Diltiazem Hydrochloride

INDICATIONS AND USAGE DILT-XR [Diltiazem Hydrochloride Extended-Release Capsules, USP (Once-a-day dosage)] are indicated for the treatment of hypertension. Diltiazem hydrochloride may be used alone or in combination with other antihypertensive medications, such as diuretics. DILT-XR [Diltiazem Hydrochloride Extended-Release Capsules, USP (Once-a-day dosage)] 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 DILT-XR [Diltiazem Hydrochloride Extended-Release Capsules, USP (Once-a-day dosage)] 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 DILT-XR [Diltiazem Hydrochloride Extended-Release Capsules, USP (Once-a-day dosage)], when ingested with a high-fat breakfast; therefore, administration in the morning on an empty stomach is recommended. Patients should be cautioned that the DILT-XR [Diltiazem Hydrochloride Extended-Release Capsules, USP (Once-a-day dosage)] 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 DILT-XR [Diltiazem Hydrochloride Extended-Release Capsules, USP (Once-a-day dosage)] 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.

CONTRAINDICATIONS Diltiazem hydrochloride extended-release capsules are 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.

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, USP (Once-a-day dosage). 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, USP (Once-a-day dosage) 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) Diltiazem Hydrochloride Extended-Release Capsules, USP (Once-a-day dosage)* N = 303 # pts (%) Placebo N = 87 # pts (%) rhinitis 29 (9.6) 7 (8.0) headache 27 (8.9) 12 (13.8) pharyngitis 17 (5.6) 4 (4.6) constipation 11 (3.6) 2 (2.3) cough increase 9 (3.0) 2 (2.3) flu syndrome 7 (2.3) 1 (1.1) edema, peripheral 7 (2.3) 0 (0.0) myalgia 7 (2.3) 0 (0.0) diarrhea 6 (2.0) 0 (0.0) vomiting 6 (2.0) 0 (0.0) sinusitis 6 (2.0) 1 (1.1) asthenia 5 (1.7) 0 (0.0) pain, back 5 (1.7) 2 (2.3) nausea 5 (1.7) 1 (1.1) dyspepsia 4 (1.3) 0 (0.0) vasodilatation 4 (1.3) 0 (0.0) injury, accident 4 (1.3) 0 (0.0) pain, abdominal 3 (1.0) 0 (0.0) arthrosis 3 (1.0) 0 (0.0) insomnia 3 (1.0) 0 (0.0) dyspnea 3 (1.0) 0 (0.0) rash 3 (1.0) 1 (1.1) tinnitus 3 (1.0) 0 (0.0) *Adverse events occurring in 1% or more of patients receiving Diltiazem Hydrochloride Extended-Release Capsules, USP (Once-a-day dosage). 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, USP (Once-a-day dosage) 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, USP (Once-a-day dosage). MOST COMMON ADVERSE EVENTS IN A DOUBLE-BLIND, PLACEBO-CONTROLLED SHORT-TERM, ANGINA TRIAL Adverse Events (COSTART Term) Diltiazem Hydrochloride Extended-Release Capsules, USP (Once-a-day dosage)* N = 139 # pts (%) Placebo N = 50 # pts (%) asthenia 5 (3.6) 2 (4.0) headache 4 (2.9) 3 (6.0) pain, back 4 (2.9) 1 (2.0) rhinitis 4 (2.9) 1 (2.0) constipation 3 (2.2) 1 (2.0) nausea 3 (2.2) 0 (0.0) edema, peripheral 3 (2.2) 1 (2.0) dizziness 3 (2.2) 0 (0.0) cough, increased 3 (2.2) 0 (0.0) bradycardia 2 (1.4) 0 (0.0) fibrillation, atrial 2 (1.4) 0 (0.0) arthralgia 2 (1.4) 0 (0.0) dream, abnormal 2 (1.4) 0 (0.0) dyspnea 2 (1.4) 0 (0.0) pharyngitis 2 (1.4) 1 (2.0) * Adverse events occurring in 1% or more of patients receiving Diltiazem Hydrochloride Extended-Release Capsules, USP (Once-a-day dosage). 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, USP (Once-a-day dosage), 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 …

Drug Interactions Due to the potential for additive effects, caution and careful titration are warranted in patients receiving diltiazem hydrochloride concomitantly with any 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 hydrochloride (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. 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 C max 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. Administration of diltiazem hydrochloride concomitantly with propranolol in five normal volunteers resulted in increased propranolol levels in all subjects and bioavailability of propranolol was increased approximately 50%. In vitro , propranolol appears to be displaced from its binding sites by diltiazem. If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted (see WARNINGS ). Buspirone In nine healthy subjects, diltiazem significantly increased the mean buspirone AUC 5.5-fold and C max 4.1-fold compared to placebo. The T 1/2 and T max 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 1,200 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 th …

