TIAZAC

INDICATIONS AND USAGE Hypertension Tiazac is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive medications. Chronic Stable Angina Tiazac is indicated for the treatment of chronic stable angina.

DOSAGE AND ADMINISTRATION 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 Tiazac 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: Tiazac (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 Tiazac (diltiazem hydrochloride) Extended-Release Capsule is not recommended.

CONTRAINDICATIONS 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.

ADVERSE REACTIONS Serious adverse reactions have been rare in studies with Tiazac, 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 Tiazac 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 Tiazac 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 Adverse events occurring in treated patients at 2% or more than placebo-treated patients. Placebo Tiazac Adverse Events (COSTART Term) n=57 # pts (%) Up to 360 mg n=149 # pts (%) 480 - 540 mg n=48 # pts (%) 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 Adverse events occurring in treated patients at 2% or more than placebo-treated patients. Placebo Tiazac Adverse Events (COSTART Term) n=50 # pts (%) Up to 360 mg n=158 # pts (%) 540 mg n=49 # pts (%) 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 …

Drug Interactions Due to the potential for additive effects, caution and careful titration are warranted in patients receiving diltiazem hydrochloride 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 Tiazac (see WARNINGS ). Diltiazem is both a substrate and an inhibitor of the Pg-p and cytochrome P450 3A4 enzyme system which may affect exposure to diltiazem and concomitant drugs metabolized by those pathways. Patients with renal and/or hepatic impairment may be particularly at risk of exposure changes. 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 channel 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 AUC (53%) after a 1-week course of cimetidine 1200 mg/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 P450, 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 the diltiazem dose may be warranted. Clonidine: Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with diltiazem. Monitor heart rate in patients receiving concomitant diltiazem and clonidine. Cyclosporine: A pharmacokinetic interaction between diltiazem and cyclosporine has be …

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. Tiazac produces 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 have been reported, but only in high intrave …

DESCRIPTION Tiazac ® (diltiazem hydrochloride) is a calcium ion cellular influx inhibitor (slow channel blocker). 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 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. Tiazac capsules contain diltiazem hydrochloride in extended-release beads at doses of 120, 180, 240, 300, 360 and 420 mg. Tiazac also contains: 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. chem structure

OVERDOSAGE The oral LD 50S in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively. The intravenous LD 50S 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 tenfold, 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 Tiazac ® (diltiazem hydrochloride) Extended-Release Capsules, USP Strength Description Quantity NDC# 120 mg #3 lavender/lavender capsule imprinted: Tiazac 120 30 90 0187-2612-30 0187-2612-90 180 mg #2 white/blue-green capsule imprinted: Tiazac 180 30 90 0187-2613-30 0187-2613-90 240 mg #1 blue-green/lavender capsule imprinted: Tiazac 240 30 90 0187-2614-30 0187-2614-90 300 mg #0 white/lavender capsule imprinted: Tiazac 300 30 90 0187-2615-30 0187-2615-90 360 mg #0 blue-green/blue-green capsule imprinted: Tiazac 360 30 90 0187-2616-30 0187-2616-90 420 mg #00 white/white capsule imprinted: Tiazac 420 30 90 0187-2617-30 0187-2617-90 Storage Conditions: Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Avoid excessive humidity.