CARDIZEM LA- diltiazem hydrochloride_tablet, extended release

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. Hypertension: Angina: In animal models, diltiazem interferes with the slow inward (depolarizing) current in excitable tissue. Diltiazem causes excitation-contraction uncoupling in various myocardial. Diltiazem produces relaxation of coronary vascular smooth muscle and dilation of both large and small coronary arteries at drug levels which cause little or no negative inotropic effect. The resultant increases in coronary blood flow (epicardial and subendocardial) occur in ischemic and nonischemic models and are accompanied by dose-dependent decreases in systemic blood pressure and decreases in peripheral resistance. Like other calcium channel antagonists, diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In the intact animal, prolongation of the AH interval can be seen at higher doses. In man, diltiazem prevents spontaneous and ergonovine-provoked coronary artery spasm. It causes a decrease in peripheral vascular resistance and a modest fall in blood pressure in normotensive individuals and, in exercise tolerance studies in patients with ischemic heart disease, reduces the heart rate-blood pressure product for any given workload. Studies to date, primarily in patients with good ventricular function, have not revealed evidence of a negative inotropic effect; cardiac output, ejection fraction, and left ventricular end diastolic pressure have not been affected. Such data have no predictive value with respect to effects in patients with poor ventricular function, and increased heart failure has been reported in patients with preexisting impairment of ventricular function. There are as yet few data on the interaction of diltiazem and beta-blockers in patients with poor ventricular function. Resting heart rate is usually slightly reduced by diltiazem. Diltiazem decreases vascular resistance, increases cardiac output (by increasing stroke volume), and produces a slight decrease or no change in heart rate. During dynamic exercise, increases in diastolic pressure are inhibited, while maximum achievable systolic pressure is usually reduced. Chronic therapy with diltiazem produces no change or an increase in plasma catecholamines. No increased activity of the renin-angiotensin-aldosterone axis has been observed. Diltiazem reduces the renal and peripheral effects of angiotensin II. Hypertensive animal models respond to diltiazem with reductions in blood pressure and increased urinary output and natriuresis without a change in urinary sodium/potassium ratio. Intravenous diltiazem hydrochloride 20 mg prolongs AH conduction time and AV node functional and effective refractory periods by approximately 20%. In a study involving single oral doses of diltiazem hydrochloride 300 mg in six normal volunteers, the average maximum PR prolongation was 14% with no instances of greater than first-degree AV block. Diltiazem associated prolongation of the AH interval is not more pronounced in patients with first-degree heart block. In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases). Chronic oral administration of diltiazem hydrochloride to patients in doses of up to 540 mg/day has resulted in small increases in PR interval, and on occasion produces abnormal prolongation [see Warnings and Precautions ( 5. Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to intravenous administration) of about 40%. Diltiazem undergoes extensive metabolism in which only 2% to 4% of the unchanged drug appears in the urine. Drugs that induce or inhibit hepatic microsomal enzymes may alter diltiazem disposition. Total radioactivity measurement following short IV administration in healthy volunteers suggests the presence of other unidentified metabolites, which attain higher concentrations than those of diltiazem and are more slowly eliminated; half-life of total radioactivity is about 20 hours compared to 2 to 5 hours for diltiazem. In vitro in vitro CARDIZEM LA Tablets: Drug Interactions Impact of Diltiazem on Other Coadministered Drugs Anesthetics: Benzodiazepines: max Beta-blockers: 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 [see Warnings and Precautions ( 5. Buspirone: max max Carbamazepine: Clonidine: Cyclosporine: Digitalis: [see Warnings and Precautions ( 5. Quinidine: (0arrowinfinity) Statins: 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 10-subject randomized, open label, 4-way cross-over 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 max Impact of Other Coadministered Drugs on Diltiazem Include, but Not Limited to: Rifampin Cimetidine and Ranitidine -.

CARDIZEM LA is a nondihydropyridine calcium channel blocker indicated for: treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. It can be used alone or in combination with other antihypertensives. 1 improving exercise tolerance in patients with chronic stable angina. 2 CARDIZEM LA is indicated for the treatment of hypertension, to lower blood pressure. 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 mm Hg 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. , 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. CARDIZEM LA is indicated to improve exercise tolerance in patients with chronic stable angina.

