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Diltiazem Hydrochloride Extended-release (Capsule)

Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/4004

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Diltiazem Hydrochloride Extended-release (Capsule)
dailymed-instance:dosage
Dosages must be adjusted to each patient's needs, starting with 60 to 120 mg twice daily. Maximum antihypertensive effect is usually observed by 14 days of chronic therapy; therefore, dosage adjustments should be scheduled accordingly. Although individual patients may respond to lower doses, the usual optimum dosage range in clinical trials was 240 to 360 mg/day. Diltiazem hydrochloride extended-release capsules have an additive antihypertensive effect when used with other antihypertensive agents. Therefore, the dosage of diltiazem hydrochloride extended-release capsules or the concomitant antihypertensives may need to be adjusted when adding one to the other. See WARNINGS and PRECAUTIONS regarding use with beta-blockers.
dailymed-instance:descripti...
Diltiazem hydrochloride is a calcium ion 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 structural formula is: Diltiazem hydrochloride, USP is a white to off-white crystalline powder with a bitter taste. It is soluble in water, methanol and chloroform. It has a molecular weight of 450.99. Each extended-release capsule, for oral administration, contains 60 mg, 90 mg, or 120 mg diltiazem hydrochloride. In addition, each capsule contains the following inactive ingredients: Diethyl phthalate, gelatin, hypromellose, maltodextrin, methacrylic acid copolymer Type B, pharmaceutical glaze, polyethylene glycol, povidone, propylene glycol, silicon dioxide, sodium lauryl sulfate, sugar spheres (25/30 mesh), synthetic black iron oxide, titanium dioxide, FD&C Red #40, FD&C Blue #2 Aluminum Lake, FD&C Red #40 Aluminum Lake, FD&C Blue #1 Aluminum Lake, D&C Yellow #10 Aluminum Lake. In addition, the 90 mg product contains D&C Yellow #10 coloring agent. Diltiazem Hydrochloride Extended-release Capsules, USP (Twice-a-Day Dosage) 60 mg, 90 mg, and 120 mg meet USP Drug Release Test 4.
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The therapeutic effects of diltiazem are believed to be related to its ability to inhibit the influx of calcium ions during membrane depolarization of cardiac and vascular smooth muscle.<br/>Mechanism of Action: Diltiazem hydrochloride 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.<br/>Hemodynamic and Electrophysiologic Effects: Like other calcium 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. Increased heart failure has, however, been reported in occasional 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 extended-release capsules decrease vascular resistance, increase cardiac output (by increasing stroke volume), and produce 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. Heart rate at maximum exercise does not change, or is slightly reduced. Chronic therapy with diltiazem produces no change or an increase in plasma catecholamines. No increased activity of the renin-angiotensin-aldosterone axis has been observed. Diltiazem hydrochloride extended-release capsules antagonizes 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. Intravenous diltiazem hydrochloride in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods approximately 20%. In a study involving single oral doses of 300 mg of diltiazem hydrochloride in six normal volunteers, the average maximum PR prolongation was 14% with no instances of greater than first-degree AV block. 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). Chronic oral administration of diltiazem hydrochloride in doses of up to 360 mg/day has resulted in small increases in PR interval, and on occasion produces abnormal prolongation .<br/>Pharmacokinetics and Metabolism: Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to intravenous administration) of about 40%. Diltiazem undergoes extensive metabolism in which 2% to 4% of the unchanged drug appears in the urine. In vitro binding studies show diltiazemis 70% to 80% bound to plasma proteins. Competitive in vitro ligand binding studies have also shown diltiazem binding is not altered by therapeutic concentrations of digoxin, hydrochlorothiazide, phenylbutazone, propranolol, salicylic acid, or warfarin. The plasma elimination half-life following single or multiple drug administration is approximately 3.0 to 4.5 hours. Desacetyl diltiazem is also present in the plasma at levels of 10% to 20% of the parent drug and is 25% to 50% as potent a coronary vasodilator as diltiazem. Minimum therapeutic plasma levels of diltiazem appear to be in the range of 50 to 200 ng/mL. There is a departure from linearity when dose strengths are increased; the half-life is slightly increased with dose. A study that compared patients with normal hepatic function to patients with cirrhosis found an increase in half-life and a 69% increase in bioavailability in the hepatically impaired patients. A single study in nine patients with severely impaired renal function showed no differencein the pharmacokinetic profile of diltiazem compared to patients with normal renal function.<br/>Diltiazem Hydrochloride Extended-release Capsules, USP (Twice-a-Day Dosage): A single 120 mg dose of the capsule results in detectable plasma levels within 2 to 3 hours and peak plasma levels at 6 to 11 hours. The apparent elimination half-life after single or multiple dosing is 5 to 7 hours. A departure from linearity similar to that observed with the diltiazem hydrochloride tablet is observed. As the dose of diltiazem hydrochloride extended-release capsules is increased from a daily dose of 120 mg (60 mg b.i.d.) to 240 mg (120 mg b.i.d.) daily, there is an increase in area-under-the-curve of 2.6 times. When the dose is increased from 240 mg to 360 mg daily, there is an increase in area-under-the-curve of 1.8 times. The average plasma levels of the capsule dosed twice daily at steady-state are equivalent to the tablet dosed four times daily when the same total daily dose is administered.
