data from a trial with erythromycin indicate that concurrent use of rivaroxaban and drugs that are combined P-gp inhibitors and moderate CYP3A4 inhibitors in patients with renal impairment results in increased exposure to rivaroxaban compared to patients with normal renal function and no inhibitor use. Significant increases in rivaroxaban exposure may increase bleeding risk. However, while an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to < 50 ml/min [HR (95% CI): 1.05 (0.77, 1.42)].
    Rofecoxib: (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.
    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.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and verapamil as coadministration may result in increased systemic exposure of verapamil. Verapamil is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of verapamil.
    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.
    Selegiline: (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.
    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) A starting dose of 25 mg of sildenafil for erectile dysfunction should be considered in patients taking verapamil. Sildenafil is metabolized principally by the hepatic cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. Verapamil is a moderate CYP3A4 inhibitor. Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects.
    Silodosin: (Moderate) During clinical trials with silodosin, the incidence of dizziness and orthostatic hypotension was higher in patients receiving concomitant antihypertensive treatment. Thus, caution is advisable when silodosin is administered with antihypertensive agents. Silodosin is extensively metabolized by CYP450 3A4 and is a substrate for P-glycoprotein (P-gp). In theory, antihypertensive drugs that inhibit CYP3A4 such as diltiazem, verapamil, and nicardipine may cause significant increases in silodosin plasma concentrations. Verapamil may also interact with silodosin through its effects as a P-gp inhibitor.
    Simeprevir: (Moderate) Coadministration of orally administered verapamil with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased verapamil plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    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 CYP3A4 metabolism and reduction of first-pass metabolism by verapamil.
    Simvastatin; Sitagliptin: (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 CYP3A4 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.
    Sirolimus: (Moderate) Monitor sirolimus concentrations during co-use. Sirolimus or verapamil dose adjustments may be necessary. Verapamil is a substrate and inhibitor of CYP3A4 and P-gp. Sirolimus is a substrate for both CYP3A4 and P-gp. Coadministration of sirolimus oral solution 2 mg daily and verapamil 180 mg PO every 12 hours to 26 healthy volunteers significantly affected the bioavailability of sirolimus and verapamil. Sirolimus Cmax and AUC were increased by 2.3- and 2.2-fold, respectively; both the Cmax and AUC of the active (S)-enantiomer of verapamil also increased by 1.5-fold, with a decrease in the Tmax by 1.2 hours.
    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.
    Solifenacin: (Moderate) Solifenacin is significantly metabolized via the CYP3A4 pathway. Patients receiving CYP3A4 inhibitors, such as verapamil, should not receive solifenacin doses greater than 5 mg per day.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and verapamil or trandolapril; verapamil as sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Increased verapamil levels may also occur if these agents are taken together. Sonidegib is a CYP3A4 substrate and a CYP2C9 inhibitor in vitro and verapamil is a moderate CYP3A4 inhibitor and a CYP2C9 substrate. If concomitant use cannot be avoided, administer the moderate CYP3A inhibitor for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 1.8-fold in cancer patients who received 14 days of sonidegib 200 mg/day and a moderate CYP3A inhibitor. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 2.8-fold in cancer patients who received sonidegib 200 mg/day and a moderate CYP3A inhibitor for 4 months.
    Sotalol: (Moderate) Oral calcium-channel blockers and beta-blockers like sotalol 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.
    St. John's Wort, Hypericum perforatum: (Major) St. John's wort appears to induce the metabolism of the calcium-channel blockers, such as amlodipine, apparently by the induction of the CYP3A4 isoenzyme leading to reduced clinical efficacy. The metabolism of calcium channel blockers may also be increased.
    Streptogramins: (Moderate) Dalfopristin; quinupristin is a major inhibitor of cytochrome P450 3A4 and may decrease the elimination of drugs metabolized by this enzyme including verapamil.
    Sufentanil: (Moderate) The incidence and degree of bradycardia and hypotension during induction with sufentanil may be increased in patients receiving calcium-channel blockers. In addition to additive hypotensive effects, calcium-channel blockers that are CYP3A4 inhibitors (e.g., diltiazem, nicardipine, and verapamil) can theoretically decrease hepatic metabolism of some opiates (CYP3A4 substrates), such as sufentanil.
    Sulfinpyrazone: (Moderate) Sulfinpyrazone may increase the oral clearance of verapamil, resulting in a reduction in verapamil bioavailability from. The clinical significance of this finding is not known.
    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.