Take CARDIZEM LA once a day at approximately the same time. Do not chew or crush the tablet. Tablet should be swallowed whole and not chewed or crushed. ( 2 Hypertension: Initial adult dose is 180 to 240 mg once daily. Adjust dose according to blood pressure response to a maximum of 540 mg daily. 1 Angina: Initial adult dose is 180 mg once daily. Adjust dose according to response to a maximum of 360 mg. 2 Switching to CARDIZEM LA: Patients may be switched to the nearest equivalent total daily diltiazem dose. 3 Initiate dosing at 180 to 240 mg once daily, although some patients may respond to lower doses. Titrate according to blood pressure to a maximum of 540 mg daily. Maximum antihypertensive effect is usually observed by 14 days of chronic therapy. Initiate dosing at 180 mg once daily and increase dose at intervals of 7 to 14 days if adequate response is not obtained, to a maximum of 360 mg. Patients controlled on diltiazem alone or in combination with other medications may be switched to CARDIZEM LA once a day at the nearest equivalent total daily dose. Higher doses of CARDIZEM LA may be needed in some patients based on clinical response.

The following adverse reactions are described in greater detail, in other sections: Bradycardia and AV block [see Warnings and Precautions ( 5. 1 )] Heart failure [see Warnings and Precautions ( 5. 2 )] Acute hepatic injury [see Warnings and Precautions ( 5. 3 )] Severe skin reactions [see Warnings and Precautions ( 5. 4 )] The most common adverse reactions (>2%) are lower limb edema, sinus congestion and rash in patients treated for hypertension, and lower limb edema, headache, dizziness, fatigue, bradycardia, first-degree AV block and cough in patients treated for angina. 1 To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. For the hypertension studies, the following table presents adverse reactions more common on diltiazem than on placebo (but excluding events with no plausible relationship to treatment), as reported in placebo-controlled hypertension trials in patients receiving a diltiazem hydrochloride extended-release formulation (once-a-day dosing) up to 540 mg. Placebo Diltiazem hydrochloride extended-release Adverse Reactions (MedDRA Term) n=120 # pts. (%) 120-360 mg n=501 # pts. (%) 540 mg n=123 # pts. (%) Edema lower limb 4 (3) 24 (5) 10 (8) Sinus congestion 0 (0) 2 (1) 2 (2) Rash 0 (0) 3 (1) 2 (2) In the angina study, the adverse event profile of CARDIZEM LA was consistent with what has been previously described for CARDIZEM LA and other formulations of diltiazem HCl. The most frequent adverse effects experienced by CARDIZEM LA-treated patients were edema lower-limb (6. 8%), dizziness (6. 4%), fatigue (4. 8%), bradycardia (3. 6%), first-degree atrioventricular block (3. 2%), and cough (2%). In addition, the following events have been reported infrequently (less than 1%) in angina or hypertension trials: Cardiovascular: [see Warnings and Precautions ( 5. Nervous System: Gastrointestinal: Dermatological: [see Warnings and Precautions ( 5. 4 Other: The following adverse reactions have been identified during post - The following post - 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.

CARDIZEM LA is contraindicated in: Patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker. Patients with second- or third-degree AV block except in the presence of a functioning ventricular pacemaker. Patients with hypotension (less than 90 mm Hg systolic). Patients who have demonstrated hypersensitivity to the drug. Patients with acute myocardial infarction and pulmonary. Sick sinus syndrome except in the presence of a functioning ventricular pacemaker. ( 4 Second- or third-degree AV block except in the presence of a functioning ventricular pacemaker. ( 4 Hypotension (less than 90 mm Hg systolic). ( 4 Hypersensitivity to the drug. ( 4 Acute myocardial infarction and pulmonary.

