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Pronunciation
(ver AP a mil)
Generic Available (U.S.)
Yes: Excludes caplet (sustained release) and tablet (extended release, controlled onset)
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Oral: Treatment of hypertension; angina pectoris (vasospastic, chronic stable, unstable) (Calan®, Covera-HS®); supraventricular tachyarrhythmia (PSVT, atrial fibrillation/flutter [rate control])
I.V.: Supraventricular tachyarrhythmia (PSVT, atrial fibrillation/flutter [rate control])
Use: Unlabeled
Migraine; hypertrophic cardiomyopathy; bipolar disorder (manic manifestations)
Pregnancy Risk Factor
C
Pregnancy Considerations
In some animal reproduction studies verapamil has been shown to cause fetal harm; adverse maternal effects were also observed. Verapamil crosses the placenta. Although verapamil is not considered a major human teratogen, use during pregnancy may cause adverse fetal effects (bradycardia, heart block, hypotension).
Lactation
Enters breast milk/not recommended (AAP considers “compatible”; AAP 2001 update pending)
Breast-Feeding Considerations
Crosses into breast milk; manufacturer recommends to discontinue breast-feeding while taking verapamil.
Contraindications
Hypersensitivity to verapamil or any component of the formulation; severe left ventricular dysfunction; hypotension (systolic pressure <90 mm Hg) or cardiogenic shock; sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker); second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker); atrial flutter or fibrillation and an accessory bypass tract (Wolff-Parkinson-White [WPW] syndrome, Lown-Ganong-Levine syndrome)
I.V.: Additional contraindications include concurrent use of I.V. beta-blocking agents; ventricular tachycardia
Warnings/Precautions
Concerns related to adverse effects:
• Conduction abnormalities: Can cause first-degree AV block or sinus bradycardia; other conduction abnormalities are rare. Use is contraindicated in patients with sick sinus syndrome, second- or third-degree AV block (except in patients with a functioning artificial pacemaker), or an accessory bypass tract (eg, WPW syndrome).
• Hypotension/syncope: Symptomatic hypotension with or without syncope can rarely occur; blood pressure must be lowered at a rate appropriate for the patient's clinical condition.
• Increased hepatic enzymes: Rare increases in liver function tests have been observed.
Disease-related concerns:
• Arrhythmia: Considered contraindicated in patients with wide complex tachycardias unless known to be supraventricular in origin; severe hypotension likely to occur upon administration (ACLS, 2010).
• Attenuated neuromuscular transmission: Decreased neuromuscular transmission has been reported with verapamil; use with caution in patients with attenuated neuromuscular transmission (Duchenne's muscular dystrophy, myasthenia gravis); dosage reduction may be required.
• Heart failure: Avoid use in heart failure; can exacerbate condition. Use is contraindicated in severe left ventricular dysfunction.
• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage reduction may be required; monitor hemodynamics and possibly ECG if severe impairment.
• Hypertrophic cardiomyopathy (HCM) with outflow tract obstruction: Use with caution in patients with HCM with outflow tract obstruction (especially those with resting outflow obstruction and severe limiting symptoms); may be used in patients who cannot tolerate beta-blockade (Maron, 2003; Nishimura, 2004).
• Renal impairment: Use with caution; monitor hemodynamics and possibly ECG if severe impairment, particularly if concomitant hepatic impairment.
Concurrent drug therapy issues:
• Agents with SA/AV nodal-blocking properties: Use caution when using verapamil together with a beta-blocker. Administration of I.V. verapamil and an I.V. beta-blocker within a few hours of each other may result in asystole and should be avoided; simultaneous administration is contraindicated. Use with other agents known to reduce SA node function and/or AV nodal conduction (eg, digoxin) or reduce sympathetic outflow (eg, clonidine) may increase the risk of serious bradycardia.
• Digoxin: Verapamil significantly increases digoxin serum concentrations; adjust digoxin dose.
• Neuromuscular-blocking agents: May prolong recovery from nondepolarizing neuromuscular-blocking agents.
Special populations:
• Pediatrics: I.V. use for SVT for is not recommended in infants; use with caution in children as myocardial depression/hypotension may occur.
Dosage form specific issues:
• Extended-release delivery system (Covera-HS®): Use with caution in patients with severe GI narrowing. In patients with extremely short GI transit times (eg, <7 hours), dosage adjustment may be required; inadequate pharmacokinetic data.
