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Medication Safety Issues
Sound-alike/look-alike issues:
Calan® may be confused with Colace®, diltiazem
Covera-HS® may be confused with Provera®
Isoptin® may be confused with Isopto® Tears
Verelan® may be confused with Virilon®, Voltaren®
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication (I.V. formulation) among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Significant differences exist between oral and I.V. dosing. Use caution when converting from one route of administration to another.
International issues:
Calan®: Brand name for vinpocetine in Japan
Pronunciation
(ver AP a mil)
U.S. Brand Names
Index Terms
Generic Available
Yes
Canadian Brand Names
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/Investigational
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. Although verapamil is not considered a major human teratogen, use during pregnancy may cause adverse fetal effects (bradycardia, heart block, hypotension). Use in pregnancy only when clearly needed and when the benefits outweigh the potential risk to the fetus. Verapamil crosses the placenta.
Lactation
Enters breast milk/not recommended
Breast-Feeding Considerations
Crosses into breast milk; manufacturer recommends to discontinue breast-feeding while taking verapamil. AAP considers compatible with breast-feeding.
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 pacemaker); second- or third-degree AV block (except in patients with a functioning artificial 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:
• 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:
• Beta-blockers: 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.
• Neuromuscular-blocking agents: May prolong recovery from nondepolarizing neuromuscular-blocking agents.
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%: Gastrointestinal: Gingival hyperplasia (?19%), constipation (7% to 12%)
1% to 10%:
Cardiovascular: Peripheral edema (2% to 4%), hypotension (3%), CHF/pulmonary edema (2%), AV block (1% to 2%), bradycardia (1%), flushing (1%)
Central nervous system: Headache (1% to 12%), fatigue (2% to 5%), dizziness (1% to 5%), lethargy (3%), pain (2%), myalgia (1%), paresthesia (1%), sleep disturbance (1%)
Dermatologic: Rash (1% to 2%)
Gastrointestinal: Dyspepsia (3%), nausea (1% to 3%), diarrhea (2%)
Hepatic: Liver enzymes increased (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, diarrhea, equilibrium disorders, erythema multiforme, exanthema, 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, 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), 2B6 (minor), 2C9 (minor), 2C18 (minor), 2E1 (minor), 3A4 (major); Inhibits CYP1A2 (weak), 2C9 (weak), 2D6 (weak), 3A4 (moderate)
Drug Interactions
Alcohol (Ethyl): Verapamil may increase the serum concentration of Alcohol (Ethyl). 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
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. Risk D: Consider therapy modification
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
BusPIRone: Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of BusPIRone. Risk D: Consider therapy modification
Calcium Channel Blockers (Dihydropyridine): Calcium Channel Blockers (Nondihydropyridine) may enhance the hypotensive effect of Calcium Channel Blockers (Dihydropyridine). Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Calcium Channel Blockers (Dihydropyridine). Exceptions: Clevidipine. Risk C: Monitor therapy
Calcium Salts: May diminish the therapeutic effect of Calcium Channel Blockers. Risk C: Monitor therapy
CarBAMazepine: Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of CarBAMazepine. CarBAMazepine may increase the metabolism of Calcium Channel Blockers (Nondihydropyridine). 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 decrease the metabolism of Cardiac Glycosides. Risk D: Consider therapy modification
Cimetidine: May decrease the metabolism of Calcium Channel Blockers. Risk D: Consider therapy modification
Clopidogrel: Calcium Channel Blockers may diminish the therapeutic effect of Clopidogrel. Risk C: Monitor therapy
Colchicine: P-Glycoprotein 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
Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine (adult) dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. Use extra caution in patients with impaired renal and/or hepatic function. Risk D: Consider therapy modification
Corticosteroids (Systemic): Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Corticosteroids (Systemic). Risk C: Monitor therapy
CycloSPORINE: Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of CycloSPORINE. CycloSPORINE may decrease the metabolism of Calcium Channel Blockers (Nondihydropyridine). 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
Dabigatran Etexilate: P-Glycoprotein Inhibitors may increase the serum concentration of Dabigatran Etexilate. Risk X: Avoid combination
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
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. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Dronedarone. Dronedarone may increase the serum concentration of Calcium Channel Blockers (Nondihydropyridine). Management: Use lower starting doses of the nondihydropyridine calcium channel blockers (i.e., verapamil, diltiazem), and only consider increasing calcium channel blocker dose after obtaining ECG-based evidence that the combination is being well-tolerated. Risk D: Consider therapy modification
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: Verapamil may increase the serum concentration of Everolimus. Everolimus may increase the serum concentration of Verapamil. Risk X: Avoid combination
Fexofenadine: Verapamil may increase the bioavailability of Fexofenadine. Risk C: Monitor therapy
Fluconazole: May decrease the metabolism of Calcium Channel Blockers. Risk C: Monitor therapy
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 (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
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: Avoid concurrent use of verapamil with lovastatin when possible. If used together, use lower lovastatin doses (max of 40 mg/day for adults). Risk D: Consider therapy modification
Macrolide Antibiotics: May decrease the metabolism of Calcium Channel Blockers. Exceptions: Azithromycin; Dirithromycin [Off Market]; 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 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 Inducers: May decrease the serum concentration of P-Glycoprotein 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 Inhibitors: May increase the serum concentration of P-Glycoprotein 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 Substrates: P-Glycoprotein Inhibitors may increase the serum concentration of P-Glycoprotein 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 decrease the metabolism of 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
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. Risk D: Consider therapy modification
QuiNIDine: Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of QuiNIDine. Risk D: Consider therapy modification
Quinupristin: May decrease the metabolism of Calcium Channel Blockers. Risk C: Monitor therapy
Ranolazine: Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Ranolazine. Risk X: Avoid combination
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. 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: P-Glycoprotein 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
Saxagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Saxagliptin. Risk C: Monitor therapy
Simvastatin: Verapamil may increase the serum concentration of Simvastatin. Management: Avoid concurrent use of verapamil with simvastatin when possible. If used together, use lower simvastatin doses (max of 20 mg/day for adults). Risk D: Consider therapy modification
Tacrolimus: Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Tacrolimus. Risk C: Monitor therapy
Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Risk X: Avoid combination
Topotecan: P-Glycoprotein Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid or limit ethanol (may increase ethanol levels).
