Pronunciation: ver-AP-a-mil HYE-droe-KLOR-ide
Class: Calcium channel blocking agent

Trade Names

Calan
- Tablets 80 mg
- Tablets 120 mg

Calan SR
- Tablets, ER 120 mg
- Tablets, ER 180 mg
- Tablets, ER 240 mg

Covera-HS
- Tablets, ER 180 mg
- Tablets, ER 240 mg

Isoptin SR
- Tablets, ER 120 mg
- Tablets, ER 180 mg
- Tablets, ER 240 mg

Verelan
- Capsules, ER 120 mg
- Capsules, ER 180 mg
- Capsules, ER 240 mg
- Capsules, ER 360 mg

Verelan PM
- Capsules, ER 100 mg
- Capsules, ER 200 mg
- Capsules, ER 300 mg

Verapamil
- Tablets 40 mg
- Injection, solution 2.5 mg/mL

Apo-Verap (Canada)
Apo-Verap SR (Canada)
Gen-Verapamil (Canada)
Gen-Verapamil SR (Canada)
Nu-Verap (Canada)

Pharmacology

Inhibits movement of calcium ions across cell membrane, resulting in depression of mechanical contraction of myocardial and vascular smooth muscle, and depression of impulse formation (automaticity) and conduction velocity.

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Pharmacokinetics

Absorption

More than 90% of an oral dose is absorbed. Bioavailability ranges from 20% to 35%. T _max is 1 to 2 h (immediate-release), 7 to 9 h ( Verelan ), and 11 h ( Covera-HS and Verelan PM ).

Distribution

Rapid early distribution phase (half-life approximately 4 min). 90% protein bound.

Metabolism

Rapidly metabolized. Extensive metabolism in the liver with 12 metabolites identified, most only in trace amounts. Major metabolites are N- and O-dealkylated products of verapamil.

Elimination

Elimination half-life is approximately 3 to 7 h (single oral dose), 4.5 to 12 h (multiple oral dose), or 2 to 5 h (IV). Approximately 70% of dose is excreted in the urine and 16% or more in feces within 5 days. Approximately 3% to 4% is excreted as unchanged drug.

Special Populations

Hepatic Function Impairment

Metabolism is delayed, elimination half-life is prolonged up to 14 to 16 h, and plasma Cl is reduced to approximately 30% of normal.

Elderly

Elimination half-life may be prolonged to 14 to 16 h.

Gender

A gender difference was not observed in the clinical trials of verapamil. Conflicting data in the literature suggest that verapamil Cl decreased with age in women to a greater degree than in men.

Body Weight

Lean body weight affects verapamil pharmacokinetics inversely.

Indications and Usage

Oral Immediate-release

Treatment of vasospastic (Prinzmetal variant), chronic stable (classic effort–associated), and unstable (crescendo, preinfarction) angina; adjunctive treatment with digitalis to control ventricular rate at rest and during stress in atrial flutter or fibrillation; prophylaxis of repetitive paroxysmal supraventricular tachycardia; management of essential hypertension.

ER

Management of essential hypertension. Management of angina ( Covera-HS only)

Parenteral

Rapid conversion of paroxysmal supraventricular tachycardia to sinus rhythm; temporary control of rapid ventricular rate in atrial flutter or fibrillation.

Unlabeled Uses

Treatment of migraine and cluster headaches; treatment of hypertrophic cardiomyopathy.

Contraindications

Hypersensitivity to verapamil; sick sinus syndrome or second- or third-degree AV block except with functioning pacemaker; patients with atrial flutter or fibrillation and accessory bypass tract; cardiogenic shock.

Oral

Hypotension (less than 90 mm Hg systolic); severe left ventricular dysfunction.

Parenteral

Severe hypotension; severe CHF, unless secondary to supraventricular tachycardia amenable to verapamil; concomitant use (within few hours) of IV beta-adrenergic blocking agents; ventricular tachycardia.

