Yes

Antiarrhythmic Agent, Class IV; Calcium Channel Blocker

Orally for treatment of angina pectoris (vasospastic, chronic stable, unstable) and hypertension; I.V. for supraventricular tachyarrhythmias (PSVT, atrial fibrillation, atrial flutter)

C

Clinical effects on the fetus: Use in pregnancy only when clearly needed and when the benefits outweigh the potential hazard to the fetus. Crosses the placenta. 1 report of suspected heart block when used to control fetal supraventricular tachycardia. May exhibit tocolytic effects.

Breast-feeding/lactation: Crosses into breast milk. American Academy of Pediatrics considers compatible with breast-feeding.

Hypersensitivity to verapamil or any component; 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 (WPW, Lown-Ganoang-Levine syndrome); pregnancy

Avoid use in heart failure; can exacerbate condition. Can cause hypotension. Rare increases in liver function tests can be observed. Can cause first-degree AV block or sinus bradycardia. Other conduction abnormalities are rare. Use caution when using verapamil together with a beta-blocker. Avoid use of I.V. verapamil with an I.V. beta-blocker; can result in asystole. Avoid use in patients with hypertrophic cardiomyopathy (IHSS). Use with caution in patients with attenuated neuromuscular transmission. Adjust the dose in severe renal dysfunction and hepatic dysfunction. Verapamil significantly increases digoxin serum concentrations (adjust digoxin's dose).

Oral (P.O.), intravenous (I.V.):

Gastrointestinal: Gingival hyperplasia (19%)

1% to 10%

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

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

Dermatologic: Rash (1.2% P.O.)

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

Respiratory: Dyspnea (1.4% P.O.)

<1% (P.O.) (Limited to important or life-threatening symptoms): Angina, atrioventricular dissociation, chest pain, claudication, myocardial infarction, palpitations, 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, sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme, blurred vision, tinnitus, gynecomastia, galactorrhea/hyperprolactinemia, increased urination, spotty menstruation, impotence, flushing, abdominal discomfort

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

Case reports: Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis, EPS, gynecomastia, eosinophilia, ventricular fibrillation, asystole, EMD, shock. myoclonus, Parkinsonian syndrome, GI obstruction, pulmonary edema, respiratory failure, hair color change

The primary cardiac symptoms of calcium blocker overdose include hypotension and bradycardia. The hypotension is caused by peripheral vasodilation, myocardial depression, and bradycardia. Bradycardia results from sinus bradycardia, second- or third-degree atrioventricular block, or sinus arrest with junctional rhythm. Intraventricular conduction is usually not affected so QRS duration is normal (verapamil does prolong the P-R interval and bepridil prolongs the Q-T and may cause ventricular arrhythmias, including torsade de pointes).

Following initial gastric decontamination, if possible, repeated calcium administration may promptly reverse the depressed cardiac contractility (but not sinus node depression or peripheral vasodilation); glucagon, epinephrine, and amrinone may treat refractory hypotension; glucagon and epinephrine also increase the 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.

In a few reported cases, overdose with calcium channel blockers has been associated with hypotension and bradycardia, initially refractory to atropine but becoming more responsive to this agent when larger doses (approaching 1 g/hour for more than 24 hours) of calcium chloride was administered.

CYP3A3/4 and 1A2 enzyme substrate; CYP3A3/4 inhibitor

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.

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.

HMG-CoA reductase inhibitors (atorvastatin, cerivastatin, lovastatin, simvastatin): Serum concentration will likely be increased; consider pravastatin/fluvastatin or a dihydropyridine calcium channel blocker.

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's neuromuscular blockade is 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.

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.

Store injection at room temperature; protect from heat and from freezing; use only clear solutions; compatible in solutions of pH of 3-6, but may precipitate in solutions having a pH greater than or equal to 6

Inhibits calcium ion from entering the "slow channels" or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization; produces a relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina; slows automaticity and conduction of A-V node.

Oral (nonsustained tablets): Peak effect: 2 hours; Duration: 6-8 hours

I.V.: Peak effect: 1-5 minutes; Duration: 10-20 minutes

Protein binding: 90%

Metabolism: In the liver; extensive first-pass effect

Bioavailability: Oral: 20% to 30%

Half-life: Infants: 4.4-6.9 hours; Adults: Single dose: 2-8 hours, increased up to 12 hours with multiple dosing; increased half-life with hepatic cirrhosis

Elimination: 70% of dose excreted in urine (3% to 4% as unchanged drug) and 16% in feces

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.: 5-10 mg (approximately 0.075-0.15 mg/kg); second dose of 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.

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: 80 mg 3 times/day or 240 mg/day (sustained release); range: 240-480 mg/day; 120 mg/day in the elderly or small patients (no evidence of additional benefit in doses >360 mg/day).

Note: One time per day dosing is recommended at bedtime with Covera-HS®.

Dosing adjustment in renal impairment: Cl_cr <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 EKG.

Sustained release product should be administered with food or milk, other formulations may be administered without regard to meals; sprinkling contents of capsule onto food does not affect oral absorption

Monitor blood pressure closely

Therapeutic: 50-200 ng/mL (SI: 100-410 nmol/L) for parent; under normal conditions norverapamil concentration is the same as parent drug. Toxic: >90 mg/mL

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. A verapamil preparation (Covera® HS) uses a chronotherapeutic approach to the treatment of hypertension and angina. This drug preparation provides peak drug effects in the early morning when the circadian distribution of cardiovascular events is also at a peak. The benefit of this theoretical approach to treatment has not been established. The CONVINCE trial is currently underway to address this issue.

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.

May cause drowsiness or dizziness

Barbiturates may decrease verapamil serum concentrations; verapamil may increase carbamazepine 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

No information available to require special precautions

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.

Oral: Take as directed, around-the-clock. Do not alter dosage or discontinue therapy without consulting prescriber. Do not crush or chew extended release form. 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, dietary fiber, fruit, or fluids may help); diarrhea (buttermilk, boiled milk, or yogurt may help). Report chest pain, palpitations, or irregular heartbeat; unusual cough, difficulty breathing, or swelling of extremities (feet/ankles); muscle tremors or weakness; confusion or acute lethargy; or skin irritation or rash. Pregnancy precautions: Inform prescriber if you are or intend to be pregnant.

Do not crush sustained release drug product

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

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

Isoptin®: 2.5 mg/mL (2 mL, 4 mL)

Tablet, as hydrochloride: 40 mg, 80 mg, 120 mg

Calan®, Isoptin®: 40 mg, 80 mg, 120 mg

Tablet, as hydrochloride, sustained release: 180 mg, 240 mg

Calan® SR, Isoptin® SR: 120 mg, 180 mg, 240 mg

Covera-HS®: 180 mg, 240 mg

A 50 mg/mL oral suspension may be made using twenty 80 mg verapamil tablets, 3 mL of purified water USP, 8 mL of methylcellulose 1% and simple syrup qs ad to 32 mL; the expected stability is 30 days under refrigeration; shake well before use. A mixture of verapamil 50 mg/mL plus hydrochlorothiazide 5 mg/mL was stable 60 days in refrigerator in a 1:1 preparation of Ora-Sweet® and Ora-Plus®, of Ora-Sweet® SF and Ora-Plus®, and of cherry syrup.

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