Diltiazem dosage

GV Guittard, PSL Wong, F Theeuwes, R Cortese. Dosage form for delivering diltiazem. US Patent 4,859,470, 1989. 

A pulsatile release diltiazem hydrochloride dosage form with a blend of fast, medium, and slow release fractions of a multilayered diltiazem bead was designed.32 Polymeric membrane coating was applied to modulate the time of release. The fast, medium, and slow release fractions... 

It has been suggested that calcium channel blockers can be used to treat cocaine dependence, and some studies have shown reductions in cocaine-induced subjective and cardiovascular responses with nifedipine and diltiazem. The cardiovascular and subjective responses to cocaine have been evaluated in a double-blind, placebo-controlled, crossover study in five subjects pretreated with two dosage of nimodipine (393). Nimodipine 60 mg attenuated the rise in systolic, but not diastolic, blood pressure after cocaine. In three subjects nimodipine 90 mg produced greater attenuation than 60 mg. The subjective effects of cocaine were not altered by either dose of nimodipine. 

SEDA-22,216). Two confirmations of these observations have been published. In a retrospective study of 103 transplant patients verapamil and diltiazem, but not nifedipine or isradipine, caused a significant increase in plasma ciclosporin concentrations (186). The effect of verapamil and diltiazem on ciclosporin concentrations was independent of dosage. In a crossover comparison between verapamil, felodipine, and isradipine in 22 renal transplant recipients, verapamil interacted... 

Concomitant diltiazem without proper dosage adjustment of ciclosporin can cause adverse neurological events. 

A colorimetric method is available which allows the estimation of diltiazem alone and in solid dosage forms. The method involves the reaction of diltiazem with cobalt thiocyanate in acidic media. The complex is extracted in benzene and monitored at 630 nm (33). 

There are approximately a dozen calcium channel antagonists marketed in the United States for the treatment of hypertension, certain dysrhythmias, and some forms of angina (see Chaps. 13,15, and 17). The calcium channel blockers are classified by their chemical structure as phenylalkylamines (e.g., verapamil), benzothiapines (e.g., diltiazem), and dihydropyridines (e.g., amlodipine, felodipine, nicardipine, and nifedipine). Several of these agents, namely, diltiazem, nicardipine, nifedipine, and verapamil, are formulated as sustained-release oral dosage forms or have a slow onset of action and longer half-life (e.g., amlodipine " ), allowing once-daily administration. 

Lithium is frequently combined with both traditional and atypical antipsychotics in euphoric acute mania with psychotic features. Case reports of neurotoxicity (e.g., delirium, cerebellar dysfunction, extrapyramidal symptoms, and severe tremors) have been reported in elderly patients receiving lithium and traditional antipsychotics. Combining lithium with calcium channel blockers is not recommended because of reports of neurotoxicity and severe bradycardia with verapamil and diltiazem. Acute neurotoxicity and delirium have been reported in patients receiving ECT with lithinm (even at reduced dosages) therefore lithium should be withdrawn and discontinued at least 2 days before ECT and should not be resumed until 2 to 3 days after the last treatment. 

NMR and infrared (IR) spectroscopy are also used to investigate the chemical stability of drug substances. Determination of the hydrolysis rate of esters such as atropine by NMR,647 a nondestructive near-IR analysis of aspirin tablets,648 and determination of the hydrolysis rate of diltiazem by polarimetry649 have been reported. Unusual methods, such as measurement of the dielectric properties of dosage forms like gelatin and methylcellulose microcapsules (Fig. 160), have been used to detect physical changes.650-651 These changes... 

Concomitant use of nephrotoxic drugs (eg, aminoglycosides, amphotericin B, vancomycin) with cyclosporine leads to enhanced nephrotoxicity. Diltiazem, ketoconazole, and verapamil inhibit the metabolism of cyclosporine, enhancing its toxic effects unless dosage is reduced. Carbamazepine induces cytochrome P450 and reduces both the therapeutic and the toxic effects of the immunosuppressant drug. The answer is (A). 