Adverse Reactions
>10%:
Central nervous system: Headache (1% to 12%)
Gastrointestinal: Gingival hyperplasia (≤19%), constipation (7% to 12%)
1% to 10%:
Cardiovascular: Peripheral edema (1% to 4%), hypotension (3%), CHF/pulmonary edema (2%), AV block (1% to 2%), bradycardia (HR <50 bpm: 1%), flushing (1%)
Central nervous system: Fatigue (2% to 5%), dizziness (1% to 5%), lethargy (3%), pain (2%), sleep disturbance (1%)
Dermatologic: Rash (1% to 2%)
Gastrointestinal: Dyspepsia (3%), nausea (1% to 3%), diarrhea (2%)
Hepatic: Liver enzymes increased (1%)
Neuromuscular & skeletal: Myalgia (1%), paresthesia (1%)
Respiratory: Dyspnea (1%)
Miscellaneous: Flu-like syndrome (4%)
Oral: ≤1%: Abdominal discomfort, alopecia, angina, arthralgia, atrioventricular dissociation, blurred vision, bruising, cerebrovascular accident, chest pain, claudication, confusion, diaphoresis, ECG abnormal, equilibrium disorders, erythema multiforme, exanthema, extrapyramidal symptoms, galactorrhea/hyperprolactinemia, gastrointestinal distress, gynecomastia, hyperkeratosis, impotence, insomnia, macules, MI, muscle cramps, palpitation, psychosis, purpura (vasculitis), shakiness, somnolence, spotty menstruation, Stevens-Johnson syndrome, syncope, tinnitus, urination increased, urticaria, weakness, xerostomia
I.V.: <1% (Limited to important or life-threatening): Bronchi/laryngeal spasm, depression, diaphoresis, itching, muscle fatigue, respiratory failure, rotary nystagmus, seizure, sleepiness, urticaria, vertigo
Postmarketing and/or case reports: Asystole, eosinophilia, EPS, exfoliative dermatitis, GI obstruction, hair color change, paralytic ileus, Parkinsonian syndrome, pulseless electrical activity, shock, ventricular fibrillation
Metabolism/Transport Effects
Substrate of CYP1A2 (minor), CYP2B6 (minor), CYP2C9 (minor), CYP2E1 (minor), CYP3A4 (major), P-glycoprotein; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak), CYP2C9 (weak), CYP2D6 (weak), CYP3A4 (moderate), P-glycoprotein
Drug Interactions
Alcohol (Ethyl): Verapamil may increase the serum concentration of Alcohol (Ethyl). Risk C: Monitor therapy
Aliskiren: Verapamil may increase the serum concentration of Aliskiren. Risk C: Monitor therapy
Alpha1-Blockers: May enhance the hypotensive effect of Calcium Channel Blockers. Risk C: Monitor therapy
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Amiodarone: Calcium Channel Blockers (Nondihydropyridine) may enhance the bradycardic effect of Amiodarone. Sinus arrest has been reported. Risk D: Consider therapy modification
Anilidopiperidine Opioids: May enhance the bradycardic effect of Calcium Channel Blockers (Nondihydropyridine). Anilidopiperidine Opioids may enhance the hypotensive effect of Calcium Channel Blockers (Nondihydropyridine). Risk C: Monitor therapy
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Calcium Channel Blockers. Risk D: Consider therapy modification
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
ARIPiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole systemic exposure/affects with concomitant use of a moderate CYP3A4 inhibitor. Decrease aripiprazole dose to 25% of the usual dose in patients receiving both a CYP3A4 and a CYP2D6 inhibitor (regardless of potencies). Risk C: Monitor therapy
ARIPiprazole: CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult product labeling for specific recommendations. Risk C: Monitor therapy
Atorvastatin: May increase the serum concentration of Verapamil. Verapamil may increase the serum concentration of Atorvastatin. Management: Consider using lower atorvastatin doses when used together with verapamil. Risk D: Consider therapy modification
Barbiturates: May increase the metabolism of Calcium Channel Blockers. Management: Monitor for decreased therapeutic effects of calcium channel blockers with concomitant barbiturate therapy. Calcium channel blocker dose adjustments may be necessary. Nimodipine Canadian labeling contraindicates concomitant use with phenobarbital. Risk C: Monitor therapy
Benzodiazepines (metabolized by oxidation): Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification
Beta-Blockers: Calcium Channel Blockers (Nondihydropyridine) may enhance the hypotensive effect of Beta-Blockers. Bradycardia and signs of heart failure have also been reported. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Beta-Blockers. Exceptions: Levobunolol; Metipranolol. Risk C: Monitor therapy
Budesonide (Systemic, Oral Inhalation): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic, Oral Inhalation). Management: Consider reducing the oral budesonide dose when used together with a CYP3A4 inhibitor. This interaction is likely less severe with orally inhaled budesonide. Monitor patients closely for signs/symptoms of corticosteroid excess. Risk D: Consider therapy modification
BusPIRone: Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of BusPIRone. Risk D: Consider therapy modification
Calcium Channel Blockers (Dihydropyridine): May enhance the hypotensive effect of Calcium Channel Blockers (Nondihydropyridine). Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Calcium Channel Blockers (Dihydropyridine). Risk C: Monitor therapy
Calcium Salts: May diminish the therapeutic effect of Calcium Channel Blockers. Risk C: Monitor therapy
