AMLODIPINE AND BENAZEPRIL HYDROCHLORIDE

Amlodipine and benazepril hydrochloride capsules USP are a combination of amlodipine besylate and benazepril hydrochloride. Benazepril hydrochloride USP is a white to off-white, crystalline powder, soluble (greater than 100 mg/mL) in water, in ethanol, and in methanol. Benazepril hydrochloride’s chemical name is 3-[[1-(ethoxycarbonyl)-3-phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1 H -1-(3S)-benzazepine-1-acetic acid monohydrochloride; its structural formula is: Its molecular formula is C 24 H 28 N 2 O 5 •HCl, and its molecular weight is 460.96. Benazeprilat, the active metabolite of benazepril, is a nonsulfhydryl ACE inhibitor. Benazepril is converted to benazeprilat by hepatic cleavage of the ester group. Amlodipine besylate USP is a white or almost white powder, slightly soluble in water and sparingly soluble in ethanol. Its chemical name is (R,S)3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4­-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulfonate; its structural formula is: Its molecular formula is C 20 H 25 ClN 2 O 5 •C 6 H 6 O 3 S, and its molecular weight is 567.1. Amlodipine besylate is the besylate salt of amlodipine, a dihydropyridine calcium channel blocker. Amlodipine and benazepril hydrochloride is available as capsules containing amlodipine besylate USP (3.5 mg, 6.9 mg or 13.9 mg, equivalent to 2.5 mg, 5 mg or 10 mg of amlodipine respectively), with 10 mg, 20 mg, or 40 mg of benazepril hydrochloride USP providing for the following available combinations: 2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, 5 mg/40 mg, 10 mg/20 mg, and 10 mg/40 mg. The inactive ingredients of the capsules are colloidal silicon dioxide, crospovidone, gelatin, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, and titanium dioxide. In addition, the hard gelatin capsule shells of 5 mg/10 mg contains iron oxide black, iron oxide red, and iron oxide yellow, 5 mg/20 mg contains iron oxide red, 5 mg/40 mg and 10 mg/40 mg contains FD&C Blue 1, FD&C Red 3, and 10 mg/20 mg contains D&C Red 28, FD&C Blue 1, FD&C Red 40, and FD&C Yellow 5. The capsules are printed with edible ink containing black iron oxide and shellac. Amlodipine Besylate Chemical Structure Benazepril Hydrochloride Chemical Structure

Amlodipine and benazepril hydrochloride capsules are a combination capsule of amlodipine, a dihydropyridine calcium channel blocker (DHP CCB) and benazepril, an angiotensin-converting enzyme (ACE) inhibitor. Amlodipine and benazepril hydrochloride capsules are indicated for the treatment of hypertension in patients not adequately controlled on monotherapy with either agent. (1) 1.1 Hypertension Amlodipine and benazepril hydrochloride capsules are indicated for the treatment of hypertension in patients not adequately controlled on monotherapy with either agent.

Usual starting dose is 2.5 mg/10 mg. ( 2.1 ) May be used as add-on therapy for patients not adequately controlled with either a dihydropyridine calcium channel blocker or an ACE inhibitor ( 2.2 ) Patients who experience edema with amlodipine may be switched to amlodipine and benazepril hydrochloride capsules containing a lower dose of amlodipine. ( 2.1 ) 2.1 General Considerations The recommended initial dose is amlodipine 2.5 mg and benazepril 10 mg orally once-daily. Begin therapy with amlodipine and benazepril hydrochloride capsules only after a patient has either (a) failed to achieve the desired antihypertensive effect with amlodipine or benazepril monotherapy, or (b) demonstrated inability to achieve adequate antihypertensive effect with amlodipine therapy without developing edema. The antihypertensive effect of amlodipine and benazepril hydrochloride capsules is largely attained within 2 weeks. If blood pressure remains uncontrolled, the dose may be titrated up to amlodipine 10 mg and benazepril 40 mg once-daily. The dosing should be individualized and adjusted according to the patient’s clinical response. In clinical trials of amlodipine and benazepril combination therapy using amlodipine doses of 2.5 to 10 mg and benazepril doses of 10 to 40 mg, the antihypertensive effects increased with increasing dose of amlodipine in all patient groups, and the effects increased with increasing dose of benazepril in nonblack groups. 2.2 Replacement Therapy Amlodipine and benazepril hydrochloride capsules may be substituted for the titrated components.

