Matzim La Drug Information

Hypertension 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.

Angina 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.

Switching to Matzim LA (Diltiazem Hydrochloride) Extended-Release Tablets Patients controlled on diltiazem

alone or in combination with other medications may be switched to diltiazem hydrochloride extended-release tablets once a day at the nearest equivalent total daily dose. Higher doses of Matzim LA (diltiazem hydrochloride) extended-release tablets may be needed in some patients based on clinical response.

Clinical Trials Experience

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. Adverse Reactions (MedDRA Term) Placebo Diltiazem hydrochloride extended-release n=120 # pts. (%) 120-360 mg n=501 # pts. (%) 540 mg n=123 # pts. (%) Edema lower limb 4 24 10 Sinus congestion 0 2 2 Rash 0 3 2 In the angina study, the adverse event profile of diltiazem hydrochloride extended-release tablets was consistent with what has been previously described for diltiazem hydrochloride extended-release tablets and other formulations of diltiazem HCl.

The most frequent adverse effects experienced by diltiazem hydrochloride extended-release tablets-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: Angina, bundle branch block, 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, 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.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of diltiazem. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. The following postmarketing reactions have been reported infrequently in patients receiving diltiazem: acute generalized exanthematous pustulosis, allergic reactions, alopecia, angioedema (including facial or periorbital edema), erythema multiforme, 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.

Agents Known to Impair Cardiac Contractility and Conduction Using other agents known

to affect cardiac conduction or contractility with diltiazem may increase the risk of bradycardia, AV block, and heart failure . Ivabradine: Concurrent use of diltiazem increases exposure to ivabradine and may exacerbate bradycardia and conduction disturbances. Avoid concomitant use of ivabradine and diltiazem.

P-glycoprotein (P-gp) and Cytochrome P450 3A4 Mediated Drug Interactions 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 .

Pregnancy 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 diltiazem 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 diltiazem.

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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 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 diltiazem, on a mg/m 2 basis) and higher, concurrent with maternal toxicity (reduced body weight gain). Daily oral administration of diltiazem at 0, 100, 200 and 400 mg/kg to pregnant rats during organogenesis (gestation day 9 to 14) resulted in embryo-fetal lethality at 200 mg/kg/day (approximately 4 times the MRHD of diltiazem, on a mg/m 2 basis) and higher. These doses, in some studies, were reported to cause increased incidence of skeletal malformations (e.g. malformations of vertebral column) or variations.

In an oral perinatal/postnatal study in rats with diltiazem at 0, 50, 100, 200 and 400 mg/kg/day from gestation day 15 to lactation/post-partum day 20, there was an increased incidence of stillbirths at 100 mg/kg/day, approximately 2 times (on a mg/m 2 basis) the MRHD of diltiazem.

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

Matzim LA (diltiazem hydrochloride) extended-release tablets are 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. Second- or third-degree AV block except in the presence of a functioning ventricular pacemaker.

Hypotension (less than 90 mm Hg systolic). Hypersensitivity to the drug. Acute myocardial infarction and pulmonary.

The oral LD 50 is 415 to 740 mg/kg in mice and 560 to 810 mg/kg in rats. The intravenous LD 50 is 60 mg/kg in mice and 38 mg/kg in rats. The oral LD 50 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. 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: Administer atropine (0.60 to 1.0 mg). If there is no response to vagal blockage, 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: Use 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.