CarBAMazepine: May decrease the serum concentration of Calcium Channel Blockers (Nondihydropyridine). Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of CarBAMazepine. Management: Consider empiric reductions in carbamazepine dose with initiation of nondihydropyridine calcium channel blockers. Monitor for increased toxic effects of carbamazepine and reduced therapeutic effects of the calcium channel blocker. Risk D: Consider therapy modification
Cardiac Glycosides: Calcium Channel Blockers (Nondihydropyridine) may enhance the AV-blocking effect of Cardiac Glycosides. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy
Cimetidine: May increase the serum concentration of Calcium Channel Blockers. Management: Consider alternatives to cimetidine. If no suitable alternative exists, monitor for increased effects of calcium channel blockers following cimetidine initiation/dose increase, and decreased effects following cimetidine discontinuation/dose decrease. Risk D: Consider therapy modification
Clopidogrel: Calcium Channel Blockers may diminish the therapeutic effect of Clopidogrel. Risk C: Monitor therapy
Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Risk D: Consider therapy modification
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination
Corticosteroids (Systemic): Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Corticosteroids (Systemic). Risk C: Monitor therapy
CycloSPORINE: May decrease the metabolism of Calcium Channel Blockers (Nondihydropyridine). Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of CycloSPORINE. Risk D: Consider therapy modification
CycloSPORINE (Systemic): May decrease the metabolism of Calcium Channel Blockers (Nondihydropyridine). Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of CycloSPORINE (Systemic). Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
CYP3A4 Substrates: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Cyproterone: May decrease the serum concentration of CYP2E1 Substrates. Risk C: Monitor therapy
Dabigatran Etexilate: Verapamil may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Consider giving dabigatran 2 hrs before oral verapamil; other dose reductions may be needed. Specific recommendations vary by US vs Canadian labeling, renal function, and indication for dabigatran. Refer to full monograph or dabigatran labeling. Risk D: Consider therapy modification
Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Disopyramide: Verapamil may enhance the adverse/toxic effect of Disopyramide. Of particular concern is the potential for profound depression of myocardial contractility. Risk X: Avoid combination
Dofetilide: Verapamil may increase the serum concentration of Dofetilide. Risk X: Avoid combination
Dronedarone: Calcium Channel Blockers (Nondihydropyridine) may enhance the AV-blocking effect of Dronedarone. Other electrophysiologic effects of Dronedarone may also be increased. Dronedarone may increase the serum concentration of Calcium Channel Blockers (Nondihydropyridine). Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Dronedarone. Management: Use lower starting doses of the nondihydropyridine calcium channel blockers (i.e., verapamil, diltiazem), and only consider increasing calcium channel blocker dose after obtaining ECG-based evidence that the combination is being well-tolerated. Risk D: Consider therapy modification
Eletriptan: Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Eletriptan. Risk C: Monitor therapy
Eplerenone: Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Eplerenone. Risk C: Monitor therapy
Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Risk D: Consider therapy modification
Fexofenadine: Verapamil may increase the bioavailability of Fexofenadine. Risk C: Monitor therapy
Fingolimod: Verapamil may enhance the bradycardic effect of Fingolimod. Risk C: Monitor therapy
Flecainide: Verapamil may enhance the adverse/toxic effect of Flecainide. In particular, this combination may significantly impair myocardial contractility and AV nodal conduction. Risk C: Monitor therapy
Fluconazole: May decrease the metabolism of Calcium Channel Blockers. Risk C: Monitor therapy
Fosphenytoin: Calcium Channel Blockers may increase the serum concentration of Fosphenytoin. Management: Monitor for phenytoin toxicity with concomitant use of a calcium channel blocker (CCB) or decreased phenytoin effects with CCB discontinuation. Monitor for decreased CCB therapeutic effects. Nimodipine Canadian labeling contraindicates use with phenytoin. Risk D: Consider therapy modification
Grapefruit Juice: May increase the serum concentration of Verapamil. Risk C: Monitor therapy
Halofantrine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine. Risk D: Consider therapy modification
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy
Lithium: Calcium Channel Blockers (Nondihydropyridine) may enhance the neurotoxic effect of Lithium. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Lithium. Decreased or unaltered lithium concentrations have also been reported with this combination. Risk C: Monitor therapy
Lovastatin: Verapamil may increase the serum concentration of Lovastatin. Management: Initiate lovastatin at a maximum adult dose of 10 mg/day, and do not exceed 20 mg/day, in patients receiving verapamil. Monitor closely for signs of HMG-CoA reductase inhibitor toxicity (e.g., myositis, rhabdomyolysis). Risk D: Consider therapy modification
Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Risk D: Consider therapy modification