Cyclodextrin-based drug delivery systems The hydrophilic cyclodextrins have been extensively )plied to enhance the oral bioavailabilily of steroids, cardiac glycosides, nonsteroidal anti-inflammatory drugs, barbiturates, antiepileptics, benzodiazepines, antidiabetics, vasodilators, etc. Delayed and prolonged release of diltiazem and molsidormine was achieved by their complexation with CD derivatives, modified release of nifedipine can be achieved by its complexation with 2-HP-P-CD fiirosemide and piretanide (loop diuretics) release can be modified after complexation with DM-P-CD. Prednisolone dosage forms can be optimized also by complex-formation with 2-HP-P-CD. 

What is known about the interaction between quinidine and verapamil suggests that a reduction in the dosage of the quinidine may be needed to avoid toxicity. If the verapamil is given intravenously, use with caution and be alert for evidence of acute hypotension. Monitor the effects of concurrent use closely. There is actually a fixed dose preparation containing verapamil and quinidine (Cordichin) available in Germany, which is used for the management of atrial fibrillation. No interaction apparently occurs between quinidine and felodipine or nisoldipine. The situation with diltiazem is as yet uncertain but be alert for the need to reduce the quinidine dosage. 

Information about the effects of calcium-channel bloekers on ear-bamazepine is limited, but what is known indicates that if carbamazepine is given with verapamil or diltiazem, the carbamazepine dosage may possibly need to be reduced to avoid toxicity. A 50% reduction in the dose of carbamazepine has been suggested if diltiazem is to be used. Nifedipine and amlodipine normally appear to be non-interaeting alternatives. Oxear-bazepine appears to be a non-interaeting alternative for carbamazepine. 

The plasma levels of diltiazem, isradipine and nifedipine are increased by cimetidine and it may possibly be necessary to reduce the dosages of these calcium-channel blockers. High doses of cimetidine may increase the bioavailability of lercanidipine. Although studies surest no important interactions occur between nicardipine or nisoldipine and cimetidine, the manufacturers advise caution. Plasma felodipine, lacidipine, nimodipine, and... 

The interactions of cimetidine with diltiazem and nifedipine are established. Concurrent use need not be avoided but the increase in the calcium-channel blocker effects should be taken into account. It has been suggested that the dosage of diltiazem should be reduced by 30 to 50% " and that of nifedipine by 40 to 50%. " The interaction between verapamil and cimetidine is not well established, but monitor the effects until more is known. It has been suggested that the verapamil dose may need to be reduced by 50%. Monitoring is advised if isradipine is given with cimetidine and a reduction in isradipine dose may be required. ... 

Information seems to be limited but the interaction would appear to be established and clinically important, although its incidence is probably low. Anticipate the need to reduce the felodipine or verapamil dosage if erythromycin or clarithromycin, or possibly also telithromycin, is added. Nifedipine may also interact. Other reports suggests that the cardiac toxicity of erythromycin may be increased by verapamil, and diltiazem, and the authors of one of these reports consider that erythromycin should not be used with CYP3A4 inhibitors (that is diltiazem and verapamil). There seem to be no reports of interactions between any of the other calcium-channel blockers and macrolides. However, because of the theoretical possibility of an interaction, many of the manufacturers of calcium-channel blockers warn of the possibility of increased plasma levels and the need to either avoid use with macrolides such as erythromycin, or troleandomycin, or to monitor and reduce doses where necessary. 

The manufacturers note that the AUC of repeated-dose nifedipine was increased 1.4-fold by quinupristin/dalfopristin, and the maximum level was increased by 1.18-fold. This is probably because quinupristin/dalfopristin inhibits the cytochrome P450 isoenzyme CYP3A4-mediated metabolism of nifedipine. Although the clinical relevance of these increases have not been assessed, the manufacturers advise blood pressure monitoring and, if necessary, a reduction of nifedipine dosage during concurrent use. It is predicted that other calcium-charmel blockers (e.g. verapamil, diltiazem) will also have their levels raised by quinupristin/dalfopristin. ... 

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