    Sunitinib: (Moderate) Concurrent administration of sunitinib with inhibitors of cytochrome P450 3A4 such as verapamil results in increased concentrations of sunitinib and its primary active metabolite. Whenever possible selection of an alternative concomitant medication with no or minimal enzyme inhibition potential is recommended. If an alternative therapy is not available, monitor patients closely for increased adverse reactions to sunitinib; a reduction in the dose of sunitinib may be required.
    Suvorexant: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors such as diltiazem or verapamil and a maximum recommended dose of 10 mg/day.
    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) Tadalafil is metabolized predominantly by the hepatic CYP3A4 isoenzyme. Inhibitors of CYP3A4 may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
    Tamoxifen: (Major) Concomitant use of verapamil and tamoxifen may result in increased verapamil exposure and decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for increased verapamil side effects and changes in the therapeutic efficacy of tamoxifen. Verapamil is a CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Verapamil may inhibit the metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Additionally, verapamil is a substrate of P-glycoprotein (P-gp); tamoxifen inhibits P-gp.
    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.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering verapamil with telaprevir due to an increased potential for verapamil-related adverse events. If verapamil dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Predictions about the interaction can be made based on the metabolic pathways of verapamil and telaprevir. Both verapamil and telaprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4 and the drug efflux transporter, P-glycoprotein (PGP). When used in combination, the plasma concentrations of both medications may be elevated.
    Telithromycin: (Moderate) Telithromycin, a ketolide antibiotic, can compete with verapamil for metabolism by CYP3A4. This can result in increased concentrations of verapamil if the two drugs are coadministered.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and verapamil is necessary, as the systemic exposure of verapamil may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of verapamil as well as an increase in adverse reactions related to telotristat ethyl. Consider increasing the dose of verapamil if necessary. Verapamil is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and verapamil is a P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with verapamil is necessary, and monitor for an increase in temsirolimus- or verapamil-related adverse reactions. Temsirolimus is a CYP3A4 and P-glycoprotein (P-gp) substrate, as well as a P-gp inhibitor in vitro; verapamil is a moderate inhibitor of CYP3A4 and a P-gp substrate/inhibitor; coadministration may increase plasma concentrations of sirolimus, the active metabolite of temsirolimus, and may also affect plasma concentrations of verapamil. The manufacturer of temsirolimus recommends a dose reduction if coadministered with a strong CYP3A4 inhibitor, but recommendations are not available for concomitant use of moderate inhibitors. Coadministration of temsirolimus with ketoconazole, a strong CYP3A4 inhibitor, had no significant effect on the AUC or Cmax of temsirolimus, but increased the sirolimus AUC and Cmax by 3.1-fold and 2.2-fold, respectively. Coadministration of sirolimus with verapamil increased the sirolimus AUC and Cmax by 2.3-fold and 2.2-fold, respectively; the AUC and Cmax of the active (S)-enantiomer of verapamil were also increased by 1.5-fold each, with a decrease in the Tmax by 1.2 hours.
    Tenofovir Alafenamide: (Moderate) Coadministration of verapamil and tenofovir alafenamide may result in elevated tenofovir concentrations. Verapamil is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir Alafenamide: (Moderate) Coadministration of verapamil and tenofovir alafenamide may result in elevated tenofovir concentrations. Verapamil is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir, PMPA: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as verapamil. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    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.
    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.
    Thiopental: (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.
    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) Oral calcium-channel blockers and beta-blockers like timolol 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.
    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) Tizanidine is primarily metabolized by CYP1A2. If possible, avoid the concurrent use of tizanidine with other CYP1A2 inhibitors. Verapamil is a weak CYP1A2 inhibitor. Concurrent use could lead to substantial increases in tizanidine blood concentrations. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    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) Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Verapamil is a moderate inhibitor of CYP3A4 and P-gp. Coadministration may cause a marked increase in tolvaptan concentrations and should be avoided.
    Topotecan: (Major) Avoid the concomitant use of verapamil, a P-glycoprotein (P-gp) inhibitor, with oral topotecan, a P-gp substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of verapamil and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant).
    Toremifene: (Minor) Coadministration of toremifene and verapamil may result in increased exposure to toremifene. Toremifene is a CYP3A4 substrate; verapamil inhibits CYP3A4.
    Trabectedin: (Moderate) Use caution if coadministration of trabectedin and verapamil is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Tranylcypromine: (Severe) The use of hypotensive agents and tranylcypromine is contraindicated by the manufacturer of tranylcypromine because the effects of hypotensive agents may be markedly potentiated.
