diltiazem HCl 60 MG Oral Tablet

Generic Name: DILTIAZEM HYDROCHLORIDE
Brand Name: Diltiazem Hydrochloride
  • Substance Name(s):
  • DILTIAZEM HYDROCHLORIDE

WARNINGS

1.

Cardiac Conduction.

Diltiazem prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome.

This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second- or third-degree AV block (six of 1243 patients for 0.48%).

Concomitant use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac conduction.

A patient with Prinzmetal’s angina developed periods of asystole (2 to 5 seconds) after a single dose of 60 mg of diltiazem (see ADVERSE REACTIONS).

2.

Congestive Heart Failure.

Although diltiazem has a negative inotropic effect in isolated animal tissue preparations, hemodynamic studies in humans with normal ventricular function have not shown a reduction in cardiac index nor consistent negative effects on contractility (dp/dt).

Experience with the use of diltiazem alone or in combination with beta-blockers in patients with impaired ventricular function is very limited.

Caution should be exercised when using the drug in such patients.

3.

Hypotension.

Decreases in blood pressure associated with diltiazem therapy may occasionally result in symptomatic hypotension.

4.

Acute Hepatic Injury.

In rare instances, significant elevations in enzymes such as alkaline phosphatase, LDH, SGOT, SGPT, and other phenomena consistent with acute hepatic injury have been noted.

These reactions have been reversible upon discontinuation of drug therapy.

The relationship to diltiazem is uncertain in most cases, but probable in some (see PRECAUTIONS).

DRUG INTERACTIONS

Drug Interactions Due to the potential for additive effects, caution and careful titration are warranted in patients receiving diltiazem concomitantly with any agents known to affect cardiac contractility and/or conduction (see WARNINGS).

Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with diltiazem (see WARNINGS).

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.

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, anesthetics and calcium blockers should be titrated carefully.

Benzodiazepines Studies showed that diltiazem increased the AUC of midazolam and triazolam by 3 to 4 fold and the Cmax by 2 fold, compared to placebo.

The elimination half-life of midazolam and triazolam also increased (1.5 to 2.5 fold) during coadministration with diltiazem.

These pharmacokinetic effects seen during diltiazem coadministration can result in increased clinical effects (e.g., prolonged sedation) of both midazolam and triazolam.

Beta-Blockers Controlled and uncontrolled domestic studies suggest that concomitant use of diltiazem and beta-blockers is usually well tolerated.

Available data are not sufficient, however, to predict the effects of concomitant treatment, particularly in patients with left ventricular dysfunction or cardiac conduction abnormalities.

Administration of diltiazem concomitantly with propranolol in five normal volunteers resulted in increased propranolol levels in all subjects, and bioavailability of propranolol was increased approximately 50%.

In vitro, propranolol appears to be displaced from its binding sites by diltiazem.

If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted (see WARNINGS).

Buspirone In nine healthy subjects, diltiazem significantly increased the mean buspirone AUC 5.5 fold and Cmax 4.1 fold compared to placebo.

The T1/2 and Tmax of buspirone were not significantly affected by diltiazem.

Enhanced effects and increased toxicity of buspirone may be possible during concomitant administration with diltiazem.

Subsequent dose adjustments may be necessary during coadministration, and should be based on clinical assessment.

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.

Patients receiving these drugs concurrently should be monitored for a potential drug interaction.

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.

The effect may be mediated by cimetidine’s known inhibition of hepatic cytochrome P-450, the enzyme system responsible for the first-pass metabolism of diltiazem.

Patients currently receiving diltiazem therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with cimetidine.

An adjustment in the diltiazem dose may be warranted.

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.

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 trough dose ranging from 15% to 48% was necessary to maintain 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.

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

Digitalis Administration of diltiazem with digoxin in 24 healthy male subjects increased plasma digoxin concentrations approximately 20%.

Another investigator found no increase in digoxin levels in 12 patients with coronary artery disease.

Since there have been conflicting results regarding the effect of digoxin levels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing diltiazem therapy to avoid possible over- or under-digitalization (see WARNINGS).

Quinidine Diltiazem significantly increases the AUC (0→∞) of quinidine by 51%, T1/ 2 by 36%, and decreases its CLoral by 33%.

Monitoring for quinidine adverse effects may be warranted and the dose adjusted accordingly.

Rifampin Coadministration of rifampin with diltiazem lowered the diltiazem plasma concentrations to undetectable levels.

Coadministration of diltiazem with rifampin or any known CYP3A4 inducer should be avoided when possible, and alternative therapy considered.

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.