Food: Grapefruit juice may increase the serum concentration of verapamil; use with caution and monitor for increased verapamil effects.
Herb/Nutraceutical: St John's wort may decrease levels. Avoid herbs with hypertensive properties (bayberry, blue cohosh, cayenne, ephedra, ginger, ginseng [American], kola, licorice); may diminish the antihypertensive effect of verapamil. Avoid herbs with hypotensive properties (black cohosh, California poppy, coleus, golden seal, hawthorn, mistletoe, periwinkle, quinine, shepherd's purse); may enhance the hypotensive effect of verapamil.
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: Alfentanil, amikacin, argatroban, ascorbic acid, atracurium, atropine, aztreonam, benztropine, bivalirudin, bumetanide, buprenorphine, butorphanol, calcium chloride, calcium gluconate, cefazolin, cefotaxime, cefotetan, cefoxitin, ceftizoxime, ceftriaxone, cefuroxime, chlorpromazine, cimetidine, ciprofloxacin, clarithromycin, clindamycin, clonidine, cyanocobalamin, cyclosporine, dexamethasone, dexmedetomidine, digoxin, diphenhydramine, dobutamine, dopamine, doxycycline, enalaprilat, ephedrine, epinephrine, epoetin alfa, eptifibatide, erythromycin, esmolol, famotidine, fenoldopam, fentanyl, fentanyl and droperidol, fluconazole, gentamicin, glycopyrrolate, heparin, hetastarch in lactate electrolyte injection, hydrocortisone, hydroxyzine, imipenem-cilastatin, inamrinone, insulin regular, isoproterenol, ketorolac, labetalol, lidocaine, linezolid, magnesium sulfate, mannitol, meperidine, methylprednisolone sodium succinate, metoclopramide, metoprolol, midazolam, milrinone, morphine, multivitamins, nalbuphine, naloxone, nesiritide, nitroglycerin, nitroprusside, norepinephrine, ondansetron, oxaliplatin, oxytocin, papaverine, penicillin G potassium, penicillin G sodium, pentamidine, pentazocine, phentolamine, phenylephrine, phytonadione, piperacillin, polymyxin B sulfate, potassium chloride, procainamide, prochlorperazine, promethazine, propranolol, protamine, pyridoxine, quinidine gluconate, ranitidine, succinylcholine, sufentanil, theophylline, thiamine, ticarcillin-clavulanate, tobramycin, urokinase, vancomycin, vasopressin. Incompatible: Albumin, aminophylline, amphotericin B (conventional), amphotericin B cholesteryl sulfate complex, ampicillin, ampicillin-sulbactam, azathioprine, chloramphenicol, dantrolene, diazepam, folic acid, furosemide, ganciclovir, indomethacin, lansoprazole, metronidazole, pantoprazole, pentobarbital, phenobarbital, phenytoin, sodium bicarbonate, trimethoprim/sulfamethoxazole. Variable (consult detailed reference): Haloperidol lactate, hydralazine, nafcillin, oxacillin, propofol
Compatibility in syringe: Compatible: Heparin, inamrinone, milrinone. Incompatible: Pantoprazole
Compatibility when admixed: Compatible: Amikacin, amiodarone, ascorbic acid, atropine, bivalirudin, calcium chloride, calcium gluconate, cefazolin, cefotaxime, cefoxitin, chloramphenicol, cimetidine, clindamycin, dexamethasone sodium phosphate, dextran, diazepam, digoxin, dopamine, epinephrine, erythromycin lactobionate, gentamicin, heparin, hydrocortisone sodium succinate, hydromorphone, inamrinone, insulin (regular), isoproterenol, lidocaine, magnesium sulfate, mannitol, meperidine, methyldopa, methylprednisolone sodium succinate, metoclopramide, milrinone, morphine, multivitamins, naloxone, nitroglycerin, norepinephrine, oxytocin, pancuronium, penicillin G potassium, penicillin G sodium, pentobarbital, phenobarbital, phentolamine, phenytoin, piperacillin, potassium chloride, potassium phosphate, procainamide, propranolol, protamine, quinidine gluconate, sodium bicarbonate, sodium nitroprusside, theophylline, tobramycin, vancomycin, vasopressin, vitamin B complex with C. Incompatible: Albumin, amphotericin B, trimethoprim/sulfamethoxazole. Variable (consult detailed reference): Aminophylline, ampicillin, dobutamine, furosemide, hydralazine, nafcillin, oxacillin.