Macrolide Antibiotics: May decrease the metabolism of Calcium Channel Blockers. Management: Consider using a noninteracting macrolide. Monitor for increased therapeutic effects of calcium channel blockers if an interacting macrolide antibiotic is initiated, or decreased effects if a macrolide is discontinued. Exceptions: Azithromycin; Azithromycin (Systemic); Fidaxomicin; Spiramycin. Risk D: Consider therapy modification
Magnesium Salts: Calcium Channel Blockers may enhance the adverse/toxic effect of Magnesium Salts. Magnesium Salts may enhance the hypotensive effect of Calcium Channel Blockers. Risk C: Monitor therapy
MAO Inhibitors: May enhance the hypotensive effect of Antihypertensives. MAO Inhibitors may enhance the orthostatic hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Midodrine: Calcium Channel Blockers (Nondihydropyridine) may enhance the bradycardic effect of Midodrine. Risk C: Monitor therapy
Nafcillin: May increase the metabolism of Calcium Channel Blockers. Risk D: Consider therapy modification
Neuromuscular-Blocking Agents (Nondepolarizing): Calcium Channel Blockers may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Risk C: Monitor therapy
Nitroprusside: Calcium Channel Blockers may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Phenytoin: Calcium Channel Blockers may increase the serum concentration of Phenytoin. Management: Monitor for phenytoin toxicity with concomitant use of a calcium channel blocker (CCB) or decreased phenytoin effects with CCB discontinuation. Monitor for decreased CCB therapeutic effects. Nimodipine Canadian labeling contraindicates use with phenytoin. Risk D: Consider therapy modification
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Risk C: Monitor therapy
Pimozide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pimozide. Risk X: Avoid combination
Propafenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Propafenone. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Protease Inhibitors: May decrease the metabolism of Calcium Channel Blockers (Nondihydropyridine). Increased serum concentrations of the calcium channel blocker may increase risk of AV nodal blockade. Management: Avoid concurrent use when possible. If this combination is used, monitor for evidence of toxicity. The manufacturer of atazanavir recommends a 50% dose reduction for diltiazem be considered. Use of ritonavir with bepridil is contraindicated. Risk D: Consider therapy modification
Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Risk C: Monitor therapy
QuiNIDine: May enhance the hypotensive effect of Verapamil. Verapamil may increase the serum concentration of QuiNIDine. Risk C: Monitor therapy
Ranolazine: Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Ranolazine. Management: Limit ranolazine dose to a maximum of 500 mg twice daily when used with diltiazem or verapamil. Risk D: Consider therapy modification
Red Yeast Rice: Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Red Yeast Rice. Specifically, concentrations of lovastatin (and possibly other related compounds) may be increased. Risk C: Monitor therapy
Rifamycin Derivatives: May increase the metabolism of Calcium Channel Blockers. This primarily affects oral forms of calcium channel blockers. Management: The labeling for some U.S. and Canadian calcium channel blockers contraindicate use with rifampin however recommendations vary. Consult appropriate labeling. Risk D: Consider therapy modification
RisperiDONE: Verapamil may increase the serum concentration of RisperiDONE. Risk C: Monitor therapy
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Rivaroxaban: Verapamil may increase the serum concentration of Rivaroxaban. Risk C: Monitor therapy
Rivaroxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Rivaroxaban. Risk C: Monitor therapy
Salicylates: Calcium Channel Blockers (Nondihydropyridine) may enhance the anticoagulant effect of Salicylates. Risk C: Monitor therapy
Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Risk C: Monitor therapy
Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Risk X: Avoid combination
Simvastatin: Verapamil may increase the serum concentration of Simvastatin. Management: Avoid concurrent use of verapamil with simvastatin when possible. If used together, limit adult maximum simvastatin dose to 10 mg/day, and avoid Simcor (simvastatin/niacin) because fixed simvastatin doses in the product exceed this maximum. Risk D: Consider therapy modification
Tacrolimus: Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Tacrolimus. Risk C: Monitor therapy
Tacrolimus (Systemic): Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Tacrolimus (Systemic). Risk C: Monitor therapy
Tacrolimus (Topical): Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Tacrolimus (Topical). Risk C: Monitor therapy
Telithromycin: May enhance the hypotensive effect of Verapamil. Risk C: Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination
Vilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone. Risk C: Monitor therapy
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Zuclopenthixol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zuclopenthixol. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Ethanol may increase ethanol levels. Management: Avoid or limit ethanol.
Food: Grapefruit juice may increase the serum concentration of verapamil. Management: Avoid grapefruit juice or use with caution and monitor for effects. Calan® SR and Isoptin® SR products should be taken with food or milk; other formulations may be administered without regard to meals.
