Cardizem Information
Cardizem (Diltiazem hcl)
Cardizem (Diltiazem hcl) Description
Cardizem (Diltiazem hcl) (diltiazem hydrochloride) is a calcium ion cellular influx inhibitor (slow channel blocker or calcium antagonist). Chemically, diltiazem hydrochloride is 1,5-Benzothiazepin-4(5)-one, 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-, monohydrochloride,(+)--. 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. It has a molecular weight of 450.98. Each tablet of Cardizem (Diltiazem hcl) contains 30 mg, 60 mg, 90 mg, or 120 mg diltiazem hydrochloride.
Also contains: colloidal silicon dioxide, D&C Yellow #10 Aluminum Lake, FD&C Blue #1 Aluminum Lake (30 mg and 90 mg), FD&C Yellow #6 Aluminum Lake (60 mg and 120 mg), hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate, methylparaben, microcrystalline cellulose, and polyethylene glycol.
For oral administration.
Cardizem (Diltiazem hcl) Clinical Pharmacology
The therapeutic benefits achieved with Cardizem (Diltiazem hcl) are believed to be related to its ability to inhibit the influx of calcium ions during membrane depolarization of cardiac and vascular smooth muscle.
Although precise mechanisms of its antianginal action are still being delineated, Cardizem (Diltiazem hcl) is believed to act in the following ways:
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 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.
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, 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. There are as yet few data on the interaction of diltiazem and beta-blockers. Resting heart rate is usually unchanged or slightly reduced by diltiazem.
Intravenous diltiazem 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 Cardizem (Diltiazem hcl) 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 Cardizem (Diltiazem hcl) in doses of up to 240 mg/day has resulted in small increases in PR interval but has not usually produced abnormal prolongation.
Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to intravenous dosing) of about 40%. Cardizem (Diltiazem hcl) undergoes extensive metabolism in which 2% to 4% of the unchanged drug appears in the urine. binding studies show Cardizem (Diltiazem hcl) is 70% to 80% bound to plasma proteins. Competitive ligand binding studies have also shown Cardizem (Diltiazem hcl) 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 as a coronary vasodilator as diltiazem. Minimum therapeutic plasma levels of Cardizem (Diltiazem hcl) appear to be in the range of 50 to 200 ng/mL. There is a departure from linearity when dose strengths are increased. A study that compared patients with normal hepatic function to patients with cirrhosis found an increase in half-life and a 69% increase in AUC (area-under-the-plasma concentration vs time curve) in the hepatically impaired patients. A single study in nine patients with severely impaired renal functions showed no difference in the pharmacokinetic profile of diltiazem as compared to patients with normal renal function.
Cardizem (Diltiazem hcl) Tablets.
Cardizem (Diltiazem hcl) Indications And Usage
Cardizem (Diltiazem hcl) is indicated for the management of chronic stable angina and angina due to coronary artery spasm.
Cardizem (Diltiazem hcl) Contraindications
Cardizem (Diltiazem hcl) 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 (Diltiazem hcl) Warnings
1. Cardiac Conduction.
2. Congestive Heart Failure.
3. Hypotension.
4. Acute Hepatic Injury.
Cardizem (Diltiazem hcl) Precautions
Due to the potential for additive effects, caution and careful titration are warranted in patients receiving Cardizem (Diltiazem hcl) concomitantly with any agents known to affect cardiac contractility and/or conduction (see ).
Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with Cardizem (Diltiazem hcl) (see ).
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.
Cardizem (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 usually have been excluded.
In domestic placebo-controlled angina trials, the incidence of adverse reactions reported during Cardizem (Diltiazem hcl) therapy was not greater than that reported during placebo therapy.
The following represent occurrences observed in clinical studies of angina patients. In many cases, the relationship to Cardizem (Diltiazem hcl) has not been established. The most common occurrences from these studies, as well their frequency of presentation, are edema (2.4%), headache (2.1%), nausea (1.9%), dizziness (1.5%), rash (1.3%), and asthenia (1.2%). In addition, the following events were reported infrequently (less than 1 %):
The following postmarketing events have been reported infrequently in patients receiving Cardizem (Diltiazem hcl) : acute generalized exanthematous pustulosis, 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, photosensitivity (including lichenoid keratosis and hyperpigmentation at sun-exposed skin areas), purpura, retinopathy, myopathy, 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 Cardizem (Diltiazem hcl) therapy cannot yet be established. Exfoliative dermatitis (proven by rechallenge) has also been reported.
Cardizem (Diltiazem hcl) Overdosage
The oral LDs in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively. The intravenous LDs 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 reports of diltiazem overdose in amounts ranging from
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.
The effectiveness of intravenous calcium administration to reverse the pharmacological effects of diltiazem overdose has been inconsistent. In a few reported cases, overdose with calcium channel blockers associated with hypotension and bradycardia that was initially refractory to atropine became more responsive to atropine after the patients received intravenous calcium. In some cases intravenous calcium has been administered (1 g calcium chloride or 3 g calcium gluconate) over 5 minutes and repeated every 10 to 20 minutes as necessary. Calcium gluconate has also been administered as a continuous infusion at a rate of 2 g per hour for 10 hours. Infusions of calcium for 24 hours or more may be required. Patients should be monitored for signs of hypercalcemia.
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 (Diltiazem hcl) Dosage And Administration
Concomitant Use With Other Cardiovascular Agents
Cardizem (Diltiazem hcl) How Supplied
Cardizem (Diltiazem hcl) 30-mg tablets are supplied in bottles of 100 (NDC 64455-771-47) and 500 (NDC 64455-771-55). Each green tablet is engraved with MARION on one side and 1771 on the other.
Cardizem (Diltiazem hcl) 60-mg scored tablets are supplied in bottles of 100 (NDC 64455-772-47) and 500 (NDC 64455-772-55). Each yellow tablet is engraved with MARION on one side and 1772 on the other.
Cardizem (Diltiazem hcl) 90-mg scored tablets are supplied in bottles of 100 (NDC 64455-791-47). Each green oblong tablet is engraved with Cardizem (Diltiazem hcl) on one side and 90 mg on the other.
Cardizem (Diltiazem hcl) 120-mg scored tablets are supplied in bottles of 100 (NDC 64455-792-47). Each yellow oblong tablet is engraved with Cardizem (Diltiazem hcl) on one side and 120 mg on the other.
Store at 25°C (77°); excursions permitted to 15-30°C (59-86°) [see USP Controlled Room Temperature].
Avoid excessive humidity.
Cardizem (Diltiazem hcl)
Cardizem (Diltiazem hcl) Principal Display Panel - Mg Tablets
Cardizem (Diltiazem hcl) Principal Display Panel - Mg Tablets
Cardizem (Diltiazem hcl) Principal Display Panel - Mg Tablets
Cardizem (Diltiazem hcl) Principal Display Panel - Mg Tablets