Mechanisms of Action Hypertension: Diltiazem produces its antihypertensive effect primarily by relaxation of vascular smooth muscle and the resultant decrease in peripheral vascular resistance. The magnitude of blood pressure reduction is related to the degree of hypertension: thus hypertensive individuals experience an antihypertensive effect, whereas there is only a modest fall in blood pressure in normotensives. Angina: Diltiazem hydrochloride has been shown to produce increases in exercise tolerance, probably due to its ability to reduce myocardial oxygen demand. This is accomplished via reductions in heart rate and systemic blood pressure at submaximal and maximal workloads. Diltiazem has been shown to be a potent dilator of coronary arteries, both epicardial and subendocardial. Spontaneous and ergonovine-induced coronary artery spasms are inhibited by diltiazem. In animal models, diltiazem interferes with the slow inward (depolarizing) current in excitable tissue. It causes excitation-contraction uncoupling in various myocardial tissues without changes in the configuration of the action potential. Diltiazem produces relaxation of the coronary vascular smooth muscle and dilation of both large and small coronary vascular smooth muscle and dilation of both large and small coronary arteries at drug levels which cause little or no negative inotropic effect. The resultant increases in coronary blood flow (epicardial and subendocardial) occur in ischemic and nonischemic models and are accompanied by dose-dependent decreases in systemic blood pressure and decreases in peripheral resistance. Hemodynamic and Electrophysiologic Effects Like other calcium channel antagonists, diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In the intact animal, prolongation of the AH interval can be seen at higher doses. In man, diltiazem prevents spontaneous and ergonovine-provoked coronary artery spasm. It causes a decrease in peripheral vascular resistance and a modest fall in blood pressure in normotensive individuals and, in exercise tolerance studies in patients with ischemic heart disease, reduces the heart rate-blood pressure product for any given workload. Studies to date, primarily in patients with good ventricular function, have not revealed evidence of a negative inotropic effect; cardiac output, ejection fraction, and left ventricular end-diastolic pressure have not been affected. Such data have no predictive value with respect to effects in patients with poor ventricular function, and increased heart failure has been reported in patients with preexisting impairment of ventricular function. There are as yet few data on the interaction of diltiazem and beta-blockers in patients with poor ventricular function. Resting heart rate is usually slightly reduced by diltiazem. Diltiazem hydrochloride extended-release capsules produce antihypertensive effects both in the supine and standing positions. Postural hypotension is infrequently noted upon suddenly assuming an upright position. No reflex tachycardia is associated with the chronic antihypertensive effects. Diltiazem hydrochloride decreases vascular resistance, increases cardiac output (by increasing stroke volume), and produces a slight decrease or no change in heart rate. During dynamic exercise, increases in diastolic pressure are inhibited while maximum achievable systolic pressure is usually reduced. Chronic therapy with diltiazem hydrochloride produces no change or an increase in plasma catecholamines. No increased activity of the renin-angiotensin-aldosterone axis has been observed. Diltiazem hydrochloride reduces the renal and peripheral effects of angiotensin II. Hypertensive animal models respond to diltiazem with reductions in blood pressure and increased urinary output and natriuresis without a change in urinary sodium/potassium ratio. In man, transient natriuresis and kaliuresis ha …

DESCRIPTION Diltiazem hydrochloride is a calcium ion cellular influx inhibitor (slow channel blocker or calcium antagonist). Chemically, diltiazem hydrochloride is 1,5-Benzothiazepin-4(5 H )-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, odourless, crystalline powder or small crystals. It is freely soluble in chloroform, in formic acid, in methanol, and in water; sparingly soluble in dehydrated alcohol; insoluble in ether. It has a molecular weight of 450.98. Diltiazem hydrochloride extended-release capsule, USP is 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). Each capsule contains the following inactive ingredients: acetyl tributyl citrate, ammonio methacrylate copolymer type A, ammonio methacrylate copolymer type B, colloidal silicon dioxide, gelatin, hypromellose, sodium lauryl sulfate, sugar sphere, talc and titanium dioxide. Additionally each 120 mg capsule shell contains D & C yellow # 10, FD & C blue # 1 and FD & C red # 40; each 180 mg capsule shell contains FD & C blue # 1, FD & C red # 3 and iron oxide black; each 240 mg capsule shell contains FD & C blue # 1 and FD & C red # 3; each 300 mg capsule shell contains D & C yellow # 10, FD & C blue # 1, FD & C red # 40 and iron oxide black; each 360 mg capsule shell contains iron oxide black. Each capsule is printed with black pharmaceutical ink which contains black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, shellac and strong ammonia solution. Diltiazem Hydrochloride Extended-release Capsule, USP meets USP Dissolution Test 3. For oral administration. figure