Herb/Nutraceutical: St John's wort may decrease levels of verapamil. Some herbal medications have hypertensive properties (eg, licorice); others may increase or decrease the antihypertensive effect of verapamil. Management: Avoid St John's wort, bayberry, blue cohosh, cayenne, ephedra, ginger, ginseng (American), kola, licorice, and yohimbe. Avoid black cohosh, California poppy, coleus, golden seal, hawthorn, mistletoe, periwinkle, quinine, and shepherd's purse.
Storage
Store at controlled room temperature of 15°C to 30°C (59°F to 86°F). Protect from light.
Compatibility
Stable in dextran 40 10% in NS, dextran 75 6% in NS, D5LR, D51/2NS, D5NS, D5W, LR, 1/2NS, NS. Note: Physically compatible in solutions of pH of 3-6, but may precipitate in solutions having a pH >6.
Y-site administration: Compatible: Argatroban, bivalirudin, ciprofloxacin, clonidine, dexmedetomidine, dobutamine, dopamine, eptifibatide, famotidine, fenoldopam, hetastarch in lactate electrolyte injection (Hextend®), hydralazine, inamrinone, linezolid, meperidine, milrinone, nesiritide, oxaliplatin, penicillin G potassium, piperacillin. Incompatible: Albumin, amphotericin B cholesteryl sulfate complex, ampicillin, nafcillin, oxacillin, pantoprazole, sodium bicarbonate. Variable (consult detailed reference): Aminophylline, propofol.
Compatibility in syringe: Compatible: Dimenhydrinate, heparin, inamrinone, milrinone. Incompatible: Pantoprazole.
Mechanism of Action
Inhibits calcium ion from entering the “slow channels” or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization; produces relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina; slows automaticity and conduction of AV node.
Pharmacodynamics/Kinetics
Onset of action: Peak effect: Oral: Immediate release: 1-2 hours; I.V.: 1-5 minutes
Duration: Oral: Immediate release tablets: 6-8 hours; I.V.: 10-20 minutes
Absorption: Well absorbed
Distribution: Vd: 3.89 L/kg (Storstein, 1984)
Protein binding: ~90%
Metabolism: Hepatic (extensive first-pass effect) via multiple CYP isoenzymes; primary metabolite is norverapamil (20% pharmacologic activity of verapamil)
Bioavailability: Oral: 20% to 35%
Half-life elimination: Infants: 4.4-6.9 hours; Adults: Single dose: 3-7 hours, Multiple doses: 4.5-12 hours; severe hepatic impairment: 14-16 hours
Time to peak, serum: Oral:
Immediate release: 1-2 hours
Extended release (Covera-HS®, Verelan PM®): ~11 hours, drug release delayed ~ 4-5 hours
Sustained release: 5.21 hours (Calan® SR, Isoptin® SR); 7-9 hours (Verelan®)
Excretion: Urine (70% as metabolites, 3% to 4% as unchanged drug); feces (16%)
Dosage
Children: Note: Verapamil is no longer included in the Pediatric Advanced Life Support (PALS) tachyarrhythmia algorithm.
Children: 1-15 years: SVT: I.V.: 0.1-0.3 mg/kg/dose over 2 minutes; maximum: 5 mg/dose, may repeat dose in 30 minutes if inadequate response; maximum for second dose: 10 mg
Adults:
SVT (ACLS, 2010): I.V.: 2.5-5 mg over 2 minutes; second dose of 5-10 mg (~0.15 mg/kg) may be given 15-30 minutes after the initial dose if patient tolerates, but does not respond to initial dose; maximum total dose: 20-30 mg
Angina: Oral: Note: When switching from immediate-release to extended/sustained release formulations, the total daily dose remains the same unless formulation strength does not allow for equal conversion.
Immediate release: Initial: 80-120 mg 3 times/day (elderly or small stature: 40 mg 3 times/day); Usual dose range (Gibbons, 2002): 80-160 mg 3 times/day
Extended release (Covera-HS®): Initial: 180 mg once daily at bedtime; if inadequate response, may increase dose at weekly intervals to 240 mg once daily, then 360 mg once daily, then 480 mg once daily; maximum dose: 480 mg/day
Chronic atrial fibrillation (rate-control), PSVT prophylaxis: Oral: Immediate release: 240-480 mg/day in 3-4 divided doses; Usual dose range (Fuster, 2006): 120-360 mg/day in divided doses
Hypertension: Oral: Note: When switching from immediate-release to extended/sustained release formulations, the total daily dose remains the same unless formulation strength does not allow for equal conversion.
Immediate release: 80 mg 3 times/day; usual dose range (JNC 7): 80-320 mg/day in 2 divided doses
Sustained release: Usual dose range (JNC 7): 120-480 mg/day in 1-2 divided doses; Note: There is no evidence of additional benefit with doses >360 mg/day.
