Home page A B C D E F G H I K L M N O P Q R S T U V W X Y Z

DailyMed


Udocheals.orgDiltiazem hcl
5.18.2017 | Logan Blare
Diltiazem hcl
DailyMed

Chemically, diltiazem hydrochloride is 1,5-Benzothiazepin-4(5 H )-one, 3-(acetyloxy)-5--2, 3-dihydro-2-(4-methoxyphenyl)-, monohydrochloride,(+)- cis -. Diltiazem hydrochloride is a calcium ion cellular influx inhibitor (slow channel blocker or calcium antagonist). The chemical structure is:.

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. 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. Diltiazem produces relaxation of coronary vascular smooth muscle and dilation of both large and small coronary arteries at drug levels that cause little or no negative inotropic effect.

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.

If you are a consumer or patient please visit this version. Rx only.

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.

Diltiazem hydrochloride is a white to off-white crystalline powder with a bitter taste. Diltiazem HCl CD is formulated as a once-a-day extended-release capsule containing 360 mg diltiazem hydrochloride. It has a molecular weight of 450.98. It is soluble in water, methanol, and chloroform.

The effect of cyclosporine on diltiazem plasma concentrations has not been evaluated.

A departure from linearity similar to that seen with diltiazem hydrochloride tablets and diltiazem HCl SR capsules is observed. A single 360 mg dose of the capsule results in detectable plasma levels within 2 hours and peak plasma levels between 10 and 14 hours; absorption occurs throughout the dosing interval. The apparent elimination half-life after single or multiple dosing is 5 to 8 hours. Dose-dumping does not occur. As the dose of diltiazem HCl CD capsules is increased from a daily dose of 120 mg to 240 mg, there is an increase in the area under the curve of 2.7 times. When the dose is increased from 240 mg to 360 mg, there is an increase in the area under the curve of 1.6 times. When diltiazem HCl CD was coadministered with a high fat content breakfast, the extent of diltiazem absorption was not affected. Diltiazem HCl CD Capsules: When compared to a regimen of diltiazem hydrochloride tablets at steady-state, more than 95% of drug is absorbed from the diltiazem HCl CD formulation.

Competitive in vitro ligand binding studies have also shown diltiazem hydrochloride 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 approximay 3.0 to 4.5 hours. 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. In vitro binding studies show diltiazem hydrochloride is 70% to 80% bound to plasma proteins. 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 diltiazem concentrations appear to be in the range of 50 to 200 ng/mL. A single study in nine patients with severely impaired renal function showed no difference in the pharmacokinetic profile of diltiazem compared to patients with normal renal function.

The therapeutic effects of diltiazem HCl CD 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.

Monitor for quinidine adverse effects and adjust the dose accordingly. Quinidine: Diltiazem significantly increases the AUC (0-∞) of quinidine by 51%, T 1/2 by 36%, and decreases its CL oral by 33%.

Drugs which induce or inhibit hepatic microsomal enzymes may alter diltiazem disposition. Diltiazem hydrochloride undergoes extensive metabolism in which only 2% to 4% of the unchanged drug appears in the urine. 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%.

The improvement in time to termination of exercise utilizing a Bruce exercise protocol, measured at trough, for placebo, 60 mg, 120 mg, 240 mg, 360 mg, and 480 mg was 29, 40, 56, 51, 69, and 68 seconds, respectively. As doses of diltiazem HCl CD were increased, overall angina frequency was decreased. Diltiazem HCl CD, 180 mg once daily, or placebo was administered in a double-blind study to patients receiving concomitant treatment with long-acting nitrates and/or beta-blockers. In a double-blind, parallel dose-response study of doses from 60 mg to 480 mg once daily, diltiazem HCl CD increased time to termination of exercise in a linear manner over the entire dose range studied. In this trial the overall frequency of adverse events in the diltiazem HCl CD treatment group was the same as the placebo group. A significant increase in time to termination of exercise and a significant decrease in overall angina frequency was observed.

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.

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.

Updated June 30, 2016.