OVERDOSAGE The oral LD 50 s in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively. The intravenous LD 50 s in these species were 60 and 38 mg/kg, respectively. The oral LD 50 in dogs is considered to be in excess of 50 mg/kg, while lethality was seen in monkeys at 360 mg/kg. The toxic dose in man is not known. Due to extensive metabolism, blood levels after a standard dose of diltiazem can vary over ten-fold, limiting the usefulness of blood levels in overdose cases. There have been 29 reports of diltiazem overdose in doses ranging from less than 1 g to 10.8 g. Sixteen of these reports involved multiple drug ingestions. Twenty-two reports indicated patients had recovered from diltiazem overdose ranging from less than 1 g to 10.8 g. There were seven reports with a fatal outcome; although the amount of diltiazem ingested was unknown, multiple drug ingestions were confirmed in six of the seven reports. Events observed following diltiazem overdose included bradycardia, hypotension, heart block, and cardiac failure. Most reports of overdose described some supportive medical measure and/or drug treatment. Bradycardia frequently responded favorably to atropine as did heart block, although cardiac pacing was also frequently utilized to treat heart block. Fluids and vasopressors were used to maintain blood pressure, and in cases of cardiac failure, inotropic agents were administered. In addition, some patients received treatment with ventilatory support, activated charcoal, and/or intravenous calcium. Evidence of the effectiveness of intravenous calcium administration to reverse the pharmacological effects of diltiazem overdose was conflicting. In the event of overdose or exaggerated response, appropriate supportive measures should be employed in addition to gastrointestinal decontamination. Diltiazem does not appear to be removed by peritoneal or hemodialysis. Based on the known pharmacological effects of diltiazem and/or reported clinical experiences, the following measures may be considered: Bradycardia: Administer atropine (0.60 to 1.0 mg). If there is no response to vagal blockage, 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). Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. In a few reported cases, overdose with calcium channel blockers has been associated with hypotension and bradycardia, initially refractory to atropine but becoming more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride. Due to extensive metabolism, plasma concentrations after a standard dose of diltiazem can vary over tenfold, which significantly limits their value in evaluation cases of overdosage. Charcoal hemoperfusion has been used successfully as an adjunct therapy to hasten drug elimination. Overdoses with as much as 10.8 g of oral diltiazem have been successfully treated using appropriate supportive care.

HOW SUPPLIED Diltiazem Hydrochloride Extended-release Capsules USP, 120 mg are white to off white pellets filled in size "2" empty hard gelatin capsules with opaque light green colored cap & opaque white colored body imprinted with "595" in black ink and are supplied as follows: NDC 68382-595-06 in bottles of 30 capsules with child-resistant closure NDC 68382-595-16 in bottles of 90 capsules with child-resistant closure NDC 68382-595-01 in bottles of 100 capsules NDC 68382-595-05 in bottles of 500 capsules NDC 68382-595-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose capsules Diltiazem Hydrochloride Extended-release Capsules USP, 180 mg are white to off white pellets filled in size "0" empty hard gelatin capsules with opaque light blue colored cap & opaque grey colored body imprinted with "596" in black ink and are supplied as follows: NDC 68382-596-06 in bottles of 30 capsules with child-resistant closure NDC 68382-596-16 in bottles of 90 capsules with child-resistant closure NDC 68382-596-01 in bottles of 100 capsules NDC 68382-596-05 in bottles of 500 capsules NDC 68382-596-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose capsules Diltiazem Hydrochloride Extended-release Capsules USP, 240 mg are white to off white pellets filled in size "00" empty hard gelatin capsules with opaque light blue colored cap & opaque white colored body imprinted with "597" in black ink and are supplied as follows: NDC 68382-597-06 in bottles of 30 capsules with child-resistant closure NDC 68382-597-16 in bottles of 90 capsules with child-resistant closure NDC 68382-597-01 in bottles of 100 capsules NDC 68382-597-05 in bottles of 500 capsules NDC 68382-597-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose capsules Diltiazem Hydrochloride Extended-release Capsules USP, 300 mg are white to off white pellets filled in size "00" empty hard gelatin capsules with opaque light green colored cap & opaque grey colored body imprinted with "598" in black ink and are supplied as follows: NDC 68382-598-06 in bottles of 30 capsules with child-resistant closure NDC 68382-598-16 in bottles of 90 capsules with child-resistant closure NDC 68382-598-01 in bottles of 100 capsules NDC 68382-598-05 in bottles of 500 capsules NDC 68382-598-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose capsules Diltiazem Hydrochloride Extended-release Capsules USP, 360 mg are white to off white pellets filled in size "00" empty hard gelatin capsules with opaque grey colored cap & opaque white colored body imprinted with "599" in black ink and are supplied as follows: NDC 68382-599-06 in bottles of 30 capsules with child-resistant closure NDC 68382-599-16 in bottles of 90 capsules with child-resistant closure NDC 68382-599-01 in bottles of 100 capsules NDC 68382-599-05 in bottles of 500 capsules NDC 68382-599-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose capsules Storage Conditions: Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature] . Avoid excessive humidity. Dispense in a tight container as defined in the USP. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Manufactured by: Zydus Lifesciences Ltd., Ahmedabad, India Distributed by: Zydus Pharmaceuticals (USA) Inc. Pennington, NJ 08534 Rev.: 05/25