Do not coadminister aliskiren with angiotensin receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, including amlodipine and benazepril hydrochloride capsules in patients with diabetes. Amlodipine and benazepril hydrochloride capsules are contraindicated in patients with a history of angioedema, with or without previous ACE inhibitor treatment, or patients who are hypersensitive to benazepril, to any other ACE inhibitor, to amlodipine, or to any of the excipients of amlodipine and benazepril hydrochloride capsules. Amlodipine and benazepril hydrochloride capsules are contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer amlodipine and benazepril hydrochloride capsules within 36 hours of switching to or from a neprilysin inhibitor, e.g., sacubitril/valsartan [see Warnings and Precautions (5.1) ]. Do not coadminister aliskiren with ACE inhibitors, including amlodipine and benazepril hydrochloride capsules, in patients with diabetes. (4) Amlodipine and benazepril hydrochloride capsules are contraindicated in patients with a history of angioedema or patients who are hypersensitive to benazepril or to amlodipine. (4) Amlodipine and benazepril hydrochloride capsules are contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer amlodipine and benazepril hydrochloride capsules within 36 hours of switching to or from a neprilysin inhibitor, e.g., sacubitril/valsartan. ( 4 )

Discontinuation because of adverse reactions occurred in 4% of amlodipine and benazepril hydrochloride-treated patients and 3% of placebo-treated patients. The most common reasons for discontinuation of therapy with amlodipine and benazepril hydrochloride were cough and edema. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Amlodipine and benazepril hydrochloride has been evaluated for safety in over 2,991 patients with hypertension; over 500 of these patients were treated for at least 6 months, and over 400 were treated for more than 1 year. In a pooled analysis of 5 placebo-controlled trials involving amlodipine and benazepril hydrochloride doses up to 5/20, the reported side effects were generally mild and transient, and there was no relationship between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy due to side effects was required in approximately 4% of patients treated with amlodipine and benazepril hydrochloride and in 3% of patients treated with placebo. The most common reasons for discontinuation of therapy with amlodipine and benazepril hydrochloride in these studies were cough and edema (including angioedema). The peripheral edema associated with amlodipine use is dose-dependent. When benazepril is added to a regimen of amlodipine, the incidence of edema is substantially reduced. The addition of benazepril to a regimen of amlodipine should not be expected to provide additional antihypertensive effect in African-Americans. However, all patient groups benefit from the reduction in amlodipine-induced edema. The side effects considered possibly or probably related to study drug that occurred in these trials in more than 1% of patients treated with amlodipine and benazepril hydrochloride are shown in the table below. Cough was the only adverse event with at least possible relationship to treatment that was more common on amlodipine and benazepril hydrochloride (3.3%) than on placebo (0.2%). Percent Incidence in U.S. Placebo-controlled Trials *Edema refers to all edema, such as dependent edema, angioedema, facial edema. Benazepril and Amlodipine Benazepril Amlodipine Placebo N = 760 N = 554 N = 475 N = 408 Cough 3.3 1.8 0.4 0.2 Headache 2.2 3.8 2.9 5.6 Dizziness 1.3 1.6 2.3 1.5 Edema* 2.1 0.9 5.1 2.2 The incidence of edema was greater in patients treated with amlodipine monotherapy (5.1%) than in patients treated with amlodipine and benazepril hydrochloride (2.1%) or placebo (2.2%). Other side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials of patients treated with amlodipine and benazepril hydrochloride or in postmarketing experience were the following: Body as a Whole: Asthenia and fatigue. CNS: Insomnia, nervousness, anxiety, tremor, and decreased libido. Dermatologic: Flushing, hot flashes, rash, skin nodule, and dermatitis. Digestive: Dry mouth, nausea, abdominal pain, dyspepsia, and esophagitis. Hematologic: Neutropenia. Musculoskeletal: cramps, and muscle cramps. Urogenital: Sexual problems, such as impotence, and polyuria. Monotherapies of benazepril and amlodipine have been evaluated for safety in clinical trials in over 6,000 and 11,000 patients, respectively. The observed adverse reactions to the monotherapies in these trials were similar to those seen in trials of amlodipine and benazepril hydrochloride. 6.2 Postmarketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In postmarketing experience with benazepril, there have been rare reports of Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, thrombocytopenia, paresthesia, dysgeusia, orthostatic symptoms and hypotension, angina pectoris and arrhythmia, pruritus, photosensitivity reaction, arthralgia, arthritis, myalgia, blood urea nitrogen (BUN) increase, serum creatinine increase, renal impairment, vision impairment, agranulocytosis, neutropenia. Rare reports in association with use of amlodipine: gingival hyperplasia, tachycardia, jaundice, and hepatic enzyme elevations (mostly consistent with cholestasis severe enough to require hospitalization), leukocytopenia, allergic reaction, hyperglycemia, dysgeusia, hypoesthesia, paresthesia, syncope, peripheral neuropathy, hypertonia, visual impairment, diplopia, hypotension, vasculitis, rhinitis, gastritis, hyperhidrosis, pruritus, skin discoloration, urticaria, erythema multiform, muscle spasms, arthralgia, micturition disorder, nocturia, erectile dysfunction, malaise, weight decrease or gain. Other potentially important adverse experiences attributed to other ACE inhibitors and calcium channel blockers include: eosinophilic pneumonitis (ACE inhibitors) and gynecomastia (CCBs).

