Get your patient on Cartia xt - Diltiazem Hydrochloride capsule, Extended Release (Diltiazem Hydrochloride)

Diltiazem hydrochloride extended-release capsules (once-a-day dosage) are indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive medications.

Diltiazem hydrochloride extended-release capsules (once-a-day dosage) are indicated for the management of chronic stable angina and angina due to coronary artery spasm.

Patients controlled on diltiazem alone or in combination with other medications may be switched to diltiazem hydrochloride extended-release capsules (once-a-day dosage) at the nearest equivalent total daily dose. Higher doses of diltiazem hydrochloride extended-release capsules (once-a-day dosage) may be needed in some patients. Monitor patients closely. Subsequent titration  to higher or lower doses may be necessary. There is limited general clinical experience with  doses above 360 mg, but doses to 540 mg have been studied in clinical trials. The incidence of side effects increases as the dose increases with first-degree AV block, dizziness, and sinus bradycardia bearing the strongest relationship to dose.

Hypertension: Adjust dosage to individual patient needs. When used as monotherapy,  reasonable starting doses are 180 to 240 mg once daily, although some patients may respond to  lower doses. Maximum antihypertensive effect is usually observed by 14 days of chronic therapy; therefore, schedule dosage adjustments accordingly. The usual dosage range studied in  clinical trials was 240 to 360 mg once daily. Individual patients may respond to higher doses of up to 480 mg once daily.

Angina : Dosages for the treatment of angina should be adjusted to each patient’s needs, starting with a dose of 120 or 180 mg once daily. Individual patients may respond to higher 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 NTG: May be taken as required to abort acute anginal attacks during diltiazem hydrochloride therapy.
Prophylactic Nitrate Therapy: Diltiazem hydrochloride may be safely coadministered with short- and long-acting nitrates.
Beta-blockers: (see WARNINGS and PRECAUTIONS ) .
Antihypertensives: 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.

Diltiazem hydrochloride extended-release capsules (once-a-day dosage) are 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.

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 have usually been excluded from these studies.

The following table presents the most common adverse reactions reported in placebo-controlled angina and hypertension trials in patients receiving diltiazem hydrochloride extended-release capsule (once-a-day dosage) up to 360 mg with rates in placebo patients shown for comparison.

In addition, the following events were reported infrequently (less than 1%) in angina or hypertension trials:

Cardiovascular: Congestive heart failure, palpitations, syncope, ventricular extrasystoles.

Nervous System: Abnormal dreams, amnesia, depression, gait abnormality, hallucinations, insomnia, nervousness, paresthesia, personality change, somnolence, tinnitus, tremor.

Gastrointestinal: Anorexia, constipation, diarrhea, dry mouth, dysgeusia, dyspepsia, mild elevations of SGOT, SGPT, LDH, and alkaline phosphatase (see WARNINGS , Acute Hepatic Injury ), thirst, vomiting, weight increase.

Dermatological: Petechiae, photosensitivity, pruritus, urticaria.

Other: Amblyopia, CPK increase, dyspnea, epistaxis, eye irritation, hyperglycemia, hyperuricemia, impotence, muscle cramps, nasal congestion, nocturia, osteoarticular pain, polyuria, sexual difficulties.

The following postmarketing events have been reported infrequently in patients receiving diltiazem hydrochloride: acute generalized exanthematous pustulosis, allergic reactions, alopecia, angioedema (including facial or periorbital edema), asystole, erythema multiforme (including Stevens-Johnson syndrome, toxic epidermal necrolysis), exfoliative dermatitis, 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. 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 number of well-documented cases of generalized rash, some characterized as leukocytoclastic vasculitis, have been reported. However, a definitive cause and effect relationship between these events and diltiazem hydrochloride therapy is yet to be established.

To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 ). Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with diltiazem hydrochloride extended-release capsules (once-a-day dosage) (see WARNINGS ).

Diltiazem is both a substrate and an inhibitor of the Pg-p and cytochrome P450 3A4 enzyme system which may affect exposure to diltiazem and concomitant drugs metabolized by those pathways. Patients with renal and/or hepatic impairment may be particularly at risk of exposure changes.

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.

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.  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 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 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 C _max 4.1-fold compared to placebo. The T _1/2 and T _max 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.

Cimetidine: A study in six healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and AUC (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 P450, 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 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. The effect of cyclosporine on diltiazem plasma concentrations has not been evaluated.

Digitalis: 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. Monitor digoxin levels when initiating, adjusting, and discontinuing diltiazem hydrochloride therapy to avoid possible over- or under-digitalization (see WARNINGS ).

Ivabradine: Concurrent use of diltiazem increases exposure to ivabradine and may exacerbate bradycardia and conduction disturbances. Avoid concomitant use of ivabradine and diltiazem.

Quinidine: Diltiazem significantly increases the AUC _(0-∞) of quinidine by 51%, T _1/2 by 36%, and decreases its CL _oral by 33%. Monitor for quinidine adverse effects and adjust the dose accordingly.

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

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, monitor for signs and symptoms of any statin-related adverse events, and adjust the doses accordingly.

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.

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. In the same study, there was no significant change in 20 mg single dose pravastatin AUC and C _max during diltiazem coadministration. Diltiazem plasma levels were not significantly affected by lovastatin or pravastatin.

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

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

Diltiazem hydrochloride, USP 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. Diltiazem hydrochloride, USP is formulated as a once-a-day extended-release capsule containing 120 mg diltiazem hydrochloride (equivalent to 110.3 mg diltiazem), 180 mg diltiazem hydrochloride (equivalent to 165.45 mg diltiazem), 240 mg diltiazem hydrochloride (equivalent to 220.6 mg diltiazem), or 300 mg diltiazem hydrochloride (equivalent to 275.75 mg diltiazem).

In addition, each capsule contains the following inactive ingredients: acetyltributyl citrate, ammonio methacrylate copolymer, black iron oxide, cornstarch, D&C Red No. 28, D&C Yellow No. 10, D&C Yellow No. 10 Aluminum Lake, ethylcellulose, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40, FD&C Red No. 40 Aluminum Lake, gelatin, magnesium stearate, methacrylic acid copolymer, propylene glycol, polysorbate 80, sucrose, talc, and titanium dioxide. The 180 mg and 240 mg capsules contain yellow iron oxide. In addition, the 240 mg capsule also contains red iron oxide.

For oral administration.

This drug meets USP Drug Release 9.

The therapeutic effects of diltiazem 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.

NOTE: THE PRODUCT MAY HAVE AN ODOR.