Bepridil

Pronunciation

(BE pri dil)

U.S. Brand Names

Vascor® [DSC]

Synonyms

Bepridil Hydrochloride

Generic Available

Canadian Brand Names

Vascor®

Use

Treatment of chronic stable angina; due to side effect profile, reserve for patients who have been intolerant of other antianginal therapy; bepridil may be used alone or in combination with nitrates or beta-blockers

Pregnancy Risk Factor

Lactation

Enters breast milk/compatible

Contraindications

Hypersensitivity to bepridil or any component of the formulation, calcium channel blockers, or adenosine; history of serious ventricular or atrial arrhythmias (especially tachycardia or those associated with accessory conduction pathways), uncompensated cardiac insufficiency, congenital QT interval prolongation, patients taking other drugs that prolong the QT interval; concurrent administration with ritonavir, amprenavir, atazanavir, or sparfloxacin

Warnings/Precautions

Use with great caution in patients with history of IHSS, second- or third-degree AV block, cardiogenic shock; reserve for patients in whom other antianginals have failed. Carefully titrate dosages for patients with impaired renal or hepatic function; use caution when treating patients with CHF, significant hypotension, severe left ventricular dysfunction, hypertrophic cardiomyopathy (especially obstructive), concomitant therapy with beta-blockers or digoxin, edema, or increased intracranial pressure with cranial tumors; do not abruptly withdraw (may cause chest pain); elderly may experience hypotension and constipation more readily.

If dosage reduction does not maintain the QT within a safe range (not to exceed 0.52 seconds during therapy), discontinue the medication; has class I antiarrhythmic properties and can induce new arrhythmias, including VT/VF; it can also cause torsade de pointes type ventricular tachycardia due to its ability to prolong the QT interval; avoid use in patients immediately post myocardial infarction.

Adverse Reactions

>10%:

Central nervous system: Dizziness

Gastrointestinal: Nausea, dyspepsia

1% to 10%:

Cardiovascular: Bradycardia, edema, palpitation, QT prolongation (dose related; up to 5% with prolongation of 25%), CHF (1%)

Central nervous system: Nervousness, headache (7% to 13%), drowsiness, psychiatric disturbances (<2%), insomnia (2% to 3%)

Dermatologic: Rash ( 2%)

Endocrine & metabolic: Sexual dysfunction

Gastrointestinal: Diarrhea, anorexia, xerostomia, constipation, abdominal pain, dyspepsia, flatulence

Neuromuscular & skeletal: Weakness (7% to 14%), tremor (<9%), paresthesia (3%)

Ocular: Blurred vision

Otic: Tinnitus

Respiratory: Rhinitis, dyspnea ( 9%), cough ( 2%)

Miscellaneous ( 2%): Flu syndrome, diaphoresis

<1%: Ventricular arrhythmia, torsade de pointes (0.01% to 1%), fever, leukopenia, neutropenia, altered behavior, akathisia, abnormal taste, arthritis, pharyngitis

Overdosage/Toxicology

Primary cardiac symptoms of calcium blocker overdose include hypotension and bradycardia. In addition, bepridil may also cause QT prolongation and torsade de pointes. 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). 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. Large doses of calcium chloride may be required to treat initially refractory hypotension and bradycardia.

Drug Interactions

Inhibits CYP2D6 (weak)

Increased toxicity/effect/levels:

Bepridil may increase cyclosporine levels (other calcium channel blockers have been shown to interact)

Bepridil may increase digitalis glycoside levels

Use with ritonavir, amprenavir, atazanavir, and other protease inhibitors may increase risk of bepridil and sparfloxacin toxicity, especially its cardiotoxicity; contraindicated.

Coadministration with beta-blocking agents may result in increased depressant effects on myocardial contractility or AV conduction

Fentanyl: Concurrent use may lead to severe hypotension.

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

Ethanol/Nutrition/Herb Interactions

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

Mechanism of Action

Bepridil, a type 4 calcium antagonist, possesses characteristics of the traditional calcium antagonists, inhibiting calcium ion from entering the "slow channels" or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization and producing a relaxation of coronary vascular smooth muscle and coronary vasodilation. However, bepridil may also inhibit fast sodium channels (inward), which may account for some of its side effects (eg, arrhythmias); a direct bradycardia effect of bepridil has been postulated via direct action on the S-A node.

Pharmacodynamics/Kinetics

Onset of action: 1 hour

Absorption: 100%

Protein binding: >99%

Metabolism: Hepatic

Bioavailability: 60%

Half-life elimination: 24 hours

Time to peak: 2-3 hours

Excretion: Urine (as metabolites)

Dosage

Adults: Oral: Initial: 200 mg/day, then adjust dose at 10-day intervals until optimal response is achieved; usual dose: 300 mg/day; maximum daily dose: 400 mg

Dosage adjustment in renal impairment: Risk of toxic reactions is greater in patients with renal impairment; dose selection should be cautious, usually starting at the low end of the dosage range

Elderly: Peak concentrations and half-life are markedly increased in the elderly (>74 years); dose selection should be cautious, usually starting at the low end of the dosage range

Monitoring Parameters

ECG and serum electrolytes, blood pressure, signs and symptoms of congestive heart failure; elderly may need very close monitoring due to underlying cardiac and organ system defects

Reference Range

1-2 ng/mL

Test Interactions

Increased aminotransferases, increased CPK, LDH

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take as directed (may be taken with food to reduce gastric side effects). Do not alter dose or discontinue without consulting prescriber. Regular ECGs and follow-up with prescriber may be required. May cause dizziness, shakiness, visual disturbances, or headache (use caution when driving or engaging in tasks that require alertness until response to drug is known); or nausea or GI upset appetite (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help). Report irregular or pounding heartbeat, respiratory difficulty, swelling of hands or feet, alterations in hearing or vision, unresolved headache, dizziness, constipation, or any unusual bleeding or bruising. Pregnancy precaution: Inform prescriber if you are or intend to become pregnant.

Anesthesia and Critical Care Concerns/Other Considerations

This therapy should be initiated in the inpatient setting with careful monitoring of ECG and QT interval and evaluation of potential drug and disease (ie, heart failure) interactions.

Cardiovascular Considerations

Therapy should be reserved for patients intolerant to other calcium channel blockers and in patients with a clear indication for therapy. This therapy should be initiated in the inpatient setting with careful monitoring of ECG and QT interval and evaluation of potential drug and disease (ie, heart failure) interactions.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation). Other drugs of this class can cause gingival hyperplasia (ie, nifedipine) but there have been no reports for bepridil.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause nervousness; rare reports of akathisia

Mental Health: Effects on Psychiatric Treatment

Concurrent use with beta-blockers may decrease AV nodal conduction

Dosage Forms

Tablet, as hydrochloride: 200 mg, 300 mg

References

Viallon A, Page Y, Lafond P, et al, "Bepridil and Torsade de Pointes: Are the Precautions of Use Respected?" Therapie , 1994, 49(5):431-4.

Zeller FP and Spinler SA, "Bepridil: A New Long-Acting Calcium Channel Blocking Agent," Drug Intell Clin Pharm , 1987, 21(6):487-92.

International Brand Names

Bepricor® (JP); Cordium® (LU); Unicordium® (FR); Vascor® (CA)

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