Drug: Cartia XT

Diltiazem hydrochloride is a calcium ion influx inhibitor (slow channel blocker or calcium antagonist). Chemically, diltiazem hydrochloride is 1,5-benzothiazepin-4(5H)one,3-(acetyloxy)-5-[2-(dimethylamino) ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-, monohydrochloride,(+)-cis-. The chemical structure is: Diltiazem hydrochloride 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 extended-release capsule (once daily dosage) is formulated as a once-a-day extended release capsule containing either 120 mg, 180 mg, 240 mg, or 300 mg diltiazem hydrochloride. In addition, each capsule contains the following inactive ingredients: acetyltributyl citrate, ammoniomethacrylate copolymer-NF, D & C Red #28, D & C Yellow #10, D & C Yellow #10 Aluminum Lake, ethylcellulose, FD & C Blue #1 Aluminum Lake, FD & C Blue #2 Aluminum Lake, FD & C Red #40, FD & C Red #40 Aluminum Lake, gelatin-NF, magnesium stearate, methacrylic acid copolymer-NF, propylene glycol, polysorbate 80-NF, starch, sucrose, talc USP, and titanium dioxide. The 180 mg and 240 mg capsules contain yellow iron oxide. In addition, the 240 mg capsule also contains black iron oxide and red iron oxide. For oral administration. This drug meets USP Drug Release 9.

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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 placebocontrolled angina and hypertension trials in patients receiving diltiazem hydrochloride extended-release capsule (once-a-day dosing) product up to 360 mg with rates in placebo patients shown for comparison. Diltiazem Hydrochloride Extended-release Capsule (once-a-day) Placebo-controlled Angina and Hypertension Trials Combined
Adverse Reactions Diltiazem Extended-release Capsule (once-a-day)
n=607 Placebo
n=301 Headache 5.4% 5.0% Dizziness 3.0% 3.0% Bradycardia 3.3% 1.3% AV Block First-Degree 3.3% 0.0% Edema 2.6% 1.3% ECG Abnormality 1.6% 1.7 Asthenia 1.8% 1.7% In clinical trials of diltiazem hydrochloride extended-release capsules (Once A Day Dosage), diltiazem hydrochloride tablets and diltiazem hydrochloride extended-release capsules involving over 3200 patients, the most common events (i.e., greater than 1%) were edema (4.6%), headache (4.6%), dizziness (3.5%), asthenia (2.6%), first-degree AV block (2.4%), bradycardia (1.7%), flushing (1.4%), nausea (1.4%) and rash (1.2%). In addition, the following events were reported infrequently (less than 1%) in angina or hypertension trials: Cardiovascular: Angina, arrhythmia, AV block (second- or third-degree), bundle branch block, congestive heart failure, ECG abnormalities, hypotension, palpitations, syncope, tachycardia, 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 hepatic warnings), 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: 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, 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 therapy is yet to be established. Read the Cartia XT (diltiazem hydrochloride extended release capsules) Side Effects Center for a complete guide to possible side effectsLearn More »

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Patients controlled on diltiazem alone or in combination with other medications may be switched to diltiazem hydrochloride extended-release capsules USP (once-a-day dosage) at the nearest equivalent total daily dose. Higher doses of diltiazem hydrochloride extended-release capsules USP (once-a-day dosage) may be needed in some patients. Patients should be closely monitored. Subsequent titration to higher or lower doses may be necessary and should be initiated as clinically warranted. 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. Dosage needs to be adjusted by titration 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, dosage adjustments should be scheduled 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
  1. Sublingual Nitroglycerin. May be taken as required to abort acute anginal attacks during diltiazem hydrochloride extended-release capsules, (Once A Day Dosage) therapy.
  2. Prophylactic Nitrate Therapy. Diltiazem hydrochloride extended-release capsules, (Once A Day Dosage) may be safely coadministered with short- and long-acting nitrates.
  3. Beta-blockers. (See WARNINGS and PRECAUTIONS.)
  4. Antihypertensives. Diltiazem hydrochloride extended-release capsules (Once A Day Dosage) have an additive antihypertensive effect when used with other antihypertensive agents.
Therefore, the dosage of diltiazem hydrochloride extended-release capsules USP (once-a-day dosage) or the concomitant antihypertensives may need to be adjusted when adding one to the other.

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Due to the potential for additive effects, caution and careful titration are warranted in patients receiving diltiazem 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. (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 3-4 fold and the Cmax by 2-fold, compared to placebo. The elimination half-life of midazolam and triazolam also increased (1.5-2.5 fold) during coadministration with diltiazem. There 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, 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 Cmax 4.1 fold compared to placebo. The T½ 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 co-administration, 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. 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 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 underdigitalization. (See WARNINGS). Lovastatin. In a ten-subject study, coadministration of diltiazem (120 mg bid, diltiazem SR) with lovastatin resulted in 3-4 times increase in mean lovastatin AUC and Cmax versus lovastatin alone; no change in pravastatin AUC and Cmax was observed during diltiazem coadministration. Diltiazem plasma levels were not significantly affected by lovastatin or pravastatin. Quinidine. Diltiazem significantly increases the AUC(0 → ∞) of quinidine by 51%, T½ 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.Last reviewed on RxList: 1/19/2010
This monograph has been modified to include the generic and brand name in many instances.

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

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Diltiazem 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 xray on admission.Last reviewed on RxList: 1/19/2010
This monograph has been modified to include the generic and brand name in many instances.

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The oral LD50's in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively. The intravenous LD50's 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 10-20 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 (0.60 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.

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Diltiazem Hydrochloride Extended-release Capsules USP (Once-a-day dosage) Strength Qty. NDC# Description 120 mg 7's 62037-597-07 White/orange opaque capsule imprinted with “Andrx 597” on one end and “120 mg” on the other. 30's 62037-597-30 90's 62037-597-90 500's 62037-597-05 1000's 62037-597-10 180 mg 7's 62037-598-07 Yellow/orange opaque capsules imprinted with “Andrx 598” on one end and &lduqo;180 mg” on the other. 30's 62037-598-30 90's 62037-598-90 500's 62037-598-05 1000's 62037-598-10 240 mg 7's 62037-599-07 Light Brown/orange opaque capsules imprinted with “Andrx 599” on one end and &lduqo;240 mg” on the other. 30's 62037-599-30 90's 62037-599-90 500's 62037-599-05 1000's 62037-599-10 300 mg 7's 62037-600-07 Orange/orange opaque capsules imprinted with “Andrx 600” on one end and “300 mg” on the other. 30's 62037-600-30 90's 62037-600-90 500's 62037-600-05 1000's 62037-600-10 NOTE: THE PRODUCT MAY HAVE AN ODOR. Storage Conditions Store at controlled room temperature, 20°-25°C (68°-77°F). [See USP] Avoid excessive humidity. Dispense in tight, light resistant container as defined in USP. Manufactured by: Watson Laboratories, Inc., Corona, CA 92880 USA. Distributed by: Watson Pharma, Inc., Rev. date: 12/06.Last reviewed on RxList: 1/19/2010
This monograph has been modified to include the generic and brand name in many instances.

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General Diltiazem hydrochloride is extensively metabolized by the liver and excreted by the kidneys and in bile. As with any drug given over prolonged periods, laboratory parameters of renal and hepatic function 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 section) may be transient and may disappear despite continued use of diltiazem. 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. Carcinogenesis, Mutagenesis, Impairment of Fertility 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. 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 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. 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. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of diltiazem did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Last reviewed on RxList: 1/19/2010
This monograph has been modified to include the generic and brand name in many instances.

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