Diltiazem Hydrochloride

INDICATIONS AND USAGE Diltiazem hydrochloride extended-release capsules are indicated for the treatment of hypertension. Diltiazem hydrochloride may be used alone or in combination with other antihypertensive medications, such as diuretics. Diltiazem hydrochloride extended-release capsules are indicated for the management of chronic stable angina.

DOSAGE AND ADMINISTRATION Hypertensive or anginal patients who are treated with other formulations of diltiazem can safely be switched to diltiazem hydrochloride extended-release capsules at the nearest equivalent total daily dose. Subsequent titration to higher or lower doses may, however, be necessary and should be initiated as clinically indicated. Studies have shown a slight increase in the rate of absorption of diltiazem hydrochloride extended-release capsules when ingested with a high-fat breakfast; therefore, administration in the morning on an empty stomach is recommended. Patients should be cautioned that the diltiazem hydrochloride extended-release capsules should not be opened, chewed or crushed, and should be swallowed whole. Dosage Hypertension Dosages must be adjusted to each patient’s needs, starting with 180 mg or 240 mg once daily. Based on the antihypertensive effect, the dose may be adjusted as needed. Individual patients, particularly ≥60 years of age, may respond to a lower dose of 120 mg. The usual dosage range studied in clinical trials was 180 mg to 480 mg once daily. Current clinical experience with the 540 mg dose is limited; the dose may be increased to 540 mg with little or no increased risk of adverse reactions. Doses should not exceed 540 mg once daily. While a dose of diltiazem hydrochloride extended-release capsules given once daily may produce an antihypertensive effect similar to the same total daily dose given in divided doses, individual dose adjustment may be needed. Dosage Angina Dosages for the treatment of angina should be adjusted to each patient’s needs, starting with a dose of 120 mg once daily, which may be titrated to 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 Nitroglycerin may be taken as required to abort acute anginal attacks during diltiazem hydrochloride therapy. Prophylactic Nitrate Therapy – Diltiazem hydrochloride may be safely co-administered with short- and long-acting nitrates. Beta-blockers. (See WARNINGS and PRECAUTIONS .) Antihypertensives – Diltiazem hydrochloride has an additive antihypertensive effect when used with other antihypertensive agents. Therefore, the dosage of diltiazem hydrochloride or the concomitant antihypertensives may need to be adjusted when adding one to the other.

WARNINGS Cardiac Conduction Diltiazem hydrochloride 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 (22 of 10,119 patients, or 0.2%); 41% of these 22 patients were receiving concomitant β-adrenoceptor antagonists versus 17% of the total group. 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 60 mg dose of diltiazem. 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 of 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 hydrochloride therapy may occasionally result in symptomatic hypotension. Acute Hepatic Injury Mild elevations of serum 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 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 6 weeks) and have been reversible upon discontinuation of drug therapy. The relationship to diltiazem is uncertain in some cases, but probable in some others. (See PRECAUTIONS .)

CONTRAINDICATIONS Diltiazem hydrochloride 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 mmHg systolic); (4) patients who have demonstrated hypersensitivity to the drug; and (5) patients with acute myocardial infarction and pulmonary congestion as documented by X-ray on admission.