Risk Summary The available data from the published literature over decades of use with diltiazem during pregnancy have not identified a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies in rats and rabbits, administration of diltiazem to pregnant animals during organogenesis at oral doses approximately 1 and 4 times the Maximum Recommended Human Dose (MRHD) of CARDIZEM LA produced embryofetal deaths and increased incidence of skeletal abnormalities. An increased incidence of stillbirths was noted at diltiazem doses approximately 2 times the MRHD of CARDIZEM LA. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss, and other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2- 4% and 15-20%, respectively. Data Animal Data Embryofetal development studies have been conducted with diltiazem in rats and rabbits. Daily oral administration of diltiazem at 0, 17. 5, 35 or 70 mg/kg to pregnant rabbits during organogenesis (gestational day 6 to 18) resulted in embryo-fetal lethality at 35 mg/kg/day (approximately 1 time the MRHD of CARDIZEM LA, on a mg/m 2 2 2 Risk Summary Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. Because of the potential for serious adverse reactions in nursing infants from diltiazem, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for diltiazem and any potential adverse effects on the breastfed child from diltiazem or from the underlying maternal condition. Safety and effectiveness in pediatric patients have not been established. 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. No dose adjustment is necessary. No dose adjustment is likely to be needed for mild-moderate hepatic impairment.

Beta-blockers, digitalis, and other agents known to impair cardiac contractility and conduction may increase risk for hypotension, bradycardia, and heart failure. 1 CYP450 3A4: Diltiazem is both a substrate and inhibitor of CYP450 3A4. CYP450 3A4 substrates may require dosage adjustment. 2 Using other agents known to affect cardiac conduction or contractility with diltiazem may increase the risk of bradycardia, AV block, and heart failure [see Warnings and Precautions ( 5. Ivabradine: 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 [see Clinical Pharmacology (12.

OVERDOSAGE
The oral LD 50 50 50 The toxic dose in man is not known. Blood levels after a standard dose of diltiazem can vary over tenfold, limiting the usefulness of blood levels in overdose cases. There have been 29 reports of diltiazem overdose in doses ranging from less than 1 g to 18 g. Sixteen of these reports involved multiple drug ingestions. Twenty-two reports indicated patients had recovered from diltiazem overdose ranging from less than 1 g to 10.8 g. There were seven reports with a fatal outcome; although the amount of diltiazem ingested was unknown, multiple drug ingestions were confirmed in six of the seven reports. 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. In the event of overdose or exaggerated response, institute appropriate supportive measures and 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: High-degree AV Block: Cardiac Failure: Hypotension: Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.
NONCLINICAL TOXICOLOGY
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 in vivo in vitro
CLINICAL STUDIES
In a randomized, double-blind, parallel-group, dose-response study involving 478 patients with essential hypertension, evening doses of CARDIZEM LA 120, 240, 360, and 540 mg were compared to placebo and to 360 mg administered in the morning. The mean reductions in diastolic blood pressure by ABPM at roughly 24 hours after the morning (4 AM to 8 AM) or evening (6 PM to 10 PM) administration (i. , the time corresponding to expected trough serum concentrations) are shown in the table below: Mean Change in Trough Diastolic Pressure by ABPM Evening Dosing Morning Dosing 120 mg 240 mg 360 mg 540 mg 360 mg -2. 4 A second randomized, double-blind, parallel-group, dose-response study (N=258) evaluated CARDIZEM LA following morning doses of placebo or 120, 180, 300, or 540 mg. Diastolic blood pressure measured by supine office cuff sphygmomanometer at trough (7 AM to 9 AM) decreased in an apparently linear manner over the dosage range studied. Group mean changes for placebo, 120 mg, 180 mg, 300 mg and 540 mg were -2. 6 mm Hg, respectively. Whether the time of administration impacts the clinical benefits of antihypertensive treatment is not known. Postural hypotension is infrequently noted upon suddenly assuming an upright position. No reflex tachycardia is associated with the chronic antihypertensive effects. The effects of CARDIZEM LA on angina were evaluated in a randomized, double-blind, parallel-group, dose-response trial of 311 patients with chronic stable angina. Evening doses of 180, 360, and 420 mg were compared to placebo and to 360 mg administered in the morning. All doses of CARDIZEM LA administered at night increased exercise tolerance when compared with placebo after 21 hours. The mean effect, placebo-subtracted, was 20 to 28 seconds for all three doses, and no dose-response was demonstrated. CARDIZEM LA, 360 mg, given in the morning, also improved exercise tolerance when measured 25 hours later. As expected, the effect was smaller than the effects measured only 21 hours following nighttime administration. CARDIZEM LA had a larger effect to increase exercise tolerance at peak serum concentrations than at trough.

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