Diltiazem Hydrochloride
FULL PRESCRIBING INFORMATION: CONTENTS*
- DILTIAZEM HYDROCHLORIDE DESCRIPTION
- CLINICAL PHARMACOLOGY
- INDICATIONS & USAGE
- DILTIAZEM HYDROCHLORIDE CONTRAINDICATIONS
- WARNINGS
- PRECAUTIONS
- DILTIAZEM HYDROCHLORIDE ADVERSE REACTIONS
- OVERDOSAGE
- DOSAGE & ADMINISTRATION
- HOW SUPPLIED
- STORAGE AND HANDLING
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION
FULL PRESCRIBING INFORMATION
DILTIAZEM HYDROCHLORIDE DESCRIPTION
CLINICAL PHARMACOLOGY
Mechanism of Action
Hemodynamic and Electrophysiologic Effects
WARNINGS).
Pharmacokinetics and Metabolism
Diltiazem Hydrochloride Extended-Release Capsules:When compared to a regimen of diltiazem hydrochloride tablets at steady-state, more than 95% of drug is absorbed from the dilitiazem hydrochloride extended-release capsules formulation. A single 360-mg dose of the capsule results in detectable plasma levels within 2 hours and peak plasma levels between 10 and 14 hours; absorption occurs throughout the dosing interval. When diltiazem hydrochloride extended-release capsules were coadministered with a high fat content breakfast, the extent of diltiazem absorption was not affected. Dose-dumping does not occur. The apparent elimination half-life after single or multiple dosing is 5 to 8 hours. A departure from linearity similar to that seen with diltiazem hydrochloride tablets and diltiazem hydrochloride sustained-release capsules is observed. As the dose of diltiazem hydrochloride extended-release capsules is increased from a daily dose of 120 mg to 240 mg, there is an increase in the area-under-the-curve of 2.7 times. When the dose is increased from 240 mg to 360 mg there is an increase in the area-under-the-curve of 1.6 times.
INDICATIONS & USAGE
DILTIAZEM HYDROCHLORIDE CONTRAINDICATIONS
WARNINGS
Cardiac Conduction:Diltiazem prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome. This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second- or third-degree AV block (13 of 3290 patients or 0.40%). Concomitant use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac conduction. A patient with Prinzmetalangina developed periods of asystole (2 to 5 seconds) after a single dose of 60 mg of diltiazem (seeADVERSE REACTIONS).Congestive Heart Failure:Although diltiazem has a negative inotropic effect in isolated animal tissue preparations, hemodynamic studies in humans with normal ventricular function have not shown a reduction in cardiac index nor consistent negative effects on contractility (dp/dt). An acute study of oral diltiazem in patients with impaired ventricular function (ejection fraction 24%6%) showed improvement in indices of ventricular function without significant decrease in contractile function (dp/dt). Worsening of congestive heart failure has been reported in patients with preexisting impairment of ventricular function. Experience with the use of diltiazem hydrochloride in combination with beta-blockers in patients with impaired ventricular function is limited. Caution should be exercised when using this combination.
Hypotension:Decreases in blood pressure associated with diltiazem therapy may occasionally result in symptomatic hypotension.
Acute Hepatic Injury:Mild elevations of transaminases with and without concomitant elevation in alkaline phosphatase and bilirubin have been observed in clinical studies. Such elevations were usually transient and frequently resolved even with continued diltiazem treatment. In rare instances, significant elevations in enzymes such as alkaline phosphatase, LDH, SGOT, SGPT, and other phenomena consistent with acute hepatic injury have been noted. These reactions tended to occur early after therapy initiation (1 to 8 weeks) and have been reversible upon discontinuation of drug therapy. The relationship to diltiazem is uncertain in some cases, but probable in some (seePRECAUTIONS).
PRECAUTIONS
GeneralADVERSE REACTIONS) may be transient and may disappear despite continued use of diltiazem hydrochloride. However, skin eruptions progressing to erythema multiforme and/or exfoliative dermatitis have also been infrequently reported. Should a dermatologic reaction persist, the drug should be discontinued.
Drug Interactions
WARNINGS). Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with diltiazem (seeWARNINGS).
Anesthetics:The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with anesthetics may be potentiated by calcium channel blockers. When used concomitantly, anesthetics and calcium blockers should be titrated carefully.
Benzodiazepines:Studies showed that diltiazem increased the AUC of midazolam and triazolam by 3- to 4-fold and the Cmax by 2-fold, compared to placebo. The elimination half-life of midazolam and triazolam also increased (1.5- to 2.5-fold) during coadministration with diltiazem. These pharmacokinetic effects seen during diltiazem coadministration can result in increased clinical effects (e.g., prolonged sedation) of both midazolam and triazolam.
Beta-blockers:Controlled and uncontrolled domestic studies suggest that concomitant use of diltiazem hydrochloride and beta-blockers is usually well tolerated, but available data are not sufficient to predict the effects of concomitant treatment in patients with left ventricular dysfunction or cardiac conduction abnormalities.
WARNINGS).
Buspirone:In nine healthy subjects, diltiazem significantly increased the mean buspirone AUC 5.5-fold and Cmax 4.1-fold compared to placebo. The T1/2 and Tmax of buspirone were not significantly affected by diltiazem. Enhanced effects and increased toxicity of buspirone may be possible during concomitant administration with diltiazem. Subsequent dose adjustments may be necessary during coadministration, and should be based on clinical assessment.
