Cardizem La Information
Cardizem la (Diltiazem hcl)
Cardizem la (Diltiazem hcl) Description
Diltiazem hydrochloride is a calcium ion cellular 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 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. Cardizem la (Diltiazem hcl) Tablets, for oral administration, are formulated as a once-a-day extended release tablet containing either 120 mg, 180 mg, 240 mg, 300 mg, 360 mg or 420 mg of diltiazem hydrochloride.
Also contains: Carnauba Wax NF, Colloidal Silicon Dioxide NF, Croscarmellose Sodium NF, Hydrogenated Vegetable Oil NF, Hypromellose USP, Magnesium Stearate NF, Microcrystalline Cellulose NF, Microcrystalline Wax NF, Pregelatinized Starch NF, Polyacrylate Dispersion 30%, Polyethylene Glycol NF, Polydextrose, Polysorbate NF, Povidone USP, Simethicone USP, Sodium Starch Glycolate NF, Sucrose Stearate, Talc USP, Titanium Dioxide USP.
Cardizem la (Diltiazem hcl) Clinical Pharmacology
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
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 only 2% to 4% of the unchanged drug appears in the urine. Drugs which induce or inhibit hepatic microsomal enzymes may alter diltiazem disposition.
Total radioactivity measurement following short IV administration in healthy volunteers suggests the presence of other unidentified metabolites, which attain higher concentrations than those of diltiazem and are more slowly eliminated; half-life of total radioactivity is about 20 hours compared to 2 to 5 hours for diltiazem.
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 has 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 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 produces no change or an increase in plasma catecholamines. No increased activity of the renin-angiotensin-aldosterone axis has been observed. Diltiazem 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.
Intravenous diltiazem hydrochloride in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods by 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 to patients in doses of up to 540 mg/day has resulted in small increases in PR interval, and on occasion produces abnormal prolongation (see ).
Cardizem la (Diltiazem hcl) Indications And Usage
Cardizem la (Diltiazem hcl) is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive medications.
Cardizem la (Diltiazem hcl) is indicated for the management of chronic stable angina.
Cardizem la (Diltiazem hcl) Contraindications
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.
Cardizem la (Diltiazem hcl) Precautions
Diltiazem hydrochloride is extensively metabolized by the liver and excreted by the kidneys and in bile. As with any drug given over prolonged periods, laboratory parameters of renal and hepatic function should be monitored at regular intervals. The drug should be used with caution in patients with impaired renal or hepatic function.
In subacute and chronic dog and rat studies designed to produce toxicity, high doses of diltiazem were associated with hepatic damage. In special subacute hepatic studies, oral doses of 125 mg/kg and higher in rats were associated with histological changes in the liver, which were reversible when the drug was discontinued. In dogs, doses of 20 mg/kg were also associated with hepatic changes; however, these changes were reversible with continued dosing.
Dermatological events (see section) may be transient and may disappear despite continued use of diltiazem. However, skin eruptions progressing to erythema multiforme and/or exfoliative dermatitis have also been infrequently reported. Should a dermatologic reaction persist, the drug should be discontinued.
Drug Interactions.
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, 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.
Pregnancy.
There are no well-controlled studies in pregnant women; therefore, use diltiazem in pregnant women only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers.
Pediatric Use.
Geriatric Use.
Cardizem la (Diltiazem hcl) Adverse Reactions
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.
In the hypertension study, the following table presents adverse reactions more common on diltiazem than on placebo (but excluding events with no plausible relationship to treatment), as reported in placebo-controlled hypertension trials in patients receiving a diltiazem hydrochloride extended-release formulation (once-a-day dosing) up to 540 mg.
In the angina study, the adverse event profile of Cardizem la (Diltiazem hcl) was consistent with what has been previously described for Cardizem la (Diltiazem hcl) and other formulations of diltiazem HCl. The most frequent adverse effects experienced by Cardizem la (Diltiazem hcl) -treated patients were edema lower-limb (6.8%), dizziness (6.4%), fatigue (4.8%), bradycardia (3.6%), first-degree atrioventricular block (3.2%), and cough (2%).
In clinical trials of other diltiazem formulations involving over 3200 patients, the most common events (i.e. greater than 1%) were edema (4.6%), headache (4.6%), dizziness (3.5%), asthenia (2.6%), first-degree AV block (2.4%), bradycardia (1.7%), flushing (1.4%), nausea (1.4%) and rash (1.2%).
In addition, the following events have been reported infrequently (less than 2%) in hypertension trials with other diltiazem products:
The following postmarketing 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), exfoliative dermatitis, 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, some characterized as leukocytoclastic vasculitis, have been reported. However, a definitive cause and effect relationship between these events and diltiazem therapy is yet to be established.
Cardizem la (Diltiazem hcl) Overdosage
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 LD 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, 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 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. 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:
Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.
Cardizem la (Diltiazem hcl) Dosage And Administration
Cardizem la (Diltiazem hcl) Tablets are an extended release formulation intended for once-a-day administration.
Patients controlled on diltiazem alone or in combination with other medications may be switched to Cardizem la (Diltiazem hcl) Tablets once-a-day at the nearest equivalent total daily dose. Higher doses of Cardizem la (Diltiazem hcl) Tablets once-a-day dosage may be needed in some patients. Patients should be closely monitored. Subsequent titration to higher or lower doses may be necessary and should be initiated as clinically warranted. There is limited general clinical experience with doses above 360 mg, but the safety and efficacy of doses as high as 540 mg have been studied in clinical trials. The incidence of side effects increases as the dose increases with first-degree AV block, dizziness, and sinus bradycardia bearing the strongest relationship to dose.
The tablet should be swallowed whole and not chewed or crushed.
Cardizem la (Diltiazem hcl) How Supplied
Cardizem la (Diltiazem hcl) is supplied as white, capsule-shaped tablets debossed with "B" on one side and the diltiazem content (mg) on the other.
Storage conditions: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Avoid excessive humidity and temperatures above 30°C (86°F).
Dispense in tight, light resistant container as defined in USP.
Cardizem la (Diltiazem hcl)
