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Tiazac Extended Release (Capsule, Extended Release)

Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1857

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Tiazac Extended Release (Capsule, Extended Release)
dailymed-instance:dosage
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.<br/>Concomitant use with Other Cardiovascular Agents.: 1. Sublingual Nitroglycerin may be taken as required to abort acute anginal attacks during diltiazem hydrochloride therapy. 2. Prophylactic Nitrate Therapy - Diltiazem hydrochloride may be safely co-administered with short- and long-acting nitrates. 3. Beta-blockers. 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 indi-cated.<br/>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 capsulecontents/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.
dailymed-instance:descripti...
Tiazac' (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)-, mono-hydrochloride, (+)-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: Microcrystalline Cellulose NF, Sucrose Stearate, Eudragit, Povidone USP, Talc USP, Magnesium Stearate NF, Hypromellose USP, Titanium Dioxide USP, Polysorbate NF, Simethicone USP, Gelatin NF, FD&C Blue #1, FD&C Red #40, D&C Red #28, FD&C Green #3, Black Iron Oxide USP, and other solids. For oral administration.
dailymed-instance:clinicalP...
The therapeutic effects of diltiazem hydrochloride are believed to be related to its ability to inhibit the cellular influx of calcium ions during membrane depolarization of cardiac and vascular smooth muscle.<br/>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 HCl 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 work loads. 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) occurin 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 work load. 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 ofventricular 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 intravenous doses of 0.5 mg/kg of body weight. Diltiazem-associated prolongation of the AH interval is not more pronounced in patients with first degree heart block. In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases). Intravenous diltiazem in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods by approximately 20%. In two short term, double-blind, placebo-controlled studies in 256 hypertensive patients with doses up to 540 mg/day, Tiazac' showed a clinically unimportant but statistically significant, dose-related increase in PR interval (0.008 seconds). There were no instances of greater than first-degree AV block in any of the clinical trials .<br/>Pharmacodynamics.: Hypertension: In short term, double blind, placebo-controlled clinical trials Tiazac' demonstrated a dose-related antihypertensive response among patients with mild to moderate hypertension. In one parallel-group study of 198 patients Tiazac' was given for four weeks. The changes in diastolic blood pressure measured at trough (24 hours after the dose) for placebo, 90 mg, 180 mg, 360 mg and 540 mg were -5.4, -6.3, -6.2, -8.2, and -11.8 mm Hg, respectively. Supine diastolic blood pressure as well as standing diastolic and systolic blood pressures also showed statistically significant linear dose response effects. In another clinical trial that followed a dose-escalation design, Tiazac' also reduced blood pressure in a linear dose-related manner. Supine diastolic blood pressure measured following two-week intervals of treatment was reduced by -3.7 mm Hg with 120 mg/day versus -2.0 mm Hg with placebo, by -7.6 mm Hg after escalation to 240 mg/day versus -2.3 mm Hg with placebo, by -8.1 mm Hg after escalation to 360 mg/day versus -0.9 mm Hg with placebo, and by -10.8 mm Hg after escalation to 480/540 mg/day versus -2.2 mm Hg with placebo. Angina: In a double-blind parallel group placebo-controlled trial (approximately 50 patients/group, in patients with chronic stable angina), Tiazac' at doses of 120-540 mg/day increased exercise tolerance time. At trough, 24 hours after dosing, exercise tolerance times using a Bruce exercise protocol, increased by 14, 26, 41, 33 and 32 seconds over baseline for placebo and the 120 mg, 240 mg, 360 mg, and 540 mg treated patient groups, respectively. At peak, 8 hours after dosing, exercise tolerance times relative to baseline were statistically significantly increased by 13, 38, 64, 55 and 42 seconds for placebo and 120 mg, 240 mg, 360 mg, and 540 mg Tiazac' treated patients, respectively. Compared to baseline, Tiazac' treated patients experienced statistically significant reductions in anginal attacks and decreased nitroglycerin requirements when compared to placebo treated patients. Pharmacokinetics and Metabolism. Diltiazem is well absorbed from the gastrointestinal tract but undergoes substantial hepatic first-pass effect. The absolute bioavailability of an oral dose of an immediate release formulation (compared to