Amlodipine And Benazepril Hydrochloride

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION 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.

6 ADVERSE REACTIONS 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).

12.3 Pharmacokinetics The rate and extent of absorption of benazepril and amlodipine from amlodipine and benazepril hydrochloride are the same as when administered as individual tablets. Absorption from the individual tablets is not influenced by the presence of food in the gastrointestinal tract; food effects on absorption from amlodipine and benazepril hydrochloride have not been studied. Absorption: Following oral administration of amlodipine and benazepril hydrochloride, peak plasma concentrations of amlodipine are reached in 6 to 12 hours. Absolute bioavailability has been calculated as between 64% and 90%. Following oral administration of amlodipine and benazepril hydrochloride, the peak plasma concentrations of benazepril are reached in 0.5 to 2 hours. The cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite, benazeprilat, which reaches peak plasma concentrations in 1.5 to 4 hours. The extent of absorption of benazepril is at least 37%. Amlodipine and benazepril exhibit dose proportional pharmacokinetics between the therapeutic dose range of 2.5 and 10 mg and 10 and 20 mg, respectively. Distribution: The apparent volume of distribution of amlodipine is about 21 L/kg. In vitro studies indicate that approximately 93% of circulating amlodipine is bound to plasma proteins in hypertensive patients. The apparent volume of distribution of benazeprilat is about 0.7 L/kg. Approximately 93% of circulating amlodipine is bound to plasma proteins, and the bound fraction of benazeprilat is slightly higher. On the basis of in vitro studies, benazeprilat’s degree of protein binding should be unaffected by age, by hepatic dysfunction, or—over the therapeutic concentration range—by concentration. Metabolism: Amlodipine is extensively (approximately 90%) metabolized in the liver to inactive metabolites. Benazepril is extensively metabolized to form benazeprilat as the main metabolite, which occurs by enzymatic hydrolysis, mainly in the liver. Two minor metabolites are the acyl glucuronide conjugates of benazepril and benazeprilat. Elimination: Amlodipine elimination from plasma is biphasic with a terminal elimination half-life of approximately 30 to 50 hours. Steady-state plasma levels are reached after once-daily dosing for 7 to 8 days. Ten percent of unchanged drug and 60% of amlodipine metabolites are excreted in urine. Effective elimination half-life of amlodipine is 2 days. Benazepril is eliminated mainly by metabolic clearance. Benazeprilat is eliminated via the kidneys and the bile; renal excretion is the main route in patients with normal renal function. In the urine, benazepril accounts for less than 1% and benazeprilat for about 20% of an oral dose. Elimination of benazeprilat is biphasic with an initial half-life of about 3 hours and a terminal half-life of about 22 hours. Benazeprilat’s effective elimination half-life is 10 to 11 hours, while that of amlodipine is about 2 days, so steady-state levels of the 2 components are achieved after about a week of once-daily dosing. Specific Populations Geriatric Patients : No specific clinical studies were performed to understand the impact of age on the pharmacokinetics of amlodipine and benazepril as fixed dose combination. As individual component amlodipine is extensively metabolized in the liver. In the elderly, clearance of amlodipine is decreased with resulting increases in peak plasma levels, elimination half-life and area-under-the-plasma-concentration curve [see Use in Specific Populations (8.5) ] . Hepatic Impairment : Patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40 to 60%. Pharmacokinetics of benazepril is not significantly influenced by hepatic impairment [see Use in Specific Populations (8.6) ] . Renal Impairment : The disposition of benazepril and benazeprilat in patients with mild-to-moderate renal insufficiency (CrCl greater than 30 mL/min) is similar to that in patients with normal renal function. In patients with CrCl less than or equal to 30 mL/min, peak benazeprilat levels and the effective half-life increase, resulting in higher systemic exposures. Pharmacokinetics of amlodipine is not significantly influenced by renal impairment [see Dosage and Administration (2.2) , Use in Specific Populations (8.7) and Warnings and Precautions (5.7) ] . Drug Interactions Amlodipine In vitro data in human plasma indicate that amlodipine has no effect on the protein binding of digoxin, phenytoin, warfarin, and indomethacin. Cimetidine : Coadministration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine. Grapefruit juice : Coadministration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine. Maalox ® (antacid) : Coadministration of the antacid Maalox with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine. Sildenafil : A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect. Atorvastatin : Coadministration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin. Digoxin : Coadministration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers. Ethanol (alcohol) : Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol. Warfarin : Coadministration of amlodipine with warfarin did not change the warfarin prothrombin response time. Simvastatin : Coadministration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. CYP3A Inhibitors : Coadministration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. Erythromycin coadministration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent. Benazepril The pharmacokinetic properties of benazepril are not affected by hydrochlorothiazide, furosemide, chlorthalidone, digoxin, propranolol, atenolol, nifedipine, amlodipine, naproxen, acetylsalicylic acid, or cimetidine. Likewise the administration of benazepril does not substantially affect the pharmacokinetics of these medications.