Diltiazem

Hypertension

CARDIZEM LA is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

CARDIZEM LA may be used alone or in combination with other antihypertensive medications.

Angina

CARDIZEM LA is indicated to improve exercise tolerance in patients with chronic stable angina.

Diltiazem is part of the drug class:

• Benzothiazepine derivatives

Oral:

• Serious side effects have been reported with oral forms of diltiazem including the following:
• Swelling of the face, eyes, lips, or tongue
• Swelling of the hands, arms, feet, ankles or lower legs
• Difficulty breathing or swallowing
• Fainting
• Yellowing of the skin or eyes
• Extreme tiredness
• Unusual bleeding or bruising
• Loss of appetite
• Pain in the upper right part of the abdomen
• Flu-like symptoms
• Increased frequency or severity of chest pain

Injectable:

Serious side effects have been reported with injectable forms of diltiazem including the following:

• Low blood pressure
• Flushing
• Unusual changes to the heart rate or rhythm

Diltiazem can cause dizziness. Do not drive or operate heavy machinery until you know how diltiazem affects you.

Do not take diltiazem if you:

• are allergic to diltiazem or to any of its ingredients
• have sick sinus syndrome, except if you have a functioning  ventricular pacemaker
• have second- or third-degree Av block, except if you have a functioning ventricular pacemaker
• have low systolic blood pressure (less than 90 mmHg)
• have acute myocardial infarction (also called a heart attack) and pulmonary congestion 

• Store diltiazem at room temperature.
• Avoid excessive humidity.
• Keep this and all medicines out of the reach of children.

Your pharmacist can provide more information about diltiazem.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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Diltiazem is used alone or together with other medicines to treat angina (severe chest pain) or hypertension (high blood pressure). High blood pressure adds to the workload of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly. This can damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. High blood pressure may also increase the risk of heart attacks. These problems may be less likely to occur if blood pressure is controlled.

Diltiazem is a calcium channel blocker. It works by affecting the movement of calcium into the cells of the heart and blood vessels. As a result, diltiazem relaxes the blood vessels and increases the supply of blood and oxygen to the heart while reducing its workload.

diltiazem is available only with your doctor's prescription.

General

Diltiazem hydrochloride is extensively metabolized by the liver and is excreted by the kidneys and in bile. As with any drug given over prolonged periods, laboratory parameters 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 ADVERSE REACTIONS) may be transient and may disappear despite continued use of Diltiazem hydrochloride. 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.

Although Diltiazem hydrochloride extended-release capsules (once-a-day dosage) utilizes a slowly disintegrating matrix, caution should still be used in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic). There have been no reports of obstructive symptoms in patients with known strictures in association with the ingestion of Diltiazem hydrochloride extended-release capsules (once-a-day dosage).

Information for Patients

Diltiazem hydrochloride extended-release capsules (once-a-day dosage) should be taken on an empty stomach. Patients should be cautioned that the Diltiazem hydrochloride extended-release capsules (once-a-day dosage) should not be opened, chewed or crushed, and should be swallowed whole.

Drug Interactions

Due to the potential for additive effects, caution and careful titration are warranted in patients receiving Diltiazem hydrochloride 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 hydrochloride (see WARNINGS). As with all drugs, care should be exercised when treating patients with multiple medications. Diltiazem hydrochloride undergoes biotransformation by cytochrome P-450 mixed function oxidase. Coadministration of Diltiazem hydrochloride with other agents which follow the same route of biotransformation may result in the competitive inhibition of metabolism. Especially in patients with renal and/or hepatic impairment, dosages of similarly metabolized drugs, particularly those of low therapeutic ratio such as cyclosporine, may require adjustment when starting or stopping concomitantly administered Diltiazem hydrochloride to maintain optimum therapeutic blood levels. Concomitant administration of Diltiazem with carbamazepine has been reported to result in elevated plasma levels of carbamazepine, resulting in toxicity in some cases.

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. Administration of Diltiazem hydrochloride concomitantly with propranolol in five normal volunteers resulted in increased propranolol levels in all subjects and the bioavailability of propranolol was increased approximately 50%. If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted.

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 1,200 mg per day and Diltiazem 60 mg per day. 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.

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.

Administration of Diltiazem hydrochloride 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 effects of digoxin levels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing Diltiazem hydrochloride therapy to avoid possible over- or under-digitalization (see WARNINGS).

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 channel blockers should be titrated carefully.

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 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 twice daily Diltiazem SR resulted in a 5-fold higher mean simvastatin AUC compared with simvastatin alone. High average steady-state exposures of Diltiazem would result in a greater increase in simvastatin exposure. A daily dose of 480 mg of Diltiazem would be expected to result in an 8-fold higher mean simvastatin AUC compared with simvastatin alone. 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, coadministration of Diltiazem (120 mg twice daily Diltiazem SR for 2 weeks) with a single 20 mg dose of lovastatin resulted in 3- to 4-fold higher mean lovastatin AUC and Cmax values compared with lovastatin alone. In the same study, there was no significant change in 20 mg single dose pravastatin AUC and Cmax during Diltiazem coadministration.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 24-month study in rats and an 18-month study in mice 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 male or female rats at oral doses of up to 100 mg/kg/day.

