>10%: Gastrointestinal: Gingival hyperplasia (19%)

1% to 10%:

Cardiovascular: Bradycardia (1.4% oral, 1.2% I.V.); first-, second-, or third-degree AV block (1.2% oral, unknown I.V.); CHF (1.8% oral); hypotension (2.5% oral, 3% I.V.); peripheral edema (1.9% oral), symptomatic hypotension (1.5% I.V.); severe tachycardia (1% I.V.)

Central nervous system: Dizziness (3.3% oral, 1.2% I.V.), fatigue (1.7% oral), headache (2.2% oral, 1.2% I.V.)

Dermatologic: Rash (1.2% oral)

Gastrointestinal: Constipation (12% up to 42% in clinical trials), nausea (2.7% oral, 0.9% I.V.)

Respiratory: Dyspnea (1.4% oral)

Oral:<1% (Limited to important or life-threatening): Angina, atrioventricular dissociation, chest pain, claudication, MI, palpitation, purpura (vasculitis), syncope, diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia, ecchymosis, bruising, cerebrovascular accident, confusion, equilibrium disorders, insomnia, muscle cramps, paresthesia, psychotic symptoms, shakiness, somnolence, arthralgia, rash, exanthema, hair loss, hyperkeratosis, macules, diaphoresis, urticaria, Stevens-Johnson syndrome, erythema multiforme, blurred vision, tinnitus, gynecomastia, galactorrhea/hyperprolactinemia, increased urination, spotty menstruation, impotence, flushing, abdominal discomfort

I.V.:<1% (Limited to important or life-threatening): Bronchi/laryngeal spasm, itching, urticaria, emotional depression, rotary nystagmus, sleepiness, vertigo, muscle fatigue, diaphoresis, respiratory failure, myoclonus

Postmarketing and/or case reports: Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis, EPS, gynecomastia, eosinophilia, ventricular fibrillation, asystole, electrical mechanical dissociation, shock, myoclonus, Parkinsonian syndrome, GI obstruction, pulmonary edema, respiratory failure, hair color change

Noncardiac symptoms include confusion, stupor, nausea, vomiting, metabolic acidosis and hyperglycemia. Following initial gastric decontamination, if possible, repeated calcium administration may promptly reverse depressed cardiac contractility (but not sinus node depression or peripheral vasodilation). Large doses of calcium chloride (up to 1 g/hour for 24 hours) have been used in refractory cases. Glucagon, epinephrine, and amrinone may treat refractory hypotension. Glucagon and epinephrine also increase heart rate (outside the U.S., 4-aminopyridine may be available as an antidote). Dialysis and hemoperfusion are not effective in enhancing elimination although repeat-dose activated charcoal may serve as an adjunct with sustained-release preparations.

Alfentanil's plasma concentration is increased. Fentanyl and sufentanil may be affected similarly.

Amiodarone use may lead to bradycardia and decreased cardiac output. Monitor closely if using together.

Aspirin and concurrent verapamil use may increase bleeding times; monitor closely, especially if on other antiplatelet agents or anticoagulants.

Azole antifungals may inhibit the calcium channel blocker's metabolism; avoid this combination. Try an antifungal like terbinafine (if appropriate) or monitor closely for altered effect of the calcium channel blocker.

Barbiturates reduce the plasma concentration of verapamil. May require much higher dose of verapamil.

Beta-blockers may have increased pharmacodynamic interactions with verapamil (see Warnings/Precautions).

Buspirone's serum concentration may increase. May require dosage adjustment.

Calcium may reduce the calcium channel blocker's effects, particularly hypotension.

Carbamazepine's serum concentration is increased and toxicity may result; avoid this combination.

Cimetidine reduced verapamil's metabolism; consider an alternative H2 antagonist.

Cyclosporine's serum concentrations are increased by verapamil; avoid this combination. Use another calcium channel blocker or monitor cyclosporine trough levels and renal function closely.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of verapamil. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of verapamil. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, and quinidine.