intravenous administration) is approximately 40%. Only 2% to 4% of unchanged diltiazemappears in the urine. The plasma elimination half-life of diltiazem is approximately 3.0 - 4.5 h. Drugs which induce or inhibit hepatic microsomal enzymes may alter diltiazem disposition. Therapeutic blood levels of diltiazem appear to be in the range of 40 - 200 ng/mL. There is a departure from linearity when dose strengths are increased; the half-life is slightly increased with dose. The two primary metabolites of diltiazem are desacetyldiltiazem and desmethyldiltiazem. The desacetyl metabolite is approximately 25% to 50% as potent a coronary vasodilator as diltiazem and is present in plasma at concentrations of 10% to 20% of parent diltiazem. However, recent studies employing sensitive and specific analytical methods have confirmed the existence of several sequential metabolic pathways of diltiazem. As many as nine diltiazem metabolites have been identified in the urine of humans. Total radioactivity measurements following single intravenous dose administration in healthy volunteers suggest the presence of other unidentified metabolites. These metabolites are more slowly excreted (with a half-life of total radioactivity of approximately 20 hours), and attain concentrations in excess of diltiazem. In vitro binding studies show diltiazem HCl is 70% to 80% bound to plasma proteins. Competitive in vitro ligand binding studies have also shown diltiazem HCl binding is not altered by therapeutic concentrations of digoxin, hydrochlorothiazide, phenylbutazone, propranolol, salicylic acid, or warfarin. A study that compared patients with normal hepatic function to patients with cirrhosis who received immediate release diltiazem found an increase in diltiazem elimination half-life and a 69% increase in bioavailability in the hepatically impaired patients. Patients with severely impaired renal function (creatinine clearance<50 mL/min) who received immediate release diltiazem had modestly increased diltiazem concentrations compared to patients with normal renal function. Tiazac' Capsules. When compared to a regimen of immediate-release tablets at steady-state, approximately 93% of drug is absorbed from the Tiazac' formulation. When Tiazac' was coadministered with a high fat content breakfast, the extent of diltiazem absorption was not affected; T, however, occurred slightly earlier. The apparent elimination half-life after single or multiple dosing is 4 to 9.5 hours (mean 6.5 hours). Tiazac' demonstrates non-linear pharmacokinetics. As the daily dose of Tiazac' capsules is increased from 120 to 540 mg, there was a more than proportional increase in diltiazem plasma concentrations as evidenced by an increase of AUC, Cand Cof 6.8, 6 and 8.6 times, respectively, for a 4.5 times increase in dose.
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Diltiazem 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 severe 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.
dailymed-instance:supply
Tiazac' (diltiazem hydrochloride) Extended Release Capsules Storage conditions: Store at controlled room temperature20��-25��C (68��-77��F).Avoid excessive humidity.
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dailymed-instance:overdosag...
The oral LD50's in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively. The intravenous LD50's in these species were 60 and 38 mg/kg, respectively. The oral LD50 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 gm to 10.8 gm. Sixteen of these reports involved multiple drug ingestions. Twenty-two reports indicated patients had recovered from diltiazem overdose ranging from less than 1 gm to 10.8 gm. 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 levarterenol bitartrate). 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 gm of oral diltiazem have been successfully treated using appropriate supportive care.
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diltiazem hydrochloride
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Tiazac Extended Release (Capsule, Extended Release)
dailymed-instance:adverseRe...
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 120-540 mg oncedaily. 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. 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 extrasysto-les. 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 hepatic warnings), 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: alopecia, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, extrapyramidal symptoms, gingival hyperplasia, hemolytic anemia, increased bleeding time, 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.
dailymed-instance:indicatio...
Hypertension:: Tiazac' is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive medications.<br/>Chronic Stable Angina:: Tiazac' is indicated for the treatment of chronic stable angina.
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Tiazac Extended Release