Cardizem LA

1 INDICATIONS AND USAGE 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. ( 1.1 ) • improving exercise tolerance in patients with chronic stable angina. ( 1.2 ) 1.1 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 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.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. 1.2 Angina CARDIZEM LA is indicated to improve exercise tolerance in patients with chronic stable angina.

2 DOSAGE AND ADMINISTRATION 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. ( 2.1 ) • Angina: Initial adult dose is 180 mg once daily. Adjust dose according to response to a maximum of 360 mg. ( 2.2 ) • Switching to CARDIZEM LA: Patients may be switched to the nearest equivalent total daily diltiazem dose. ( 2.3 ) 2.1 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. 2.2 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. 2.3 Switching to CARDIZEM LA Tablets 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.

4 CONTRAINDICATIONS 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. ( 4 )

5 WARNINGS AND PRECAUTIONS • Bradycardia, second- or third-degree AV block: Monitor heart rate and rhythm. ( 5.1 ) • Heart failure: Monitor for signs and symptoms. ( 5.2 ) • Increased liver enzymes and acute hepatic injury. ( 5.3 ) • Severe skin reactions. ( 5.4 ) 5.1 Bradycardia or AV Block CARDIZEM LA may cause abnormally slow heart rates or second- or third-degree AV block. Patients with sick sinus syndrome are at increased risk of bradycardia. Concomitant use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac conduction. A patient with Prinzmetal’s angina developed periods of asystole (2 to 5 seconds) after a single dose of 60 mg of diltiazem [see Adverse Reactions ( 6 )] . Monitor for effects on heart rate and cardiac conduction. 5.2 Heart Failure Worsening of heart failure has been reported in patients with impairment of ventricular function. Experience with the use of diltiazem in combination with beta-blockers in patients with impaired ventricular function is limited. 5.3 Acute Hepatic Injury Significant elevations in liver enzymes such as alkaline phosphatase, LDH, AST (SGOT), ALT (SGPT) and signs of acute hepatic injury have been reported with diltiazem therapy. These reactions tended to occur early after therapy initiation (1 to 8 weeks) and have been reversible upon discontinuation of drug therapy. Mild elevations of transaminases with and without concomitant elevation in alkaline phosphatase and bilirubin have also been observed. Such elevations were usually transient and frequently resolved even with continued diltiazem treatment. 5.4 Severe Skin Reactions Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme and/or exfoliative dermatitis have been reported.

7 DRUG INTERACTIONS • Beta-blockers, digitalis, and other agents known to impair cardiac contractility and conduction may increase risk for hypotension, bradycardia, and heart failure. ( 7.1 ) • CYP450 3A4: Diltiazem is both a substrate and inhibitor of CYP450 3A4. CYP450 3A4 substrates may require dosage adjustment. ( 7.2 ) 7.1 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 [see Warnings and Precautions ( 5.1 , 5.2 )] . Ivabradine: Concurrent use of diltiazem increases exposure to ivabradine and may exacerbate bradycardia and conduction disturbances. Avoid concomitant use of ivabradine and diltiazem. 7.2 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 [see Clinical Pharmacology ( 12.3 )] .

6 ADVERSE REACTIONS 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. 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: Angina, bundle branch block, palpitations, syncope, tachycardia, ventricular extrasystoles [see Warnings and Precautions ( 5.1 , 5.2 )] . 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 [see Warnings and Precautions ( 5.4 )] . Other: Amblyopia, CPK increase, dyspnea, epistaxis, eye irritation, hyperglycemia, hyperuricemia, impotence, muscle cramps, nasal congestion, nocturia, osteoarticular pain, polyuria, sexual difficulties. 6.2 Post-Marketing 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 post-marketing 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.

8.1 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 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. In the U.S. 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/m2 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 CARDIZEM LA, 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 CARDIZEM LA.