Dosage and Administration

Angina
Adults Immediate Release

PO 80 to 120 mg 3 times daily (max, 480 mg/day). 40 mg 3 times daily (may be warranted in patients with increased sensitivity to verapamil (eg, hepatic impairment, elderly). Base upward titration on therapeutic efficacy and safety evaluated approximately 8 h after dosing. Dosage may be increased daily or weekly.

Covera-HS

PO Start with 180 mg once daily at bedtime. If response is inadequate, titrate upward in the following manner: 240 mg each evening, 360 mg each evening, 480 mg each evening. Usual dose ranges between 180 and 540 mg once daily at bedtime.

Arrhythmias
Adults Immediate Release

PO In digitalized patients with chronic atrial fibrillation, the dose ranges from 240 to 320 mg/day divided into 3 or 4 times a day dosing (max, 480 mg/day). Dosage for prophylaxis of paroxysmal supraventricular tachycardia in nondigitalized patients ranges from 240 to 480 mg daily divided into 3 or 4 times a day dosing (max, 480 mg/day). In general, max effects for any given dosage will be apparent during the first 48 h of therapy.

Hypertension
Adults Immediate Release

PO 80 mg 3 times/day initially. Consider beginning at 40 mg 3 times/day in patients who might respond to lower doses (elderly, patients of small stature). Max, 480 mg/day. Base upward titration on therapeutic efficacy, assessed at the end of the dosing interval. The antihypertensive effects are evident within the first week of therapy.

Verelan PM

200 mg/day at bedtime; however, 100 mg once daily may be warranted in patients who have an increased response to verapamil (elderly, patients of small stature, renal or hepatic impairment). Upward titration should be based on therapeutic efficacy and safety evaluated approximately 24 h after dosing. The antihypertensive effects are evident within the first week of therapy. If an adequate response is not obtained with 200 mg, the dose may be titrated to 300 mg each evening, then, if needed, to 400 mg each evening.

Verelan

120 mg once daily may be warranted in patients who have an increased response to verapamil (elderly, patients of small stature). Upward titration should be based on therapeutic efficacy and safety evaluated approximately 24 h after dosing. Dose may be titrated upward in the following manner: 180 mg each morning, 240 mg each morning, 360 mg each morning, 480 mg each morning. The antihypertensive effects are evident within the first week of therapy.

Calan SR / Isoptin SR

Initially, 180 mg given once daily in the morning. 120 mg once daily may be warranted in patients who have an increased response to verapamil (elderly, patients of small stature). Dose may be titrated upward in the following manner: 240 mg each morning, 180 mg each morning plus 180 mg each evening, or 240 mg each morning plus 120 mg each evening; 240 mg every 12 h.

Covera-HS

Start with 180 mg once daily at bedtime. If response is inadequate, titrate upward in the following manner: 240 mg each evening, 360 mg each evening, 480 mg each evening. Usual dose ranges between 180 to 540 mg once daily at bedtime.

Supraventricular Tachycardia, Atrial Flutter or Fibrillation
Adults

IV Initial dose 5 to 10 mg (0.075 to 0.15 mg/kg) IV bolus over at least 2 min. Give 10 mg (0.15 mg/kg) 30 min after the first dose if initial response is not adequate. An optimal interval for subsequent IV doses has not been determined; individualize for each patient.

Elderly

IV Administer the dose over at least 3 min to minimize risk of untoward drug effects.

Children 1 to 15 y of age

IV 0.1 to 0.3 mg/kg administered as an IV bolus over at least 2 min (max, 5 mg). Give 0.1 to 0.3 mg/kg 30 min after first dose if initial response is not adequate (max, 10 mg as a single dose). An optimal interval for subsequent IV doses has not been determined; individualize for each patient.

0 to 1 y of age

IV 0.1 to 0.2 mg/kg administered as an IV bolus over at least 2 min under continuous ECG monitoring. Give 0.1 to 0.2 mg 30 min after the first dose under continuous ECG monitoring if the initial response is not adequate. An optimal interval for subsequent IV doses has not been determined; individualize for each patient.

