Diltiazem Hydrochloride (Page 2 of 6)

Hypertension

In a randomized, double-blind, parallel-group, dose-response study involving 478 patients with essential hypertension, evening doses of diltiazem hydrochloride extended-release tablets 120, 240, 360, and 540 mg were compared to placebo and to 360 mg administered in the morning. The mean reductions in diastolic blood pressure by ABPM at roughly 24 hours after the morning (4 AM to 8 AM) or evening (6 PM to10 PM) administration (i.e., the time corresponding to expected trough serum concentrations) are shown in the table below:

Mean Change in Trough Diastolic Pressure by ABPM

Evening Dosing Morning
120 mg 240 mg 360 mg 540 mg Dosing 360 mg
-2.0 -4.4 -4.4 -8.1 -6.4

A second randomized, double-blind, parallel-group, dose-response study (N=258) evaluated diltiazem hydrochloride extended-release tablets following morning doses of placebo or 120, 180, 300, or 540 mg. Diastolic blood pressure measured by supine office cuff sphygmomanometer at trough (7 AM to 9 AM) decreased in an apparently linear manner over the dosage range studied. Group mean changes for placebo, 120 mg, 180 mg, 300 mg and 540 mg were -2.6, -1.9, -5.4, -6.1, and — 8.6 mm Hg, respectively.

Whether the time of administration impacts the clinical benefits of antihypertensive treatment is not known.

Postural hypotension is infrequently noted upon suddenly assuming an upright position. No reflex tachycardia is associated with the chronic antihypertensive effects.

Angina

The effects of diltiazem hydrochloride extended-release tablets on angina were evaluated in a randomized, double-blind, parallel-group, dose-response trial of 311 patients with chronic stable angina. Evening doses of 180, 360 and 420 mg were compared to placebo and to 360 mg administered in the morning. All doses of diltiazem hydrochloride extended-release tablets administered at night increased exercise tolerance when compared with placebo after 21 hours. The mean effect, placebo-subtracted, was 20 to 28 seconds for all three doses, and no dose-response was demonstrated. Diltiazem hydrochloride extended-release tablets, 360 mg, given in the morning, also improved exercise tolerance when measured 25 hours later.

As expected, the effect was smaller than the effects measured only 21 hours following nighttime administration. Diltiazem hydrochloride extended-release tablets had a larger effect to increase exercise tolerance at peak serum concentrations than at trough.

INDICATIONS AND USAGE

Diltiazem hydrochloride extended-release tablets are indicated for the treatment of hypertension. They may be used alone or in combination with other antihypertensive medications.

Diltiazem hydrochloride extended-release tablets are indicated for the management of chronic stable angina.

CONTRAINDICATIONS

Diltiazem is contraindicated in (1) patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker, (2) patients with second- or third-degree AV block except in the presence of a functioning ventricular pacemaker, (3) patients with hypotension (less than 90 mm Hg systolic), (4) patients who have demonstrated hypersensitivity to the drug, and (5) patients with acute myocardial infarction and pulmonary congestion documented by x-ray on admission.

WARNINGS

  1. 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 Prinzmetal’s angina developed periods of asystole (2 to 5 seconds) after a single dose of 60 mg of diltiazem (see ADVERSE REACTIONS).
  2. 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 in combination with beta-blockers in patients with impaired ventricular function is limited. Caution should be exercised when using this combination.
  3. Hypotension Decreases in blood pressure associated with diltiazem therapy may occasionally result in symptomatic hypotension.
  4. 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 (See PRECAUTIONS).

PRECAUTIONS

General

Diltiazem hydrochloride is extensively metabolized by the liver and excreted by the kidneys and in bile. As with any drug given over prolonged periods, laboratory parameters of renal and hepatic function should be monitored at regular intervals. The drug should be used with caution in patients with impaired renal or hepatic function.

In subacute and chronic dog and rat studies designed to produce toxicity, high doses of diltiazem were associated with hepatic damage. In special subacute hepatic studies, oral doses of 125 mg/kg and higher in rats were associated with histological changes in the liver, which were reversible when the drug was discontinued. In dogs, doses of 20 mg/kg were also associated with hepatic changes; however, these changes were reversible with continued dosing.

Dermatological events (see ADVERSE REACTIONS) may be transient and may disappear despite continued use of diltiazem. 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

Due to the potential for additive effects, caution and careful titration are warranted in patients receiving diltiazem concomitantly with other agents known to affect cardiac contractility and/or conduction (See WARNINGS). Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with diltiazem (See WARNINGS).

As with all drugs, care should be exercised when treating patients with multiple medications. Diltiazem is both a substrate and an inhibitor of the cytochrome P-450 3A4 enzyme system. Other drugs that are specific substrates, inhibitors, or inducers of this enzyme system may have a significant impact on the efficacy and side effect profile of diltiazem. Patients taking other drugs that are substrates of CYP450 3A4, especially patients with renal and/or hepatic impairment, may require dosage adjustment when starting or stopping concomitantly administered diltiazem in order to maintain optimum therapeutic blood levels.

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