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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 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
Diltiazem Hydrochloride Capsules Extended-release Capsules, USP (Twice-a-Day Dosage) are available containing 60 mg, 90 mg and 120 mg of diltiazem hydrochloride, USP. The 60 mg capsule is a hard-shell gelatin capsule with a coral opaque cap and a white opaque body filled with white to off-white beads. The capsule is axially printed with MYLAN over 6060 in black ink on both the cap and the body. They are available as follows: NDC 0378-6060-01 bottles of 100 capsules The 90 mg capsule is a hard-shell gelatin capsule with a coral opaque cap and an ivory opaque body filled with white to off-white beads. The capsule is axially printed with MYLAN over 6090 in black ink on both the cap and the body. They are available as follows: NDC 0378-6090-01 bottles of 100 capsules The 120 mg capsule is a hard-shell gelatin capsule with a coral opaque cap and a coral opaque body filled with white to off-white beads. The capsule is axially printed with MYLAN over 6120 in black ink on both the cap and the body. They are available as follows: NDC 0378-6120-01 bottles of 100 capsules Store at 20��to 25��C (68��to 77��F). [See USP for Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
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dailymed-instance:overdosag...
The oral LD's in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively. The intravenous LD's in these species were 60 and 38 mg/kg, respectively. The oral LDin 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 gram to 10.8 grams. Sixteen of these reports involve multiple drug ingestions. Twenty-two reports indicated patients had recovered from diltiazem overdose ranging from less than 1 gram to 10.8 grams. 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, gastric lavage, 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 overdosage 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. Limited data suggest that plasmapheresis or charcoal hemoperfusion may hasten diltiazem elimination following overdose. Based on the known pharmacological effects of diltiazem and/or reported clinical experiences the following measures may be considered: Bradycardia: Administer atropine (0.6 to 1 mg). If there is no response to vagal blockade, 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 bitartrate). Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.
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Diltiazem Hydrochloride
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Diltiazem Hydrochloride Extended-release (Capsule)
dailymed-instance:adverseRe...
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 adverse events described below represent events observed in clinical studies of hypertensive patients receiving either diltiazem hydrochloride tablets or diltiazem hydrochloride extended-release capsules, as well as experiences observed in studies of angina and during marketing. The most common events in hypertension studies are shown in a table with rates in placebo patients shown for comparison. Less common events are listed by body system; these include any adverse reactions seen in angina studies that were not observed in hypertension studies. In all hypertensive patients studied (over 900), the most common adverse events were edema (9%), headache (8%), dizziness (6%), asthenia (5%), sinus bradycardia (3%), flushing (3%), and first degree AV block (3%). Only edema and perhaps bradycardia and dizziness were dose related. The most common events observed in clinical studies (over 2,100 patients) of angina patients and hypertensive patients receiving diltiazem hydrochloride tablets or diltiazem hydrochloride extended-release capsules were (i.e., greater than 1%) edema (5.4%), headache (4.5%), dizziness (3.4%), asthenia (2.8%), first degree AV block (1.8%), flushing (1.7%), nausea (1.6%), bradycardia (1.5%), and rash (1.5%). In addition, the following events were reported infrequently (less than 1%) with diltiazem hydrochloride extended-release capsules or diltiazem hydrochloride tablets or have been observed in angina or hypertension trials. Cardiovascular: Angina, arrhythmia, second- or third-degree AV block (see Conduction Warning), bundle branch block, congestive heart failure, syncope, tachycardia, ventricular extrasystoles. Nervous System: Abnormal dreams, amnesia, depression, gait abnormality, hallucinations, nervousness, paresthesia, personality change, tremor. Gastrointestinal: Anorexia, diarrhea, dry mouth, dysgeusia, mild elevations of SGOT, SGPT, and LDH (see Hepatic Warnings), 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, sexual difficulties, tinnitus. The following post-marketing events have been reported infrequently in patients receiving diltiazem: allergic reactions, alopecia, angioedema (including facial or periorbital edema), asystole, erythema multiforme (including Stevens-Johnson Syndrome, toxic epidermal necrolysis), extrapyramidal symptoms, gingival hyperplasia, hemolytic anemia, increased bleeding time, leukopenia, purpura, retinopathy, and thrombocytopenia. There have been observed cases of a generalized rash, some characterized as leukocytoclastic vasculitis. 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 definitive cause and effect relationship between these events and diltiazem therapy cannot yet be established. Exfoliative dermatitis (proven by rechallenge) has also been reported.
dailymed-instance:indicatio...
Diltiazem Hydrochloride Extended-release Capsules, USP (Twice-a-Day Dosage) are indicated for the treatment of hypertension. They may be used alone or in combination with other antihypertensive medications, such as diuretics.
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Diltiazem Hydrochloride Extended-release