General Advice

Oral

• Verelan , Verelan PM : May be administered by opening the capsule and sprinkling the beads onto 1 tablespoonful of applesauce. The applesauce should be swallowed immediately without chewing and followed by a glass of cool water. The applesauce should not be hot and should be soft enough to swallow without chewing.
• Calan SR , Isoptin SR : Administer with food; tablets may be divided in half.
• Covera-HS : Swallow tablets whole; do not break, crush, or chew.

Parenteral

• Administer as a slow IV injection over at least 2 min under continuous ECG and BP monitoring.
• Discard unused amounts of solution immediately following withdrawal of any portion of the contents.
• Incompatibilities: Do not mix IV product with sodium lactate in PVC bags, albumin, amphotericin B, hydralazine, or trimethoprim-sulfamethoxazole. Do not mix solution with pH above 6.

Storage/Stability

Covera-HS

Store between 68° and 77°F. Protect from light.

Immediate-release tablets, Calan SR , Isoptin SR

Store between 59° and 77°F. Protect from light and moisture.

Verelan , Verelan PM

Store between 68° and 77°F. Protect from excessive heat and moisture.

Parenteral

Store between 68° and 77°F. Protect from light.

Drug Interactions

Alcohol

Alcohol blood levels may be elevated, prolonging the intoxicating effects. Patients should limit their alcohol consumption while taking verapamil.

Antihypertensive agents (eg, ACE inhibitors [eg, captopril], diuretics [eg, chlorothiazide], vasodilators [eg, hydralazine])

Verapamil has additive effects on lowering blood pressure. Monitor blood pressure and adjust treatment as needed.

Antineoplastic regimens (cyclophosphamide, oncovin, prednisone, and procarbazine, or vindesine, adriamycin, and cisplatin)

These regimens can reduce verapamil absorption. Closely monitor the clinical response of the patient and adjust the verapamil dose as needed.

Aspirin

Risk of bleeding may be increased compared with aspirin alone. Monitor bleeding times.

Barbiturates (eg, phenobarbital)

Verapamil Cl may be increased, reducing plasma concentrations and the pharmacologic effect. Monitor the clinical response of the patient and adjust the verapamil dose as needed.

Beta-blockers (eg, metoprolol)

May result in increased hypotension and adverse reactions because of additive depressant effects on myocardial contractility or AV conduction. Avoid verapamil in patients with any degree of ventricular dysfunction if they are receiving beta-blockers.

Buspirone

Pharmacologic and adverse reactions may be increased by verapamil. Closely monitor the clinical response of the patient and adjust buspirone dose as needed.

Calcium salts

Clinical effects and toxicities of verapamil may be reversed. Unless calcium salts are being used as an antagonist in treating verapamil overdose, use calcium salts with caution in patients taking verapamil.

Carbamazepine

Increased carbamazepine serum levels. Monitor serum levels and adjust dose as needed.

Cimetidine

The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on Cl have been obtained in acute studies of healthy volunteers; Cl of verapamil was either reduced or unchanged. If an interaction is suspected, adjust the verapamil dose as needed.

Clonidine

Synergistic effects resulting in sinus bradycardia have been reported in association with coadministration of clonidine and verapamil. Monitor heart rate during concurrent use of verapamil and clonidine.

Colchicine

Colchicine plasma concentrations may be elevated by verapamil, increasing the risk of toxicity. Colchicine dosing adjustment may be needed for patients also receiving verapamil. Use with caution and closely monitor for colchicine toxicity. The recommended colchicine dose for the treatment of a gout flare in patients receiving verapamil is 1.2 mg for one dose. A 3-day lapse should occur before subsequent colchicine administration. The recommended max colchicine dose for treatment of familial Mediterranean fever in patients receiving verapamil is 1.2 mg daily.

Cyclosporine

Increased cyclosporine levels may result, increasing the pharmacologic effect and risk of toxicity. However, verapamil may be nephroprotective when given before cyclosporine. Monitor cyclosporine levels and adjust dose as needed.

CYP3A4 inducers (eg, rifampin)

Verapamil plasma levels may be reduced, decreasing the pharmacologic effect. Closely monitor CV status and adjust dose as needed.