Carbamazepine:Concomitant administration of diltiazem with carbamazepine has been reported to result in elevated serum levels of carbamazepine (40% to 72% increase), resulting in toxicity in some cases. Patients receiving these drugs concurrently should be monitored for a potential drug interaction.
Cimetidine:A study in six healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and area-under-the-curve (53%) after a 1-week course of cimetidine at 1200 mg per day and a single dose of diltiazem 60 mg. Ranitidine produced smaller, nonsignificant increases. The effect may be mediated by cimetidine's known inhibition of hepatic cytochrome P-450, the enzyme system responsible for the first-pass metabolism of diltiazem. Patients currently receiving diltiazem therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with cimetidine. An adjustment in the diltiazem dose may be warranted.
Clonidine:Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with diltiazem. Monitor heart rate in patients receiving concomitant diltiazem and clonidine.
Cyclosporine:A pharmacokinetic interaction between diltiazem and cyclosporine has been observed during studies involving renal and cardiac transplant patients. In renal and cardiac transplant recipients, a reduction of cyclosporine dose ranging from 15% to 48% was necessary to maintain cyclosporine trough concentrations similar to those seen prior to the addition of diltiazem. If these agents are to be administered concurrently, cyclosporine concentrations should be monitored, especially when diltiazem therapy is initiated, adjusted, or discontinued.
Digitalis:Administration of diltiazem hydrochloride with digoxin in 24 healthy male subjects increased plasma digoxin concentrations approximately 20%. Another investigator found no increase in digoxin levels in 12 patients with coronary artery disease. Since there have been conflicting results regarding the effect of digoxin levels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing diltiazem hydrochloride therapy to avoid possible over- or under-digitalization (seeWARNINGS).
Quinidine:Diltiazem significantly increases the AUC (0of quinidine by 51%, T1/2 by 36%, and decreases its CLoral by 33%. Monitoring for quinidine adverse effects may be warranted and the dose adjusted accordingly.
Rifampin:Coadministration of rifampin with diltiazem lowered the diltiazem plasma concentrations to undetectable levels. Coadministration of diltiazem with rifampin or any known CYP3A4 inducer should be avoided when possible, and alternative therapy considered.
Statins:
Carcinogenesis, Mutagenesis, Impairment of Fertility
Pregnancy
Nursing Mothers
Pediatric Use
Geriatric Use
DILTIAZEM HYDROCHLORIDE ADVERSE REACTIONS
DILTIAZEM HYDROCHLORIDE EXTENDED-RELEASE CAPSULE PLACEBO-CONTROLLED ANGINA ANDHYPERTENSION TRIALS COMBINED
Diltiazem Hydrochloride Extended-Release Capsules Placebo Adverse Reaction n=607 n=301
Cardiovascular:Angina, arrhythmia, AV block (second- or third-degree), bundle branch block, congestive heart failure, ECG abnormalities, hypotension, palpitations, syncope, tachycardia, ventricular extrasystoles.
Nervous System:Abnormal dreams, amnesia, depression, gait abnormality, hallucinations, insomnia, nervousness, paresthesia, personality change, somnolence, tinnitus, tremor.
Gastrointestinal:Anorexia, constipation, diarrhea, dry mouth, dysgeusia, dyspepsia, mild elevations of SGOT, SGPT, LDH, and alkaline phosphatase (seeWARNINGS, Acute Hepatic Injury), thirst, vomiting, weight increase
Dermatological:Petechiae, photosensitivity, pruritus, urticaria.
Other:Amblyopia, CPK increase, dyspnea, epistaxis, eye irritation, hyperglycemia, hyperuricemia, impotence, muscle cramps, nasal congestion, nocturia, osteoarticular pain, polyuria, sexual difficulties.
OVERDOSAGE
Bradycardia:Administer atropine (0.60 to 1.0 mg). If there is no response to vagal blockade, administer isoproterenol cautiously.
High-degree AV Block:Treat as for bradycardia above. Fixed high-degree AV block should be treated with cardiac pacing.
Cardiac Failure:Administer inotropic agents (isoproterenol, dopamine, or dobutamine) and diuretics.
Hypotension:Vasopressors (e.g., dopamine or norepinephrine).
DOSAGE & ADMINISTRATION
Hypertension:
Angina:Dosages for the treatment of angina should be adjusted to each patientneeds, starting with a dose of 120 or 180 mg once daily. Individual patients may respond to higher doses of up to 480 mg once daily. When necessary, titration may be carried out over a 7- to 14-day period.
Concomitant Use With Other Cardiovascular Agents
Sublingual NTG- May be taken as required to abort acute anginal attacks during diltiazem hydrochloride extended-release capsules therapy.
Prophylactic Nitrate Therapy- Diltiazem hydrochloride extended-release capsules may be safely coadministered with short-and long-acting nitrates.
Beta-Blockers- (SeeWARNINGSandPRECAUTIONS).
Antihypertensives- Diltiazem hydrochloride extended-release capsules have an additive antihypertensive effect when used with other antihypertensive agents. Therefore, the dosage of diltiazem hydrochloride extended-release capsules or the concomitant antihypertensives may need to be adjusted when adding one to the other.
HOW SUPPLIED
STORAGE AND HANDLING
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION
Diltiazem HydrochlorideDILTIAZEM HYDROCHLORIDE CAPSULE, EXTENDED RELEASE
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