    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.
    Tretinoin, ATRA: (Moderate) Verapamil may decrease the CYP450 metabolism of tretinoin, ATRA, potentially resulting in increased plasma concentrations of tretinoin, ATRA. Monitor for tretinoin toxicity while receiving concomitant therapy.
    Triazolam: (Moderate) Triazolam is metabolized by the cytochrome CYP3A4 enzyme and, as a result, is susceptible to drug interactions with drugs that can inhibit this enzyme, such as verapamil. Patients receiving triazolam should be monitored for signs of an exaggerated response these drugs are used concomitantly.
    Ulipristal: (Minor) Ulipristal is a substrate of CYP3A4 and verapamil is a CYP3A4 inhibitor. Concomitant use may increase the plasma concentration of ulipristal resulting in an increased risk for adverse events.
    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.
    Vandetanib: (Moderate) Use caution if coadministration of vandetanib with verapamil is necessary, due to a possible increase in verapamil-related adverse reactions. Verapamil is a substrate of P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of digoxin, another P-gp substrate, by 29% and 23%, respectively. Verapamil is also a moderate CYP3A4 inhibitor. While strong CYP3A4 inducers affect serum concentrations of both vandetanib and its active metabolite, N-desmethyl-vandetanib, verapamil is not expected to affect vandetanib exposure based on a crossover study (n = 14) in which no clinically significant interaction was noted between vandetanib and the strong CYP3A4 inhibitor itraconazole.
    Vardenafil: (Moderate) Vardenafil is metabolized by hepatic CYP3A4 and to a lesser extent CYP2C9. Inhibitors of CYP3A4, such as verapamil, can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects. Patients taking moderate CYP3A4 inhibitors, such as verapamil, may need to have their vardenafil dose decreased to 5 mg PO in a 24-hour period. Antihypertensives, when used with vardenafil, additionally have additive effects on blood pressure. In a clinical pharmacology study of patients with erectile dysfunction, single doses of vardenafil 20 mg caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing.
    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) Avoid the concomitant use of venetoclax and verapamil; venetoclax is a substrate of CYP3A4 and P-glycoprotein (P-gp) and verapamil is a CYP3A4 (moderate) and P-gp inhibitor. Consider alternative agents. If concomitant use of these drugs is required, reduce the venetoclax dosage by at least 50% (maximum dose of 200 mg/day). If verapamil is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were increased by 106% and 78%, respectively, when a P-gp inhibitor was co-administered in healthy subjects.
    Vinblastine: (Major) Verapamil is an inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1) and an inhibitor of cytochrome P450 (CYP) isoenzyme 3A4. Vinblastine is a P-glycoprotein and CYP3A4 substrate. Increased concentrations of vinblastine are likely if it is coadministered with verapamil; exercise caution.
    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: (Minor) Use caution with concurrent use of verapamil, a CYP3A4 and P-glycoprotein (P-gp) inhibitor, and vinorelbine, a CYP3A4 and P-gp substrate, as the metabolism of vinorelbine may be decreased. However, verapamil must be given in toxic doses to achieve this effect. Monitor patients for an earlier onset and/or an increased severity of adverse effects including neurotoxicity and myelosuppression.
    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) Voriconazole may inhibit the metabolism of many calcium-channel blockers via inhibition of CYP3A4. Although clinical data are lacking, it may be prudent to exercise caution when co-administering voriconazole and any calcium-channel blocker. Monitor heart rate and blood pressure.
    Yohimbine: (Moderate) Yohimbine (a selective central alpha 2-adrenoceptor antagonist) can increase blood pressure, and therefore can antagonize the therapeutic action of antihypertensive drugs in general. One study in patients with essential hypertension (n = 25) reported an average rise of 5 mmHg in mean blood pressure and a 66% increase in plasma norepinephrine (NE) concentrations following yohimbine administration (4 x 5.4 mg tablets PO). Use with particular caution in hypertensive patients with high or uncontrolled BP.
    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.
    Zileuton: (Minor) Caution should be used when CYP3A4 inhibitors, such as zileuton, are co-administered with verapamil, a CYP3A4 substrate and inhibitor.
    Ziprasidone: (Major) Verapamil may reduce ziprasidone metabolism via inhibition of CYP3A4 isoenzymes.
    Zolpidem: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of verapamil, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
    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.

    PREGNANCY AND LACTATION

    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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.