CYP3A4 inhibitors (eg, erythromycin, ritonavir)

Verapamil plasma levels may be elevated, increasing the pharmacologic effects and adverse reactions. Closely monitor cardiac function and adjust the dose as needed.

Dantrolene

Hyperkalemia and myocardial depression has been reported in a patient following coadministration of oral verapamil and IV dantrolene. Monitor serum potassium and cardiac function.

Digitalis glycosides

Increased serum digoxin or digitoxin levels may occur. Monitor digoxin levels and adjust dose as needed. Because both drugs slow AV conduction, also monitor for AV block or excessive bradycardia. If possible, control patients with mild ventricular dysfunction with optimum doses of digitalis and/or diuretics before starting verapamil treatment.

Disopyramide

Do not use 48 h before or 24 h after verapamil.

Dofetilide

Risk of life-threatening ventricular arrhythmias, including torsades de pointes, may be increased. Coadministration with verapamil is contraindicated.

Doxorubicin

Doxorubicin serum concentrations may be elevated. Monitor the clinical response of the patient and adjust treatment as needed.

Dronedarone

Dronedarone plasma concentrations and pharmacologic effects may be increased. Verapamil may enhance the electrophysiologic effects of dronedarone. Also, verapamil plasma concentrations and pharmacologic effects may be increased. Initiate verapamil at low doses in patients receiving dronedarone. Monitor the ECG. Increase the verapamil dosage if the ECG demonstrates tolerability.

Eletriptan

Eletriptan plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Closely monitor for signs of eletriptan adverse reactions.

Eplerenone

Verapamil may elevate eplerenone plasma concentrations, increasing the pharmacologic effects and risk of toxicity. Closely monitor the clinical response of the patient and adjust the eplerenone dose as needed.

Everolimus

Verapamil may elevate everolimus plasma concentrations, increasing the pharmacologic effects and risk of adverse reactions. If coadministration cannot be avoided, closely monitor everolimus blood concentrations when verapamil is started or stopped. Adjust the everolimus dose as needed.

Fentanyl

Verapamil may elevate fentanyl plasma concentrations, increasing the pharmacologic effects and risk of toxicity. When fentanyl and verapamil are coadministered, the manufacturer recommends closely monitoring patients for an extended period of time. Dosage increases should be done conservatively.

Flecainide

May prolong AV conduction. Concurrent therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction. Carefully monitor cardiac function and adjust treatment as needed.

Grapefruit juice

Verapamil plasma concentrations may be elevated. This increase is not expected to have any clinical consequences.

HMG-CoA reductase inhibitors (eg, atorvastatin, lovastatin, simvastatin)

Plasma concentrations of certain HMG-CoA reductase inhibitors may be elevated. In addition, verapamil concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity. If coadministration cannot be avoided, administer a conservative dose of the HMG-CoA reductase inhibitor. The dose of simvastatin should not exceed 10 mg/day. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor the clinical response and for adverse reactions to verapamil. Adjust the dose as needed.

Hydantoins (eg, phenytoin)

The pharmacologic effects of verapamil may be decreased. Monitor CV status closely. Adjust dose as needed.

Imipramine

Coadministration increases imipramine serum concentrations and the risk of adverse reactions (eg, anticholinergic effects, sedation). Monitor imipramine serum concentrations and the clinical response of the patient. Adjust the imipramine dose as needed.

Inhalational anesthetics (eg, enflurane)

Coadministration may potentiate cardiac effects and vascular dilation. Titrate doses carefully to avoid excessive CV depression.

Lithium

Coadminister with verapamil with caution because of variable effects.

Macrolide antibiotics (eg, clarithromycin, erythromycin, telithromycin)

Increased risk of cardiotoxicity. Closely monitor cardiac function.

Midazolam

Midazolam plasma concentrations may be elevated, increasing and prolonging CNS depression. The dosage of midazolam may need to be decreased when given with verapamil. Monitor the patient for possible prolonged sedation.

Nondepolarizing muscle relaxants (eg, pancuronium)

Enhanced muscle relaxant effects and prolonged respiratory depression may occur. If coadministration cannot be avoided, closely monitor the patient and adjust doses as needed.