CYP3A4 substrates: Verapamil may increase the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, cyclosporine, mirtazapine, nateglinide, nefazodone, sildenafil (and other PDE-5 inhibitors), tacrolimus, and venlafaxine. Selected benzodiazepines (midazolam and triazolam), cisapride, ergot alkaloids, selected HMG-CoA reductase inhibitors (lovastatin and simvastatin), and pimozide are generally contraindicated with strong CYP3A4 inhibitors.

Digoxin's serum concentration is increased; reduce digoxin's dose when adding verapamil.

Doxorubicin's clearance was reduced; monitor for altered doxorubicin's effect.

Erythromycin may increase verapamil's effects; monitor altered verapamil effect.

Ethanol's effects may be increased by verapamil; reduce ethanol consumption.

Flecainide may have additive negative effects on conduction and inotropy.

Grapefruit juice: Verapamil serum concentrations may be increased by grapefruit juice. Avoid concurrent use.

HMG-CoA reductase inhibitors (atorvastatin, cerivastatin, lovastatin, simvastatin): Serum concentration will likely be increased; consider pravastatin/fluvastatin or a dihydropyridine calcium channel blocker. If concurrent use with lovastatin is unavoidable, dose of lovastatin should not exceed 40 mg/day.

Lithium neurotoxicity may result when verapamil is added; monitor lithium levels.

Midazolam's plasma concentration is increased by verapamil; monitor for prolonged CNS depression.

Nafcillin decreases plasma concentration of verapamil; avoid this combination.

Nondepolarizing muscle relaxant: Neuromuscular blockade may be prolonged. Monitor closely.

Prazosin's serum concentration increases; monitor blood pressure.

Quinidine's serum concentration is increased; adjust quinidine's dose as necessary.

Rifampin increases the metabolism of calcium channel blockers; adjust the dose of the calcium channel blocker to maintain efficacy.

Sildenafil, tadalafil, vardenafil: Blood pressure-lowering effects may be additive; use caution.

Tacrolimus's serum concentrations are increased by verapamil; avoid the combination. Use another calcium channel blocker or monitor tacrolimus trough levels and renal function closely.

Theophylline's serum concentration may be increased by verapamil. Those at increased risk include children and cigarette smokers.

Ethanol: Avoid or limit ethanol (may increase ethanol levels).

Food: Grapefruit juice may increase the serum concentration of verapamil; avoid concurrent use.

Herb/Nutraceutical: St John's wort may decrease levels. Avoid dong quai if using for hypertension (has estrogenic activity). Avoid ephedra, yohimbe, ginseng (may worsen arrhythmia or hypertension). Avoid garlic (may have increased antihypertensive effect).

Y-site administration: Compatible: Ciprofloxacin, clarithromycin, dobutamine, dopamine, famotidine, gatifloxacin, hydralazine, inamrinone, linezolid, meperidine, milrinone, penicillin G potassium, piperacillin, ticarcillin. Incompatible: Albumin, amphotericin B cholesteryl sulfate complex, ampicillin, nafcillin, oxacillin, propofol, sodium bicarbonate

Compatibility in syringe: Compatible: Heparin, inamrinone, milrinone

Compatibility when admixed: Compatible: Amikacin, amiodarone, ascorbic acid, atropine, bretylium, calcium chloride, calcium gluconate, cefamandole, cefazolin, cefotaxime, cefoxitin, chloramphenicol, cimetidine, clindamycin, dexamethasone sodium phosphate, diazepam, digoxin, dopamine, epinephrine, erythromycin lactobionate, gentamicin, heparin, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydromorphone, insulin (regular), isoproterenol, lidocaine, magnesium sulfate, mannitol, meperidine, metaraminol, methyldopate, methylprednisolone sodium succinate, metoclopramide, morphine, multivitamins, naloxone, nitroglycerin, norepinephrine, oxytocin, pancuronium, penicillin G potassium, penicillin G sodium, pentobarbital, phenobarbital, phentolamine, phenytoin, piperacillin, potassium chloride, potassium phosphates, procainamide, propranolol, protamine, quinidine gluconate, sodium bicarbonate, sodium nitroprusside, theophylline, ticarcillin, tobramycin, tolazoline, vancomycin, vasopressin, vitamin B complex with C. Incompatible: Albumin, amphotericin B, floxacillin, hydralazine, trimethoprim/sulfamethoxazole. Variable (consult detailed reference): Aminophylline, ampicillin, dobutamine, furosemide, nafcillin, oxacillin