Calan® SR, Isoptin® SR: Initial: 180 mg once daily in the morning (elderly or small stature: 120 mg/day); if inadequate response, may increase dose at weekly intervals to 240 mg once daily, then 180 mg twice daily (or 240 mg in the morning followed by 120 mg in the evening); maximum dose: 240 mg twice daily.
Verelan®: Initial: 180 mg once daily in the morning (elderly or small stature: 120 mg/day); if inadequate response, may increase dose at weekly intervals to 240 mg once daily, then 360 mg once daily, then 480 mg once daily; maximum dose: 480 mg/day
Extended release: Usual dose range (JNC 7): 120-360 mg once daily (once-daily dosing is recommended at bedtime)
Covera-HS®: Initial: 180 mg once daily at bedtime; if inadequate response, may increase dose at weekly intervals to 240 mg once daily, then 360 mg once daily, then 480 mg once daily; maximum dose: 480 mg/day
Verelan® PM: Initial: 200 mg once daily at bedtime (elderly or small stature: 100 mg/day); if inadequate response, may increase dose at weekly intervals to 300 mg once daily, then 400 mg once daily; maximum dose: 400 mg/day
Elderly: Hypertension: Oral: Note: When switching from immediate release to extended or sustained release formulations, the total daily dose remains the same unless formulation strength does not allow for equal conversion.
Manufacturer's recommendations:
Immediate release: Initial: 40 mg 3 times daily
Sustained release: Calan® SR, Isoptin® SR,Verelan®: Initial: 120 mg once daily in the morning
Extended release:
Covera-HS®: Initial: 180 mg once daily at bedtime
Verelan® PM: Initial: 100 mg once daily at bedtime
ACCF/AHA Expert Consensus recommendations: Consider lower initial doses and titrating to response (Aronow, 2011)
Dosing adjustment in renal impairment: Manufacturer recommends caution and additional ECG monitoring in patients with renal insufficiency. The manufacturer of Verelan PM® recommends an initial dose of 100 mg/day at bedtime. Note: A multiple dose study in adults suggests reduced renal clearance of verapamil and its metabolite (norverapamil) with advanced renal failure (Storstein, 1984). Additionally, several clinical papers report adverse effects of verapamil in patients with chronic renal failure receiving recommended doses of verapamil (Pritza, 1991; Váquez, 1996). In contrast, a number of single dose studies show no difference in verapamil (or norverapamil metabolite) disposition between chronic renal failure and control patients (Beyerlein, 1990; Hanyok, 1988; Mooy, 1985; Zachariah, 1991).
Dialysis: Not removed by hemodialysis (Mooy, 1985); supplemental dose is not necessary.
Dosing adjustment/comments in hepatic disease: In cirrhosis, reduce dose to 20% and 50% of normal for oral and intravenous administration, respectively, and monitor ECG (Somogyi, 1981). The manufacturer of Verelan PM® recommends an initial adult dose of 100 mg/day at bedtime. The manufacturers of Calan®, Calan® SR, Covera-HS®, Isoptin® SR, and Verelan® recommend giving 30% of the normal dose to patients with severe hepatic impairment.
Administration: Oral
Do not crush or chew sustained or extended release products.
Calan® SR, Isoptin® SR: Administer with food.
Verelan®, Verelan® PM: Capsules may be opened and the contents sprinkled on 1 tablespoonful of applesauce, then swallowed immediately without chewing. Do not subdivide contents of capsules.
Administration: I.V.
Administer over 2 minutes (over 3 minutes in older patients [ACLS, 2010])
Administration: I.V. Detail
pH: 4-6.5
Monitoring Parameters
Monitor blood pressure and heart rate; periodic liver function tests; ECG, especially with renal and/or hepatic impairment
Test Interactions
May interfere with urine detection of methadone (false-positive).
Dietary Considerations
Calan® SR and Isoptin® SR products may be taken with food or milk, other formulations may be administered without regard to meals; sprinkling contents of Verelan® or Verelan® PM capsule onto applesauce does not affect oral absorption.
Patient Education
Oral: Do not crush or chew sustained or extended release forms. Avoid grapefruit juice; avoid (or limit) alcohol and caffeine. Maintain good oral hygiene to avoid gum disease. You may experience dizziness or lightheadedness, nausea, vomiting, constipation, or diarrhea. Report chest pain, palpitations, or irregular heartbeat; unusual cough, respiratory difficulty, or swelling of extremities (feet/ankles); muscle tremors or weakness; confusion or acute lethargy; or skin irritation or rash. Pregnancy precaution: Inform prescriber if you are or intend to become pregnant.
Geriatric Considerations
Elderly may experience a greater hypotensive response. Constipation may be more of a problem in the elderly. Calcium channel blockers are no more effective in the elderly than other therapies; however, they do not cause significant CNS effects which is an advantage over some antihypertensive agents. Generic verapamil products which are bioequivalent in young adults may not be bioequivalent in the elderly; use generics cautiously.