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
Adults:
SVT (ACLS, 2005): 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 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 in 3-4 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
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; if inadequate response, may increase dose at weekly intervals to 300 mg once daily, then 400 mg once daily; maximum dose: 400 mg/day
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 dose of 100 mg/day at bedtime. The manufacturers of Calan®, Calan® SR, Covera-HS®, Isoptin® SR, and Verelan® recommend a 30% dose reduction 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.
Rate of infusion: Over 2 minutes
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
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: Take as directed. Do not alter dosage or discontinue therapy without consulting prescriber. Do not crush or chew sustained or extended release forms. Avoid grapefruit juice; avoid (or limit) alcohol and caffeine. You may experience dizziness or lightheadedness (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea or vomiting (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, fruit, or fiber may help); 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. Verapamil should be avoided in patients with left ventricular dysfunction, pulmonary congestion, or heart failure. 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.
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.
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
Assess other medications patient may be taking for effectiveness and interactions. I.V. requires use of infusion pump and continuous cardiac and hemodynamic monitoring. Assess results of laboratory tests, therapeutic effectiveness, and adverse reactions when beginning therapy, when titrating dosage, and periodically during long-term oral therapy. Assess knowledge/teach patient appropriate use (oral), interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Caplet, sustained release, as hydrochloride: 120 mg, 180 mg, 240 mg
Calan® SR: 120 mg
Calan® SR: 180 mg, 240 mg [scored]
Capsule, extended release, as hydrochloride: 120 mg, 180 mg, 240 mg
Capsule, extended release, controlled onset, as hydrochloride: 100 mg, 200 mg, 300 mg
Verelan® PM: 100 mg, 200 mg, 300 mg
Capsule, sustained release, 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, as hydrochloride: 40 mg, 80 mg, 120 mg
Calan®: 40 mg [DSC]
Calan®: 80 mg, 120 mg [scored]
Tablet, extended release, as hydrochloride: 120 mg, 180 mg, 240 mg
Tablet, extended release, controlled onset, as hydrochloride:
Covera-HS®: 180 mg, 240 mg
Tablet, sustained release, as hydrochloride: 120 mg, 180 mg, 240 mg
Isoptin® SR: 120 mg
Isoptin® SR: 180 mg, 240 mg [scored]
Pricing: U.S. (www.drugstore.com)
Capsule, 24-hour (Verapamil HCl CR)
100 mg (100): $149.98
180 mg (30): $26.99
200 mg (30): $69.99
300 mg (30): $99.93
360 mg (30): $62.99
Capsule, 24-hour (Verelan)
180 mg (30): $99.80
240 mg (30): $120.13
360 mg (30): $191.19
Capsule, 24-hour (Verelan PM)
100 mg (30): $100.79
200 mg (30): $127.19
300 mg (30): $175.18
Tablet, 24-hour (Covera-HS)
180 mg (30): $62.99
240 mg (30): $83.99
Tablet, controlled release (Calan SR)
120 mg (30): $62.99
180 mg (30): $73.49
240 mg (30): $83.96
Tablet, controlled release (Isoptin SR)
120 mg (30): $62.38
180 mg (30): $68.99
240 mg (30): $79.69
Tablet, controlled release (Verapamil HCl CR)
120 mg (30): $21.99
180 mg (30): $13.99
240 mg (30): $18.99
Tablets (Calan)
40 mg (90): $69.28
80 mg (30): $37.79
120 mg (90): $129.99
Tablets (Verapamil HCl)
80 mg (90): $16.99
120 mg (90): $16.99
Extemporaneously Prepared
To prepare a verapamil 50 mg/mL liquid, crush 75 verapamil hydrochloride 80 mg tablets into a fine powder. Add ~40 mL of either Ora-Sweet® and Ora-Plus® (1:1 preparation), or Ora-Sweet® SF and Ora-Plus® (1:1 preparation), or cherry syrup. Mix to a uniform paste. Continue to add the vehicle to bring the final volume to 120 mL. The preparation is stable for 60 days; shake well before using and protect from light.
Allen LV and Erickson III MA, “Stability of Labetalol Hydrochloride, Metoprolol Tartrate, Verapamil Hydrochloride, and Spironolactone With Hydrochlorothiazide in Extemporaneously Compounded Oral Liquids,” Am J Health Syst Pharm, 1996, 53:304-9.
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International Brand Names
Lexi-Comp.com
Last full review/revision November 2009
Content last modified November 2009
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