When possible, use a non-CYP3A4-metabolized statin together with diltiazem; otherwise, dose adjustments for both diltiazem and the statin should be considered along with close monitoring for signs and symptoms of any statin related adverse events.

In a healthy volunteer cross-over 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.

In a ten-subject randomized, open label, 4 way cross-over study, co-administration 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 Cmax versus lovastatin alone.

In the same study, there was no significant change in 20 mg single dose pravastatin AUC and Cmax during diltiazem coadministration.

Diltiazem plasma levels were not significantly affected by lovastatin or pravastatin.

OVERDOSAGE

The oral LD50s in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively.

The intravenous LD50s in these species were 60 and 38 mg/kg, respectively.

The oral LD50 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 < 1 g to 18 g.

Of cases with known outcome, most patients recovered and in cases with a fatal outcome, the majority involved multiple drug ingestion.

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: 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).

Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.

DESCRIPTION

Diltiazem hydrochloride tablets USP are a calcium ion cellular influx inhibitor (slow channel blocker or calcium antagonist).

Chemically, diltiazem hydrochloride, USP 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: C22H26N2O4S•HCl M.W.

450.98 Diltiazem hydrochloride, USP is a white to off-white crystalline powder with a bitter taste.

It is soluble in water, methanol, and chloroform.

Each tablet for oral administration contains 30 mg, 60 mg, 90 mg, or 120 mg of diltiazem hydrochloride, USP.

Each tablet also contains the following inactive ingredients: hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, titanium dioxide and FD&C yellow #6 aluminum lake.

Diltiazem hydrochloride tablets meet USP Dissolution Test 1.

HOW SUPPLIED

Diltiazem hydrochloride tablets USP are available as: 30 mg – faint orange, round, film-coated, biconvex, unscored tablets, debossed with “93” and “318” on one side and plain on the other side.

Available in bottles of 100 and 500.

60 mg – orange, round, film-coated, biconvex tablets, scored in half on one side, debossed with “93” and “319” on each side of the score and plain on the other side.

Available in bottles of 100 and 500.

90 mg – faint orange, oblong, film-coated tablets, scored in half on one side, debossed with “93” and “320” on each side of the score and plain on the other side.

Available in bottles of 100.

120 mg – orange, oblong, film-coated tablets, scored in half on one side, debossed with “93” and “321” on each side of the score and plain on the other side.

Available in bottles of 100.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

Manufactured In India By: PIRAMAL ENTERPRISES LIMITED Pithampur, Madhya Pradesh, India Manufactured For: TEVA PHARMACEUTICALS USA Sellersville, PA 18960 Rev.

M 8/2012

INDICATIONS AND USAGE

Diltiazem hydrochloride tablets USP are indicated for the management of chronic stable angina and angina due to coronary artery spasm.

PEDIATRIC USE

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

PREGNANCY

Pregnancy Teratogenic Effects Pregnancy Category C Reproduction studies have been conducted in mice, rats, and rabbits.

Administration of doses ranging from five to ten times greater (on a mg/kg basis) than the daily recommended therapeutic dose has resulted in embryo and fetal lethality.

These doses, in some studies, have been reported to cause skeletal abnormalities.

In the perinatal/postnatal studies, there was some reduction in early individual pup weights and survival rates.

There was an increased incidence of stillbirths at doses of 20 times the human dose or greater.

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.

NUSRING MOTHERS

Nursing Mothers Diltiazem is excreted in human milk.

One report suggests that concentrations in breast milk may approximate serum levels.

If use of diltiazem is deemed essential, an alternative method of infant feeding should be instituted.

DOSAGE AND ADMINISTRATION

Exertional Angina Pectoris Due to Atherosclerotic Coronary Artery Disease or Angina Pectoris at Rest Due to Coronary Artery Spasm Dosage must be adjusted to each patient’s needs.

Starting with 30 mg four times daily, before meals and at bedtime, dosage should be increased gradually (given in divided doses three or four times daily) at 1 to 2 day intervals until optimum response is obtained.

Although individual patients may respond to any dosage level, the average optimum dosage range appears to be 180 to 360 mg/day.

There are no available data concerning dosage requirements in patients with impaired renal or hepatic function.

If the drug must be used in such patients, titration should be carried out with particular caution.

Concomitant Use With Other Cardiovascular Agents Sublingual NTG may be taken as required to abort acute anginal attacks during diltiazem hydrochloride tablet therapy.

Prophylactic Nitrate Therapy: Diltiazem hydrochloride tablets may be safely coadministered with short- and long-acting nitrates, but there have been no controlled studies to evaluate the antianginal effectiveness of this combination.

Beta-blockers.

(See WARNINGS and PRECAUTIONS.)