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: I.V. administration, concomitant hypertrophic cardiomyopathy, sick sinus syndrome, or moderate-to-severe heart failure, and concomitant therapy with beta-blockers or digoxin can all increase incidence of adverse effects.
Cardiovascular Considerations
Hypertension: Verapamil is an effective antihypertensive alone or in combination with other agents. Therapy should be individualized with consideration given to the patient's concomitant diseases and compelling indications for therapy. Covera® HS and Verelan® PM use a chronotherapeutic approach to the treatment of hypertension and angina. The formulations provide peak drug effects in the early morning when the circadian distribution of cardiovascular events is also at a peak. The benefit of this approach to treatment has been evaluated. The CONVINCE trial randomized 16,602 patients with hypertension who had ≥1 additional risk factors for cardiovascular disease to either 180 mg of controlled onset extended-release (COER) verapamil (ie, Covera-HS®) or either 50 mg of atenolol or 12.5 mg of hydrochlorothiazide (other drugs could be added in a specified sequence if necessary). The primary endpoint of the trial was time to first occurrence of stroke, MI, or cardiovascular disease-related death. The use of COER did not demonstrate a difference in the primary endpoint compared to a regimen beginning with a beta-blocker or a diuretic.
Myocardial infarction: There is some evidence that verapamil may reduce mortality in nonfatal cardiac events, primarily myocardial infarction, in patients with history of myocardial infarction (DAVIT-II). It is important to note that this benefit was observed in patients with coronary artery disease without heart failure.
In the treatment of acute myocardial infarction, verapamil may be used to treat hypertension or ongoing ischemia if beta-blocker therapy is ineffective or contraindicated and in the absence of left ventricular dysfunction, pulmonary congestion, or AV block. In this setting, verapamil may be beneficial. Verapamil should be avoided in patients with left ventricular dysfunction or pulmonary congestion.
Tachyarrhythmias: Verapamil may be administered intravenously in the acute setting to attain ventricular rate control in patients with atrial fibrillation or flutter. Patients who respond, defined in general as at least a 20% decrease in ventricular response rate or attaining a rate <100 beats/minute, can be continued on oral therapy to maintain control. It is important to consider the potential drug interaction with digoxin, as these agents are both used in this setting. Avoid use in wide complex tachycardias unless known to be of supraventricular origin (ACLS, 2010).
Unstable Angina/Non-ST-Segment Elevation MI: In the treatment of unstable angina/non-ST-segment elevation MI, a nondihydropyridine calcium antagonist (diltiazem or verapamil) may be considered in patients with continuing or frequently recurring ischemia when beta-blockers are contraindicated (Class I). Oral long-acting calcium antagonists may also be considered in addition to beta-blockers and nitrates (Class IIa).
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Gingival hyperplasia. Calcium channel blockers (CCB) have been reported to cause gingival hyperplasia (GH). Verapamil-induced GH has appeared 11 months or more after subjects took daily doses of 240-360 mg. The severity of hyperplastic syndrome does not seem to be dose dependent. Gingivectomy is only successful if CCB therapy is discontinued. GH regresses markedly 1 week after CCB discontinuance with all symptoms resolving in 2 months. If a patient must continue CCB therapy, begin a program of professional cleaning and patient plaque control to minimize severity and growth rate of gingival tissue.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause drowsiness, dizziness, confusion, insomnia, psychotic symptoms, and extrapyramidal symptoms
Mental Health: Effects on Psychiatric Treatment
Barbiturates may decrease verapamil serum concentrations; verapamil may increase buspirone, carbamazepine, and midazolam serum concentrations; concurrent use with lithium may cause an increase or decrease in serum lithium concentrations; monitor; verapamil has been used to treat bipolar disorder, mania
Nursing: Physical Assessment/Monitoring
I.V. requires use of infusion pump and continuous cardiac and hemodynamic monitoring. Monitor gums for gingival hyperplasia. Encourage good oral hygiene. Refer to dentist if indicated.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Caplet, sustained release, oral, as hydrochloride:
Calan® SR: 120 mg
Calan® SR: 180 mg, 240 mg [scored]
Capsule, extended release, oral, as hydrochloride: 120 mg, 180 mg, 240 mg
Capsule, extended release, controlled onset, oral, as hydrochloride: 100 mg, 200 mg, 300 mg