ADVERSE REACTIONS Serious adverse reactions to diltiazem hydrochloride have been rare in studies with other formulations, as well as with diltiazem hydrochloride extended-release capsules. It should be recognized, however, that patients with impaired ventricular function and cardiac conduction abnormalities have usually been excluded from these studies. Hypertension The most common adverse events (frequency ≥1%) in placebo-controlled, clinical hypertension studies with diltiazem hydrochloride extended-release capsules using daily doses up to 540 mg, are listed in the table below with placebo-treated patients included for comparison. MOST COMMON ADVERSE EVENTS IN DOUBLE-BLIND, PLACEBO-CONTROLLED HYPERTENSION TRIALS Adverse Events (COSTART Term) D iltiazem Hydrochloride Extended-Release Capsules * n=303 # pts (%) Placebo n=87 # pts (%) rhinitis 29 (9.6) 7 (8) headache 27 (8.9) 12 (13.8) pharyngitis 17 (5.6) 4 (4.6) constipation 11 (3.6) 2 (2.3) cough increase 9 (3) 2 (2.3) flu syndrome 7 (2.3) 1 (1.1) edema, peripheral 7 (2.3) 0 (0) myalgia 7 (2.3) 0 (0) diarrhea 6 (2) 0 (0) vomiting 6 (2) 0 (0) sinusitis 6 (2) 1 (1.1) asthenia 5 (1.7) 0 (0) pain, back 5 (1.7) 2 (2.3) nausea 5 (1.7) 1 (1.1) dyspepsia 4 (1.3) 0 (0) vasodilatation 4 (1.3) 0 (0) injury, accident 4 (1.3) 0 (0) pain, abdominal 3 (1) 0 (0) arthrosis 3 (1) 0 (0) insomnia 3 (1) 0 (0) dyspnea 3 (1) 0 (0) rash 3 (1) 1 (1.1) tinnitus 3 (1) 0 (0) *Adverse events occurring in 1% or more of patients receiving diltiazem hydrochloride extended-release capsules. Angina The most common adverse events (frequency ≥1%) in a placebo-controlled, short-term (2 week) clinical angina study with diltiazem hydrochloride extended-release capsules are listed in the table below with placebo-treated patients included for comparison. In this trial, following a placebo phase, patients were randomly assigned to once daily doses of either 120, 240, or 480 mg of diltiazem hydrochloride extended-release capsules. MOST COMMON ADVERSE EVENTS IN A DOUBLE-BLIND, PLACEBO-CONTROLLED SHORT-TERM, ANGINA TRIALS Adverse Events (COSTART Term) D iltiazem Hydrochloride Extended-Release Capsules* n=139 # pts (%) Placebo n=50 # pts (%) asthenia 5 (3.6) 2 (4) headache 4 (2.9) 3 (6) pain, back 4 (2.9) 1 (2) rhinitis 4 (2.9) 1 (2) constipation 3 (2.2) 1 (2) nausea 3 (2.2) 0 (0) edema, peripheral 3 (2.2) 1 (2) dizziness 3 (2.2) 0 (0) cough, increased 3 (2.2) 0 (0) bradycardia 2 (1.4) 0 (0) fibrillation, atrial 2 (1.4) 0 (0) arthralgia 2 (1.4) 0 (0) dream, abnormal 2 (1.4) 0 (0) dyspnea 2 (1.4) 0 (0) pharyngitis 2 (1.4) 1 (2) *Adverse events occurring in 1% or more of patients receiving diltiazem hydrochloride extended-release capsules. Infrequent Adverse Events The following additional events (COSTART Terms), listed by body system, were reported infrequently (less than 1%) in all subjects, hypertensive (n=425) or angina (n=318) patients who received diltiazem hydrochloride extended-release capsules, or with other formulations of diltiazem. Hypertension Cardiovascular: First-degree AV block, arrhythmia, postural hypotension, tachycardia, pallor, palpitations, phlebitis, ECG abnormality, ST elevation. Nervous System: Vertigo, hypertonia, paresthesia, dizziness, somnolence. Digestive System: Dry mouth, anorexia, tooth disorder, eructation. Skin and Appendages: Sweating, urticaria, skin hypertrophy (nevus). Respiratory System: Epistaxis, bronchitis, respiratory disorder. Urogenital System: Cystitis, kidney calculus, impotence, dysmenorrhea, vaginitis, prostate disease. Metabolic and Nutritional Disorders: Gout, edema. Musculoskeletal System: Arthralgia, bursitis, bone pain. Hemic and Lymphatic System: Lymphadenopathy. Body as a Whole: Pain, unevaluable reaction, neck pain, neck rigidity, fever, chest pain, malaise. Special Senses: Amblyopia (blurred vision), ear pain. Angina Cardiovascular: Palpitations, AV block, sinus bradycardia, bigeminal extrasystole, angina pectoris, hypertension, hypotension, myocardial infarct, my…