Pregnancy

Reproduction studies have been conducted in mice, rats, and rabbits. Administration of doses ranging from 4 to 6 times (depending on species) the upper limit of the optimum dosage range in clinical trials (480 mg once daily or 8 mg/kg once daily for a 60 kg patient) has resulted in embryo and fetal lethality. These studies have revealed, in one species or another, a propensity to cause abnormalities of the skeleton, heart, retina, and tongue. Also observed were reductions in early individual pup weights and pup survival, prolonged delivery, and increased incidence of stillbirths.

There are no well-controlled studies in pregnant women; therefore, use Diltiazem hydrochloride in pregnant women only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. If use of Diltiazem hydrochloride is deemed essential, an alternate method of infant feeding should be instituted.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Hypertensive or anginal patients who are treated with other formulations of Diltiazem can safely be switched to Diltiazem hydrochloride extended-release capsules (once-a-day dosage) at the nearest equivalent total daily dose. Subsequent titration to higher or lower doses may, however, be necessary and should be initiated as clinically indicated.

Studies have shown a slight increase in the rate of absorption of Diltiazem hydrochloride extended-release capsules (once-a-day dosage), when ingested with a high-fat breakfast; therefore, administration in the morning on an empty stomach is recommended.

Patients should be cautioned that the Diltiazem hydrochloride extended-release capsules should not be opened, chewed or crushed, and should be swallowed whole.

Dosage

Dosages must be adjusted to each patient's needs, starting with 180 mg or 240 mg once daily. Based on the antihypertensive effect, the dose may be adjusted as needed. Individual patients, particularly ≥ 60 years of age, may respond to a lower dose of 120 mg. The usual dosage range studied in clinical trials was 180 mg to 480 mg once daily.

Current clinical experience with the 540 mg dose is limited; the dose may be increased to 540 mg with little or no increased risk of adverse reactions. Doses should not exceed 540 mg once daily.

While a dose of Diltiazem hydrochloride extended-release capsules given once daily may produce an antihypertensive effect similar to the same total daily dose given in divided doses, individual dose adjustment may be needed.

Dosages for the treatment of angina should be adjusted to each patient's needs, starting with a dose of 120 mg once daily, which may be titrated to doses of up to 480 mg once daily. When necessary, titration may be carried out over a 7 to 14 day period.

Concomitant Use with Other Cardiovascular Agents

Sublingual nitroglycerin may be taken as required to abort acute anginal attacks during Diltiazem hydrochloride therapy.

Diltiazem hydrochloride extended-release capsules (once-a-day dosage) may be safely coadministered with short- and long-acting nitrates.

(See WARNINGS and PRECAUTIONS.)

Diltiazem hydrochloride has an additive antihypertensive effect when used with other antihypertensive agents. Therefore, the dosage of Diltiazem hydrochloride or the concomitant antihypertensives may need to be adjusted when adding one to the other.

IV: Bolus: 1 to 3 hours; Continuous infusion (after discontinuation): 0.5 to 10 hours

Half-Life Elimination

Immediate release tablet: 3 to 4.5 hours; Extended release tablet: 6 to 9 hours; Extended release capsules: 4 to 9.5 hours; IV: single dose: ~3.4 hours; continuous infusion: 4 to 5 hours

Protein Binding

70% to 80%

Concerns related to adverse effects:

• Conduction abnormalities: May cause first-, second-, and third-degree AV block or sinus bradycardia; risk increases with agents known to slow cardiac conduction.

• Dermatologic reactions: Transient dermatologic reactions have been observed with use; if reaction persists, discontinue. Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and/or exfoliative dermatitis have been reported.

• Hepatic effects: Mild elevations of transaminases with and without concomitant elevation in alkaline phosphatase and bilirubin have been observed and frequently resolve spontaneously. Significant elevations in hepatic transaminases (eg, alkaline phosphatase, LDH, AST, ALT) and signs of acute hepatic injury have also been observed 1 to 8 weeks after therapy initiation and have been reversible upon discontinuation.

• Hypotension/syncope: Symptomatic hypotension with or without syncope can rarely occur; blood pressure must be lowered at a rate appropriate for the patient's clinical condition.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Hypertrophic obstructive cardiomyopathy (HOCM): Use with caution in patients with HOCM; routine use is currently not recommended due to insufficient evidence (Maron 2003).

• Left ventricular dysfunction: Use with caution in left ventricular dysfunction; due to negative inotropic effects, may exacerbate condition. The ACCF/AHA heart failure guidelines recommend to avoid use in patients with heart failure due to lack of benefit and/or worse outcomes with calcium channel blockers in general (ACCF/AHA [Yancy 2013]).

• Renal impairment: Use with caution in patients with renal impairment.

Concurrent drug therapy:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: IV: Unless otherwise contraindicated, appropriate vagal maneuvers should be attempted prior to administration of IV diltiazem. Use with caution in patients hemodynamically compromised; continuously monitor ECG and blood pressure during administration (especially during continuous IV infusion). Initial use should be, if possible, in a setting where monitoring and resuscitation equipment, including DC cardioversion/defibrillation, are present.