Onset of action: Peak effect: Oral: Immediate release: 2 hours; I.V.: 1-5 minutes

Duration: Oral: Immediate release tablets: 6-8 hours; I.V.: 10-20 minutes

Protein binding: 90%

Metabolism: Hepatic via multiple CYP isoenzymes; extensive first-pass effect

Bioavailability: Oral: 20% to 30%

Half-life elimination: Infants: 4.4-6.9 hours; Adults: Single dose: 2-8 hours, Multiple doses: Up to 12 hours; prolonged with hepatic cirrhosis

Excretion: Urine (70%, 3% to 4% as unchanged drug); feces (16%)

Children: SVT:

I.V.:

<1 year: 0.1-0.2 mg/kg over 2 minutes; repeat every 30 minutes as needed

1-15 years: 0.1-0.3 mg/kg over 2 minutes; maximum: 5 mg/dose, may repeat dose in 15 minutes if adequate response not achieved; maximum for second dose: 10 mg/dose

Oral (dose not well established):

1-5 years: 4-8 mg/kg/day in 3 divided doses or 40-80 mg every 8 hours

>5 years: 80 mg every 6-8 hours

Adults:

SVT: 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: Initial dose: 80-120 mg 3 times/day (elderly or small stature: 40 mg 3 times/day); range: 240-480 mg/day in 3-4 divided doses

Hypertension: Oral:

Immediate release: 80 mg 3 times/day; usual dose range (JNC 7): 80-320 mg/day in 2 divided doses

Sustained release: 240 mg/day; usual dose range (JNC 7): 120-360 mg/day in 1-2 divided doses; 120 mg/day in the elderly or small patients (no evidence of additional benefit in doses >360 mg/day).

Extended release:

Covera-HS®: Usual dose range (JNC 7): 120-360 mg once daily (once-daily dosing is recommended at bedtime)

Verelan® PM: Usual dose range: 200-400 mg once daily at bedtime

Dosing adjustment in renal impairment: Clcr<10 mL/minute: Administer at 50% to 75% of normal dose.

Dialysis: Not dialyzable (0% to 5%) via hemo- or peritoneal dialysis; supplemental dose is not necessary.

Dosing adjustment/comments in hepatic disease: Reduce dose in cirrhosis, reduce dose to 20% to 50% of normal and monitor ECG.

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 without chewing.

I.V.: Rate of infusion: Over 2 minutes.

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.

Verapamil may be administered intravenously in the acute setting to attain ventricular rate control in patients with atrial fibrillation or flutter. Patients that 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.

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).

Caplet, sustained release (Calan® SR): 120 mg, 180 mg, 240 mg

Capsule, extended release: 120 mg, 180 mg, 240 mg

Verelan® PM: 100 mg, 200 mg, 300 mg

Capsule, sustained release, as hydrochloride (Verelan®): 120 mg, 180 mg, 240 mg, 360 mg

Injection, solution, as hydrochloride: 2.5 mg/mL (2 mL, 4 mL)

Tablet, as hydrochloride (Calan®): 40 mg, 80 mg, 120 mg

Tablet, extended release: 120 mg, 180 mg, 240 mg

Covera HS®: 180 mg, 240 mg

Tablet, sustained release, as hydrochloride (Isoptin® SR): 120 mg, 180 mg, 240 mg

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