diltiazem hydrochloride

1 INDICATIONS AND USAGE Diltiazem Hydrochloride Extended-Release Tablets 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 Diltiazem Hydrochloride Extended-Release Tablets are 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. Diltiazem Hydrochloride Extended-Release Tablets may be used alone or in combination with other antihypertensive medications. 1.2 Angina Diltiazem Hydrochloride Extended-Release Tablets are indicated to improve exercise tolerance in patients with chronic stable angina.

2 DOSAGE AND ADMINISTRATION Take Diltiazem Hydrochloride Extended-Release Tablets 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 Diltiazem Hydrochloride Extended-Release Tablets: 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 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 Diltiazem Hydrochloride Extended-Release Tablets may be needed in some patients based on clinical response.

3 DOSAGE FORMS AND STRENGTHS Extended-release tablets with 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, or 420 mg diltiazem hydrochloride per tablet. Diltiazem Hydrochloride Extended-Release Tablets, 120 mg are white to off-white, capsules-shaped tablet, debossed with “ ” on one side and “157” on the other side. Diltiazem Hydrochloride Extended-Release Tablets, 180 mg are white to off-white, capsules-shaped tablet, debossed with “ ” on one side and “156” on the other side. Diltiazem Hydrochloride Extended-Release Tablets, 240 mg are white to off-white, capsules-shaped tablet, debossed with “ ” on one side and “155” on the other side. Diltiazem Hydrochloride Extended-Release Tablets, 300 mg are white to off-white, capsules-shaped tablet, debossed with “ ” on one side and “153” on the other side. Diltiazem Hydrochloride Extended-Release Tablets, 360 mg are white to off-white, capsules-shaped tablet, debossed with “ ” on one side and “152” on the other side. Diltiazem Hydrochloride Extended-Release Tablets, 420 mg are white to off-white, capsules-shaped tablet, debossed with “ ” on one side and “15” on the other side. Extended-release tablets with 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, or 420 mg diltiazem hydrochloride per tablet. ( 3 ) logo-1 logo-2 logo-3 logo-4 logo-5 logo-6

4 CONTRAINDICATIONS 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. ( 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 )

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 Slate Run Pharmaceuticals, LLC at 1-888-341-9214 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 Tablets Adverse Reactions (MedDRA Term) n=120 # pts. (%) 120 to 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 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 [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 disea …

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 )] .

8 USE IN SPECIFIC POPULATIONS 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 diltiazem hydrochloride extended-release tablets 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 hydrochloride extended-release tablets. 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 embryofetal lethality at 35 mg/kg/day (approximately 1 time the MRHD of diltiazem hydrochloride extended-release tablets, 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 hydrochloride extended-release tablets, 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 hydrochloride extended-release tablets. 8.2 Lactation 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. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 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. 8.6 Use in Renal Impairment No dose adjustment is necessary. 8.7 Use in Hepatic Impairment No dose adjustment is likely to be needed for mild-moderate hepatic impairment.

12.1 Mechanism of Action 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: Diltiazem produces its antihypertensive effect primarily by relaxation of vascular smooth muscle and the resultant decrease in peripheral vascular resistance. The magnitude of blood pressure reduction is related to the degree of hypertension; thus hypertensive individuals experience an antihypertensive effect, whereas there is only a modest fall in blood pressure in normotensives. Angina: Diltiazem has been shown to produce increases in exercise tolerance, probably due to its ability to reduce myocardial oxygen demand. This is accomplished via reductions in heart rate and systemic blood pressure at submaximal and maximal workloads. Diltiazem has been shown to be a potent dilator of coronary arteries, both epicardial and subendocardial. Spontaneous and ergonovine-induced coronary artery spasms are inhibited by diltiazem. 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.

11 DESCRIPTION Diltiazem hydrochloride is a nondihydropyridine calcium channel blocker (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 structural formula 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 Tablets are formulated as a once-a-day extended-release tablet for oral administration containing 120 mg, 180 mg, 240 mg, 300 mg, 360 mg or 420 mg of diltiazem hydrochloride. Tablets also contain: carnauba wax, colloidal silicon dioxide, croscarmellose sodium, ethyl acrylate and methyl methacrylate copolymer dispersion, hydrogenated vegetable oil, hypromellose, magnesium stearate, microcrystalline cellulose, paraffin wax, polydextrose, polyethylene glycol, polysorbate, povidone, pregelatinized starch, simethicone, sodium starch glycolate, sucrose stearate, talc, and titanium dioxide. A molecule of a chemical formula AI-generated content may be incorrect.

10 OVERDOSAGE The oral LD 50 is 415 mg/kg to 740 mg/kg in mice and 560 mg/kg 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 mg 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Diltiazem Hydrochloride Extended-Release Tablets are supplied as follows: 120 mg: White to off-white, capsules-shaped tablet, debossed with “ ” on one side and “157” on the other side. Bottles of 30 tablets with child-resistant closure, NDC 70436-195-04 Bottles of 90 tablets with child-resistant closure, NDC 70436-195-06 180 mg: White to off-white, capsules-shaped tablet, debossed with “ ” on one side and “156” on the other side. Bottles of 30 tablets with child-resistant closure, NDC 70436-196-04 Bottles of 90 tablets with child-resistant closure, NDC 70436-196-06 240 mg: White to off-white, capsules-shaped tablet, debossed with “ ” on one side and “155” on the other side. Bottles of 30 tablets with child-resistant closure, NDC 70436-197-04 Bottles of 90 tablets with child-resistant closure, NDC 70436-197-06 300 mg: White to off-white, capsules-shaped tablet, debossed with “ ” on one side and “153” on the other side. Bottles of 30 tablets with child-resistant closure, NDC 70436-198-04 Bottles of 90 tablets with child-resistant closure, NDC 70436-198-06 360 mg: White to off-white, capsules-shaped tablet, debossed with “ ” on one side and “152” on the other side. Bottles of 30 tablets with child-resistant closure, NDC 70436-199-04 Bottles of 90 tablets with child-resistant closure, NDC 70436-199-06 420 mg: White to off-white, capsules-shaped tablet, debossed with “ ” on one side and “15” on the other side. Bottles of 30 tablets with child-resistant closure, NDC 70436-200-04 Bottles of 90 tablets with child-resistant closure, NDC 70436-200-06 Storage conditions: Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Avoid excessive humidity and temperatures above 30°C (86°F). Dispense in a tight, light resistant container as defined in the USP with a child-resistant closure. Keep out of reach of children. A-1 A-2 A-3 A-4 A-5 A-6