Verelan® PM: 100 mg, 200 mg, 300 mg
Capsule, sustained release, oral, as hydrochloride: 120 mg, 180 mg, 240 mg, 360 mg
Verelan®: 120 mg, 180 mg, 240 mg, 360 mg
Injection, solution, as hydrochloride: 2.5 mg/mL (2 mL, 4 mL)
Tablet, oral, as hydrochloride: 40 mg, 80 mg, 120 mg
Calan®: 80 mg, 120 mg [scored]
Tablet, extended release, oral, as hydrochloride: 120 mg, 180 mg, 240 mg
Tablet, extended release, controlled onset, oral, as hydrochloride:
Covera-HS®: 180 mg, 240 mg
Tablet, sustained release, oral, as hydrochloride: 120 mg, 180 mg, 240 mg
Isoptin® SR: 120 mg
Isoptin® SR: 180 mg, 240 mg [DSC] [scored]
Pricing: U.S. (www.drugstore.com)
Capsule, 24-hour (Verapamil HCl CR)
100 mg (100): $189.98
120 mg (30): $29.99
180 mg (30): $26.99
200 mg (30): $72.99
240 mg (30): $25.99
300 mg (30): $105.99
360 mg (30): $61.99
Capsule, 24-hour (Verelan)
180 mg (30): $115.99
240 mg (30): $136.00
360 mg (30): $237.98
Capsule, 24-hour (Verelan PM)
100 mg (30): $123.99
200 mg (30): $139.98
300 mg (30): $207.99
Tablet, 24-hour (Covera-HS)
180 mg (30): $72.99
240 mg (30): $102.89
Tablet, controlled release (Calan SR)
120 mg (30): $75.59
180 mg (30): $94.48
240 mg (30): $108.99
Tablet, controlled release (Verapamil HCl CR)
120 mg (30): $22.99
180 mg (30): $18.99
240 mg (30): $21.99
Tablets (Calan)
40 mg (90): $69.29
80 mg (30): $46.86
120 mg (90): $156.94
Tablets (Verapamil HCl)
40 mg (90): $24.99
80 mg (90): $16.99
120 mg (90): $17.99
Extemporaneously Prepared
A 50 mg/mL oral suspension may be made with immediate release tablets and either a 1:1 mixture of Ora-Sweet® and Ora-Plus® or a 1:1 mixture of Ora-Sweet® SF and Ora-Plus® or cherry syrup. When using cherry syrup, dilute cherry syrup concentrate 1:4 with simple syrup, NF. Crush seventy-five verapamil hydrochloride 80 mg tablets in a mortar and reduce to a fine powder. Add small portions of chosen vehicle (40 mL total) and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label "shake well", "refrigerate", and "protect from light". Stable for 60 days refrigerated (preferred) or at room temperature (Allen, 1996).
A 50 mg/mL oral suspension may be made with immediate release tablets, a 1:1 preparation of methylcellulose 1% and simple syrup, and purified water. Crush twenty 80 mg verapamil tablets in a mortar and reduce to a fine powder. Add 3 mL purified water USP and mix to a uniform paste; mix while adding the vehicle incremental proportions to almost 32 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 32 mL. Label "shake well" and "refrigerate". Stable for 91 days refrigerated (preferred) or at room temperature (Nahata, 1997).
Allen LV Jr and Erickson MA 3rd, "Stability of Labetalol Hydrochloride, Metoprolol Tartrate, Verapamil Hydrochloride, and Spironolactone With Hydrochlorothiazide in Extemporaneously Compounded Oral Liquids," Am J Health Syst Pharm, 1996, 53(19):304-9.
Nahata MC, "Stability of Verapamil in an Extemporaneous Liquid Dosage Form," J Appl Ther Res, 1997,1(3):271-3.
References
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Antman EM, Anbe SC, Alpert JS, et al, “ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction - Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction),” Circulation, 2004, 110(5):588-636.
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Fraker TD, Fihn SD, Gibbons RJ, et al, “2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients With Chronic Stable Angina: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to Develop the Focused Update of the 2002 Guidelines for the Management of Patients With Chronic Stable Angina,” Circulation, 2007, 116(23):2762-72.
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Gibbons RJ, Abrams J, Chatterjee K, et al, “ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina - Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina),” J Am Coll Cardiol, 2003, 41(1):159-68.
Hanyok JJ, Chow MS, Kluger J, et al, “An Evaluation of the Pharmacokinetics, Pharmacodynamics, and Dialyzability of Verapamil in Chronic Hemodialysis Patients,” J Clin Pharmacol, 1988, 28(9):831-6.
Lichtenwalner MR, Mencken T, Tully R, et al, “False-Positive Immunochemical Screen for Methadone Attributable to the Metabolites of Verapamil,” Clin Chem, 1998, 44(5):1039-41.
Magee LA, Schick B, Donnenfeld AE, et al, “The Safety of Calcium Channel Blockers in Human Pregnancy: A Prospective, Multicenter Cohort Study,” Am J Obstet Gynecol, 1996, 174(3):823-8.
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Storstein L, Larsen A, Midtbo K, et al, “Pharmacokinetics of Calcium Channel Blockers in Patients With Renal Insufficiency and in Geriatric Patients,” Acta Med Scand Suppl, 1984, 681:25-30.
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International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
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