DILTIAZEM HYDROCHLORIDE EXTENDED RELEASE

Diltiazem hydrochloride is a calcium ion cellular influx inhibitor (slow channel blocker). 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: [Chemical Structure] Diltiazem hydrochloride is a white to off-white crystalline powder with a bitter taste. It is soluble in water, methanol and chloroform and has a molecular weight of 450.98. Diltiazem hydrochloride extended-release capsules contain diltiazem hydrochloride in extended-release beads at doses of 120, 180, 240, 300, 360 and 420 mg. Diltiazem Hydrochloride Extended-Release Capsules, USP also contain: black iron oxide, D&C Red No. 28, ethyl acrylate and methyl methacrylate copolymer dispersion, FD&C Blue No. 1, FD&C Green No. 3, FD&C Red No. 40, gelatin, hypromellose, magnesium stearate, microcrystalline cellulose, polysorbate, povidone, simethicone, sucrose stearate, talc, and titanium dioxide. USP Drug Release Test 6 For oral administration.

Hypertension Diltiazem hydrochloride extended-release capsules are indicated for the treatment of hypertension. They may be used alone or in combination with other antihypertensive medications. Chronic Stable Angina Diltiazem hydrochloride extended-release capsules are indicated for the treatment of chronic stable angina.

Hypertension: Dosage needs to be adjusted by titration to individual patient needs. When used as monotherapy, usual starting doses are 120 to 240 mg once daily. Maximum antihypertensive effect is usually observed by 14 days of chronic therapy; therefore, dosage adjustments should be scheduled accordingly. The usual dosage range studied in clinical trials was 120 to 540 mg once daily. Current clinical experience with 540 mg dose is limited; however, the dose may be increased to 540 mg once daily. Angina: Dosages for the treatment of angina should be adjusted to each patient's needs, starting with a dose of 120 mg to 180 mg once daily. Individual patients may respond to higher doses of up to 540 mg once daily. When necessary, titration should be carried out over 7 to 14 days. Concomitant Use with Other Cardiovascular Agents: 1. Sublingual Nitroglycerin (NTG): May be taken as required to abort acute anginal attacks during diltiazem hydrochloride therapy. 2. Prophylactic Nitrate Therapy: Diltiazem hydrochloride may be safely coadministered with short- and long-acting nitrates. 3. Beta-blockers: (See WARNINGS and PRECAUTIONS.) 4. 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. 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. Sprinkling the Capsule Contents on Food: Diltiazem hydrochloride extended-release capsules may also be administered by carefully opening the capsule and sprinkling the capsule contents on a spoonful of applesauce. The applesauce should be swallowed immediately without chewing and followed with a glass of cool water to ensure complete swallowing of the capsule contents. The applesauce should not be hot, and it should be soft enough to be swallowed without chewing. Any capsule contents/applesauce mixture should be used immediately and not stored for future use. Subdividing the contents of a diltiazem hydrochloride extended-release capsule is not recommended.

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

Serious adverse reactions have been rare in studies with diltiazem hydrochloride extended-release capsules, as well as with other diltiazem formulations. It should be recognized that patients with impaired ventricular function and cardiac conduction abnormalities have usually been excluded from these studies. A total of 256 hypertensives were treated for between 4 and 8 weeks; a total of 207 patients with chronic stable angina were treated for 3 weeks with doses of diltiazem hydrochloride extended-release capsules ranging from 120 to 540 mg once daily. Two patients experienced first-degree AV block at the 540 mg dose. The following table presents the most common adverse reactions, whether or not drug-related, reported in placebo-controlled trials in patients receiving diltiazem hydrochloride extended-release capsules up to 360 mg and up to 540 mg with rates in placebo patients shown for comparison. MOST COMMON ADVERSE EVENTS IN DOUBLE-BLIND PLACEBO-CONTROLLED HYPERTENSION TRIALS* Placebo Diltiazem Hydrochloride Extended-Release Capsules Adverse Events (COSTART Term) n=57 # pts (%) Up to 360 mg n=149 # pts (%) 480 - 540 mg n=48 # pts (%) * Adverse events occurring in treated patients at 2% or more than placebo-treated patients. edema, peripheral 1 (2) 8 (5) 7 (15) dizziness 4 (7) 6 (4) 2 (4) vasodilation 1 (2) 5 (3) 1 (2) dyspepsia 0 (0) 7 (5) 0 (0) pharyngitis 2 (4) 3 (2) 3 (6) rash 0 (0) 3 (2) 0 (0) infection 2 (4) 2 (1) 3 (6) diarrhea 0 (0) 2 (1) 1 (2) palpitations 0 (0) 2 (1) 1 (2) nervousness 0 (0) 3 (2) 0 (0) MOST COMMON ADVERSE EVENTS IN DOUBLE-BLIND PLACEBO-CONTROLLED ANGINA TRIALS* Placebo Diltiazem Hydrochloride Extended-Release Capsules Adverse Events (COSTART Term) n=50 # pts (%) Up to 360 mg n=158 # pts (%) 540 mg n=49 # pts (%) * Adverse events occurring in treated patients at 2% or more than placebo-treated patients. headache 1 (2) 13 (8) 4 (8) edema, peripheral 1 (2) 3 (2) 5 (10) pain 1 (2) 10 (6) 3 (6) dizziness 0 (0) 5 (3) 5 (10) asthenia 0 (0) 1 (1) 2 (4) dyspepsia 0 (0) 2 (1) 3 (6) dyspnea 0 (0) 1 (1) 3 (6) bronchitis 0 (0) 1 (1) 2 (4) AV block 0 (0) 0 (0) 2 (4) infection 0 (0) 2 (1) 1 (2) flu syndrome 0 (0) 0 (0) 1 (2) cough increase 0 (0) 2 (1) 1 (2) extrasystoles 0 (0) 0 (0) 1 (2) gout 0 (0) 2 (1) 1 (2) myalgia 0 (0) 0 (0) 1 (2) impotence 0 (0) 0 (0) 1 (2) conjunctivitis 0 (0) 0 (0) 1 (2) rash 0 (0) 2 (1) 1 (2) abdominal enlargement 0 (0) 0 (0) 1 (2) In addition, the following events have been reported infrequently (less than 2%) in clinical trials with other diltiazem products: 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, mild elevations of SGOT, SGPT, LDH, and alkaline phosphatase (see WARNINGS, ACUTE HEPATIC INJURY), nausea, thirst, vomiting, weight increase. Dermatological: Petechiae, photosensitivity, pruritus. Other: Albuminuria, allergic reaction, amblyopia, asthenia, CPK increase, crystalluria, dyspnea, edema, epistaxis, eye irritation, headache, hyperglycemia, hyperuricemia, impotence, muscle cramps, nasal congestion, neck rigidity, nocturia, osteoarticular pain, pain, polyuria, rhinitis, sexual difficulties, gynecomastia. In addition, the following postmarketing events have been reported infrequently in patients receiving diltiazem hydrochloride: acute generalized exanthematous pustulosis, alopecia, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, extrapyramidal symptoms, gingival hyperplasia, hemolytic anemia, increased bleeding time, photosensitivity (including lichenoid keratosis and hyperpigmentation at sun-exposed skin areas), leukopenia, purpura, retinopathy, 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, 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 Oceanside Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.