Paclitaxel, theophylline

Cl of these agents may be reduced by verapamil, increasing plasma levels. Close clinical monitoring and adjustments in the dose of these agents as needed is appropriate.

Prazosin

Increased prazosin serum levels may result, increasing sensitivity to prazosin-induced postural hypotension. Advise patients to take precautions regarding postural hypotension. If an excessive fall in BP occurs, consider decreasing the prazosin dose during verapamil coadministration.

Quinidine

Coadministration may increase the therapeutic and adverse reactions of quinidine. Use quinidine with verapamil only when no alternatives exist. Closely monitor quinidine serum levels and cardiac effects. Verapamil may counteract the effects of quinidine on AV conductions. In patients with hypertrophic cardiomyopathy, coadministration of verapamil and quinidine may cause clinically important hypotension. Avoid concurrent use of verapamil and quinidine in patients with hypertrophic cardiomyopathy.

Ranolazine

Ranolazine plasma concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity. Limit the dosage of ranolazine to 500 mg twice daily. During verapamil coadministration, closely monitor for signs of ranolazine toxicity, including QT interval prolongation.

Rifampin

Loss of effectiveness of oral verapamil may occur. Closely monitor CV status and adjust the verapamil dose as needed.

Risperidone

Risperidone plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. In patients receiving risperidone, closely monitor the clinical response of the patient after starting, stopping, or changing the verapamil dose. Adjust the risperidone dose as needed.

St. John's wort

Verapamil plasma concentrations may be reduced, decreasing the efficacy. If St. John's wort cannot be avoided, assess the clinical response of the patient to verapamil when St. John's wort is started or stopped. Adjust the verapamil dose as needed.

Sulfinpyrazone

Coadministration may decrease the therapeutic effects of oral verapamil. Monitor CV status closely. Adjust the verapamil dose as needed.

Tolvaptan

Tolvaptan concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Avoid coadministration.

Adverse Reactions

Cardiovascular

PO

Hypotension (3%); first-degree AV block (2%); abnormal ECG, angina pectoris, AV dissociation, chest pain, CHF/pulmonary edema, claudication, hypertension, MI, palpitation, purpura, syncope (2% or less); AV block, bradycardia (1%).

IV

Symptomatic hypotension (2%); bradycardia, severe tachycardia (1%).

CNS

PO

Headache (12%); dizziness, fatigue (5%); lethargy (3%); asthenia, cerebrovascular accident, confusion, equilibrium disorders, extrapyramidal symptoms, insomnia, paresthesia, psychotic symptoms, shakiness, somnolence (2% or less); sleep disturbance (1%).

IV

Dizziness, headache (1%).

Dermatologic

PO

Erythema multiforme, exanthema, hair loss, hyperkeratosis, macules, rash, sweating, Stevens-Johnson syndrome, urticaria (2% or less).

EENT

PO

Pharyngitis, rhinitis (3%); blurred vision, tinnitus (2% or less).

GI

PO

Constipation (12%); dyspepsia, nausea (3%); diarrhea, dry mouth, GI distress, gingival hyperplasia (2% or less).

IV

Nausea (1%).

Genitourinary

PO

Gynecomastia, impotence, increased urination, spotty menstruation (2% or less).

Hematologic-Lymphatic

PO

Ecchymosis or bruising (2% or less).

Hepatic

PO

Elevated liver enzymes (2% or less).

Metabolic-Nutritional

PO

Galactorrhea/hyperprolactinemia (2% or less).

Musculoskeletal

PO

Arthralgia, muscle cramps (2% or less); myalgia (1%).

Respiratory

PO

Upper respiratory tract infection (5%); sinusitis (3%); dyspnea (2% or less).

Miscellaneous

PO

Infection (12%); flu-syndrome, peripheral edema (4%); aggravated allergy, edema, pain (2% or less).