Potassium supplements/potassium-sparing diuretics: hyperkalemia ( 7.1 ) Lithium: Increased serum lithium levels; toxicity symptoms ( 7.1 ) Injectable gold: facial flushing, nausea, vomiting, hypotension ( 7.1 ) Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Risk of renal dysfunction, loss of antihypertensive effect (7.1) Do not exceed doses greater than 20 mg daily of simvastatin (7.1) mTOR inhibitors: increased risk of angioedema ( 7.1 ) Dual inhibition of the RAS: Increased risk of renal impairment, hypotension, and hyperkalemia (7.1) Neprilysin inhibitors: increased risk of angioedema ( 7.1 ) 7.1 Drug/Drug Interactions Amlodipine Simvastatin : Coadministration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily. CYP3A4 Inhibitors : Coadministration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is coadministered with CYP3A4 inhibitors to determine the need for dose adjustment. CYP3A4 Inducers : No information is available on the quantitative effects of CYP3A4 inducers on amlodipine. Blood pressure should be monitored when amlodipine is coadministered with CYP3A4 inducers (e.g. rifampicin, St. John’s Wort). Benazepril Potassium Supplements and Potassium-Sparing Diuretics: Benazepril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, the patient’s serum potassium should be monitored frequently. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. When coadministering amlodipine and benazepril hydrochloride and lithium, frequent monitoring of serum lithium levels is recommended. Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including benazepril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving benazepril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including benazepril, may be attenuated by NSAIDs. Antidiabetic Agents: In rare cases, diabetic patients receiving an ACE inhibitor (including benazepril) concomitantly with insulin or oral antidiabetics may develop hypoglycemia. Such patients should therefore be advised about the possibility of hypoglycemic reactions and should be monitored accordingly. Mammalian Target of Rapamycin (mTOR) Inhibitors: The risk of angioedema may be increased in patients receiving coadministration of ACE inhibitors and mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus). Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on amlodipine and benazepril hydrochloride and other agents that block the RAS. Do not coadminister aliskiren with amlodipine and benazepril hydrochloride in patients with diabetes. Avoid use of aliskiren with amlodipine and benazepril hydrochloride in patients with renal impairment [glomerular filtration rate (GFR) < 60 mL/min]. Neprilysin Inhibitor: Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema [see Warnings and Precautions (5.1) ].