These pharmacokinetic effects seen during diltiazem coadministration can result in increased clinical effects (e.g., prolonged sedation) of both midazolam and triazolam. The elimination half-life of midazolam and triazolam also increased (1.5- to 2.5-fold) during coadministration with diltiazem. 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.

Hypertension: Diltiazem HCl CD 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.

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, titrate anesthetics and calcium blockers slowly.

Alcohol: Alcohol increases the rate at which diltiazem HCl CD releases diltiazem in vitro. Avoid consumption of alcohol with diltiazem HCl CD (see CLINICAL PHARMACOLOGY ). This effect may lead to more rapid absorption and an increase in the systemic exposure of diltiazem, and associated dose-related adverse reactions.

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 WARNINGS ).

A 24-month study in rats at oral dosage levels of up to 100 mg/kg/day and a 21-month study in mice at oral dosage levels of up to 30 mg/kg/day showed no evidence of carcinogenicity. There was also no mutagenic response in vitro or in vivo in mammalian cell assays or in vitro in bacteria. No evidence of impaired fertility was observed in a study performed in male and female rats at oral dosages of up to 100 mg/kg/day.

Diltiazem HCl CD is indicated for the management of chronic stable angina and angina due to coronary artery spasm.

In man, diltiazem prevents spontaneous and ergonovine-provoked coronary artery spasm. There are few data on the interaction of diltiazem and beta-blockers in patients with poor ventricular function. Studies, 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. 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. 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. Resting heart rate is usually slightly reduced by diltiazem.

Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with diltiazem hydrochloride (see WARNINGS ). Because of the potential for additive effects, slow titration is warranted in patients receiving diltiazem hydrochloride concomitantly with other agents known to affect cardiac contractility and/or conduction (see WARNINGS ).

In a healthy volunteer crossover study (N=10), coadministration of a single 20 mg dose of simvastatin at the end of a 14-day regimen with 120 mg BID diltiazem SR resulted in a 5-fold increase in mean simvastatin AUC versus simvastatin alone. Subjects with increased average steady-state exposures of diltiazem showed a greater fold increase in simvastatin exposure. Computer-based simulations showed that at a daily dose of 480 mg of diltiazem, an 8- to 9-fold mean increase in simvastatin AUC can be expected. If coadministration of simvastatin with diltiazem is required, limit the daily doses of simvastatin to 10 mg and diltiazem to 240 mg.

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. Diltiazem is both a substrate and an inhibitor of the cytochrome P450 3A4 enzyme system.

Patients currently receiving diltiazem therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with cimetidine. Cimetidine: A study in six healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and area under the curve (53%) after a 1-week course of cimetidine at 1200 mg per day and a single dose of diltiazem 60 mg. Ranitidine produced smaller, nonsignificant increases. An adjustment in the diltiazem dose may be warranted. 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.

For oral administration. Capsules also contain: FD&C Blue #1, gelatin, hypromellose, magnesium stearate, microcrystalline cellulose, ethyl acrylate and methyl methacrylate copolymer, polysorbate, povidone, simethicone emulsion, sucrose stearate, talc, and titanium dioxide.

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. Dermatological events (see ADVERSE REACTIONS ) may be transient and may disappear despite continued use of diltiazem hydrochloride.

Cyclosporine: A pharmacokinetic interaction between diltiazem and cyclosporine has been observed during studies involving renal and cardiac transplant patients. In renal and cardiac transplant recipients, a reduction of cyclosporine dose ranging from 15% to 48% was necessary to maintain cyclosporine trough concentrations similar to those seen prior to the addition of diltiazem. If these agents are to be administered concurrently, cyclosporine concentrations should be monitored, especially when diltiazem therapy is initiated, adjusted, or discontinued.

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. In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases). Diltiazem-associated prolongation of the AH interval is not more pronounced in patients with first-degree heart block. Intravenous diltiazem in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods by approximay 20%.