Precautions

Monitor Oral Monitor BP during dosage titration, dosage increases, and addition of drugs that affect cardiac conduction or BP. Monitor hepatic and renal function during long-term therapy. Carefully monitor abnormal prolongation of the PR interval and for other signs of excessive pharmacologic effects. Parenteral Continuously monitor ECG, BP, and heart rate during administration. If repeated injections are needed, closely monitor BP and PR interval.

Pregnancy

Category C .

Lactation

Excreted in breast milk. The American Academy of Pediatrics classifies verapamil as compatible with breast-feeding.

Children

Oral

Safety and efficacy not established.

Parenteral

Controlled studies have not been conducted in children, but uncontrolled experience with IV administration to children and newborns indicates that results of treatment are similar to those in adults. Use with caution.

Elderly

Because elimination may be prolonged in elderly patients, lower doses may be warranted.

Renal Function

Use with caution.

Hepatic Function

Use with caution.

Cardiac conduction

May be associated with variety of cardiac conduction abnormalities including first-, second-, or third-degree AV block; bradycardia; asystole; severe hypotension; nodal escape rhythms; PR prolongation; and ventricular tachycardia in patients with atrial flutter/fibrillation and Wolff-Parkinson-White syndrome caused by antegrade conduction.

Decreased neuromuscular transmission

May decrease neuromuscular transmission in patients with Duchenne muscular dystrophy, prolong recovery from neuromuscular blocking agent vecuronium, and cause worsening of myasthenia gravis. Use with caution in patents with decreased neuromuscular transmission.

GI narrowing

Use caution when administering Covera-HS to patients with preexisting severe GI narrowing.

Heart failure

Verapamil has a negative inotropic effect and should be avoided in patients with severe left ventricular dysfunction.

Hepatic effects

Elevated transaminases with or without elevations in alkaline phosphatase and bilirubin have been reported.

Hypertrophic cardiomyopathy

Serious adverse effects were seen in patients with hypertrophic cardiomyopathy who received oral verapamil.

Hypotension

Decreased BP may occur, resulting in dizziness or symptomatic hypotension.

Increased intracranial pressure

IV verapamil has increased intracranial pressure in patients with supratentorial tumors at time of anesthesia induction.

Premature ventricular contractions

May occur after IV use; consider possibility with oral use.

Overdosage

Symptoms

Arrhythmias, bradycardia, cardiac conduction defects (eg, junctional rhythm with AV dissociation and high-degree AV block, including asystole), convulsions, decreased mental status, hyperglycemia, hypoperfusion, hyperkalemia, hypotension, metabolic acidosis, noncardiogenic pulmonary edema, renal dysfunction.

Patient Information

• Tell patient if dose is missed, to take as soon as possible. If several hours have passed or if it is nearing time for next dose, tell patient not to double dose to catch up unless advised by health care provider.
• If more than one dose is missed, tell patient to contact health care provider.
• Caution patient not to change dose unless directed by health care provider.
• Advise patient not to suddenly stop taking medication.
• Remind patient to brush and floss teeth and see dentist regularly.
• Instruct patient to report any irregular heartbeat, shortness of breath, swelling of hands and feet, pronounced dizziness, constipation, nausea, or hypotension.
• Advise patient to avoid use of alcohol and nonprescription medications without consulting health care provider first.
• Instruct patient to limit caffeine consumption.
• Advise patient that drug may cause dizziness and to use caution while driving or performing other tasks requiring mental alertness until effects of drug have stabilized.
• Stress to patient the importance of compliance in all areas of treatment regimen: diet, exercise, stress reduction, and drug therapy.
• Advise patients that Verelan and Verelan PM capsules and the contents of the capsules should not be crushed or chewed. The capsules may be opened and the contents sprinkled on a tablespoon of applesauce. Instruct patient to swallow the applesauce immediately without chewing and follow by drinking a glass of cool water to ensure complete swallowing of the pellets.
• Advise patients to swallow verapamil ER tablets whole and not to crush or chew them. Calan SR and Isoptin SR may be split in half.
• The medication in Covera-HS is released slowly through an outer shell that does not dissolve. Advise patients not to be concerned if they occasionally observe this outer shell in their stool as it passes from the body.

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