DILTIAZEM HYDROCHLORIDE

Diltiazem hydrochloride, USP is a calcium ion cellular influx inhibitor (slow channel blocker or calcium antagonist). Chemically, diltiazem hydrochloride is 1,5-Benzothiazepin-4(5H)-one, 3-(acetyloxy)-5-[2-(dimethylamino) ethyl]-2, 3-dihydro-2-(4-methoxyphenyl)-, monohydrochloride, (+)-cis-. The chemical structure is: Diltiazem hydrochloride, USP is a white to off-white crystalline powder with a bitter taste. It is freely soluble in chloroform, in formic acid, in methanol and in water, sparingly soluble in dehydrated ethanol, insoluble in ether. It has a molecular weight of 450.98. Diltiazem hydrochloride extended-release capsules, USP are formulated as a once-a-day extended-release capsule containing 120 mg diltiazem hydrochloride, USP (equivalent to 110.3 mg diltiazem), 180 mg diltiazem hydrochloride, USP (equivalent to 165.45 mg diltiazem), 240 mg diltiazem hydrochloride, USP (equivalent to 220.6 mg diltiazem), 300 mg diltiazem hydrochloride, USP (equivalent to 275.75 mg diltiazem), or 360 mg diltiazem hydrochloride, USP (equivalent to 330.9 mg diltiazem). The 120 mg, 180 mg, 240 mg, 300 mg and 360 mg capsules contain acetyl tributyl citrate, ethylcellulose, hypromellose, microcrystalline cellulose, povidone K-30, sucrose stearate, talc. The 120 mg, 180 mg, 240 mg, 300 mg and 360 mg capsule shells contain FD&C Blue 1, gelatin and titanium dioxide. The 300 mg capsule shell also contain iron oxide black. The 120 mg capsule shells are imprinted with edible blue ink containing FD&C Blue # 2 Aluminum Lake and shellac. The 180 mg, 240 mg, 300 mg and 360 mg capsule shells are imprinted with edible white ink containing potassium hydroxide, shellac and titanium dioxide. For oral administration. FDA approved dissolution test specifications differ from USP. diltiazem-str.jpg

Diltiazem hydrochloride extended-release capsules are indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive medications. Diltiazem hydrochloride extended-release capsules are indicated for the management of chronic stable angina and angina due to coronary artery spasm.

Patients controlled on diltiazem alone or in combination with other medications may be switched to diltiazem hydrochloride extended-release capsules at the nearest equivalent total daily dose. Higher doses of diltiazem hydrochloride extended-release capsules may be needed in some patients. Monitor patients closely. Subsequent titration to higher or lower doses may be necessary. There is limited general clinical experience with doses above 360 mg, but doses to 540 mg have been studied in clinical trials. The incidence of side effects increases as the dose increases with first-degree AV block, dizziness, and sinus bradycardia bearing the strongest relationship to dose. Hypertension: Adjust dosage to individual patient needs. When used as monotherapy, reasonable starting doses are 180 to 240 mg once daily, although some patients may respond to lower doses. Maximum antihypertensive effect is usually observed by 14 days of chronic therapy; therefore, schedule dosage adjustments accordingly. The usual dosage range studied in clinical trials was 240 to 360 mg once daily. Individual patients may respond to higher doses of up to 480 mg once daily. Angina: Dosages for the treatment of angina should be adjusted to each patient’s needs, 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 therapy. Prophylactic Nitrate Therapy: Diltiazem hydrochloride may be safely coadministered 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.

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 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.

Serious adverse reactions have been rare in studies carried out to date, but it should be recognized that patients with impaired ventricular function and cardiac conduction abnormalities have usually been excluded from these studies. The following table presents the most common adverse reactions reported in placebo-controlled angina and hypertension trials in patients receiving diltiazem hydrochloride extended-release capsules up to 360 mg with rates in placebo patients shown for comparison. Diltiazem Hydrochloride Extended-Release Capsule Placebo-Controlled Angina and Hypertension Trials Combined Adverse Reactions Diltiazem Hydrochloride Extended-Release Capsule (n=607) Placebo (n=301) Headache 5.4% 5% Dizziness 3% 3% Bradycardia 3.3% 1.3% AV Block First Degree 3.3% 0% Edema 2.6% 1.3% Asthenia 1.8% 1.7% In addition, the following events were reported infrequently (less than 1%) in angina or hypertension trials: Cardiovascular: Congestive heart failure, palpitations, syncope, 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 (see WARNINGS, 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. The following postmarketing events have been reported infrequently in patients receiving diltiazem hydrochloride: acute generalized exanthematous pustulosis, allergic reactions, alopecia, angioedema (including facial or periorbital edema), asystole, erythema multiforme (including Stevens-Johnson syndrome, toxic epidermal necrolysis), exfoliative dermatitis, extrapyramidal symptoms, gingival hyperplasia, hemolytic anemia, increased bleeding time, leukopenia, photosensitivity (including lichenoid keratosis and hyperpigmentation at sun-exposed skin areas), purpura, retinopathy, myopathy, and thrombocytopenia. In addition, events such as myocardial infarction have been observed which are not readily distinguishable from the natural history of the disease in these patients. A number of well-documented cases of generalized rash, some characterized as leukocytoclastic vasculitis, have been reported. However, a definitive cause and effect relationship between these events and diltiazem hydrochloride therapy is yet to be established. To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.