In a ten-subject randomized, open-label, 4-way crossover study, coadministration of diltiazem (120 mg BID diltiazem SR for 2 weeks) with a single 20 mg dose of lovastatin resulted in 3- to 4-fold increase in mean lovastatin AUC and C max versus lovastatin alone. Diltiazem plasma levels were not significantly affected by lovastatin or pravastatin. In the same study, there was no significant change in 20 mg single dose pravastatin AUC and C max during diltiazem coadministration.

Another investigator found no increase in digoxin levels in 12 patients with coronary artery disease. Monitor digoxin levels when initiating, adjusting, and discontinuing diltiazem hydrochloride therapy to avoid possible over- or under-digitalization (see WARNINGS ). Digitalis: Administration of diltiazem hydrochloride with digoxin in 24 healthy male subjects increased plasma digoxin concentrations approximay 20%.

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 an in vitro dissolution study, the release rate of diltiazem from diltiazem HCl CD increased significantly as the alcohol percentage in the dissolution medium increased. The effect of alcohol on the release rate may lead to a change in the pharmacokinetics of diltiazem, such as a more rapid absorption and/or an increase in the systemic exposure of diltiazem (see PRECAUTIONS, Drug Interactions ).

Diltiazem HCl CD is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive medications.

Avoid coadministration of diltiazem with rifampin or any known CYP3A4 inducer. Rifampin: Coadministration of rifampin with diltiazem lowered the diltiazem plasma concentrations to undetectable levels.

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.

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. No increased activity of the renin-angiotensin-aldosterone axis has been observed. Diltiazem HCl CD decreases vascular resistance, increases cardiac output (by increasing stroke volume), and produces a slight decrease or no change in heart rate. Postural hypotension is infrequently noted upon suddenly assuming an upright position. Chronic therapy with diltiazem HCl CD produces no change or an increase in plasma catecholamines. The changes in diastolic blood pressure, measured at trough, for placebo, 90 mg, 180 mg, 360 mg, and 540 mg were –2.9, –4.5, –6.1, –9.5, and –10.5 mm Hg, respectively. In a double-blind, parallel, dose-response study utilizing doses ranging from 90 to 540 mg once daily, diltiazem HCl CD lowered supine diastolic blood pressure in an apparent linear manner over the entire dose range studied. Diltiazem HCl CD reduces the renal and peripheral effects of angiotensin II. In hypertensive patients, diltiazem HCl CD produces antihypertensive effects both in the supine and standing positions. No reflex tachycardia is associated with the chronic antihypertensive effects. During dynamic exercise, increases in diastolic pressure are inhibited, while maximum achievable systolic pressure is usually reduced.

Diltiazem hydrochloride is extensively metabolized by the liver and excreted by the kidneys and in bile. Laboratory parameters of renal and hepatic function should be monitored at regular intervals. In subacute and chronic dog and rat studies designed to produce toxicity, high doses of diltiazem were associated with hepatic damage. In dogs, doses of 20 mg/kg were also associated with hepatic changes; however, these changes were reversible with continued dosing. 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.

When possible, use a non-CYP3A4-metabolized statin together with diltiazem; otherwise, monitor for signs and symptoms of any statin related adverse events, and adjust the doses accordingly. Statins: Diltiazem is an inhibitor of CYP3A4 and has been shown to increase significantly the AUC of some statins. The risk of myopathy and rhabdomyolysis with statins metabolized by CYP3A4 may be increased with concomitant use of diltiazem.

Subsequent dose adjustments may be necessary during coadministration, and should be based on clinical assessment. The T 1/2 and T max of buspirone were not significantly affected by diltiazem. Buspirone: In nine healthy subjects, diltiazem significantly increased the mean buspirone AUC 5.5-fold and C max 4.1-fold compared to placebo. Enhanced effects and increased toxicity of buspirone may be possible during concomitant administration with diltiazem.

If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted (see WARNINGS ). In vitro, propranolol appears to be displaced from its binding sites by diltiazem. 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 approximay 50%.

Spontaneous and ergonovine-induced coronary artery spasms are inhibited by diltiazem. Diltiazem has been shown to be a potent dilator of coronary arteries, both epicardial and subendocardial. Angina: Diltiazem HCl CD 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 hcl