Amlodipine Besylate And Olmesartran Medoxomil

1 INDICATIONS AND USAGE Amlodipine and olmesartan medoxomil tablets are indicated for the treatment of hypertension, alone or with other antihypertensive agents, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular (CV) 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 the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with amlodipine and olmesartan medoxomil tablets. 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 mmHg 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. Amlodipine and olmesartan medoxomil tablets may also be used as initial therapy in patients who are likely to need multiple antihypertensive agents to achieve their blood pressure goals. Patients with moderate or severe hypertension are at relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. The decision to use a combination as initial therapy should be individualized and should be shaped by considerations such as baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared to monotherapy. Individual blood pressure goals may vary based upon the patient’s risk. Data from an 8-week, placebo-controlled, parallel-group factorial study [ see Clinical Studies (14.1) ] provide estimates of the probability of reaching a blood pressure goal with amlodipine and olmesartan medoxomil tablets compared to amlodipine or olmesartan medoxomil monotherapy. The figures below provide estimates of the likelihood of achieving the targeted systolic or diastolic blood pressure goals with amlodipine and olmesartan medoxomil tablets 10/40 mg compared with amlodipine or olmesartan medoxomil monotherapy, based upon baseline systolic or diastolic blood pressure. The curve of each treatment group was estimated by logistic regression modeling from all available data of that treatment group. The right tail of each curve is less reliable because of small numbers of subjects with high baseline blood pressures. The figures above provide an approximation of the likelihood of reaching a targeted blood pressure goal (e.g., Week 8 SBP <140 mmHg or <130 mmHg or a DBP <90 mmHg or <80 mmHg) for the high-dose treatment groups evaluated in the study. Amlodipine and olmesartan medoxomil tablets 5/20 mg, the lowest dose combination treatment group, increases the probability of reaching blood pressure goal compared with the highest dose monotherapies, amlodipine 10 mg and olmesartan medoxomil 40 mg. For example, a patient with a baseline blood pressure of 160/100 mmHg has about a 48% likelihood of achieving a goal of <140 mmHg (systolic) and a 51% likelihood of achieving a goal of <90 mmHg (diastolic) on monotherapy with olmesartan medoxomil 40 mg, and about a 46% likelihood of achieving a goal of <140 mmHg (systolic) and a 60% likelihood of achieving a goal of <90 mmHg (diastolic) on monotherapy with amlodipine 10 mg. The likelihood of achieving these same goals increases to 63% (systolic) and 71% (diastolic) on amlodipine and olmesartan medoxomil tablets 5/20 mg, and to 68% (systolic) and 85% (diastolic) on amlodipine and olmesartan medoxomil tablets 10/40 mg. • Amlodipine and olmesartan medoxomil tablets are a combination of amlodipine besylate, a dihydropyridine calcium channel blocker, and olmesartan medoxomil, an angiotensin II receptor blocker, indicated for the treatment of hypertension, alone or with other antihypertensive agents, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions ( 1 ). • Amlodipine and olmesartan medoxomil tablets may also be used as initial therapy in patients likely to need multiple antihypertensive agents to achieve their blood pressure goals ( 1 ). Figure 1

2 DOSAGE AND ADMINISTRATION The usual starting dose of amlodipine and olmesartan medoxomil tablet is 5/20 mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum dose of one 10/40 mg tablet once daily as needed to control blood pressure [see Clinical Studies (14.1)]. • Recommended starting dose: 5/20 mg once daily ( 2 ). • Titrate as needed in two-week intervals up to a maximum of 10/40 mg once daily ( 2 ).

6 ADVERSE REACTIONS Most common adverse reaction (incidence ≥3%) is edema ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Amlodipine and Olmesartan Medoxomil Tablets The data described below reflect exposure to amlodipine and olmesartan medoxomil tablets in more than 1600 patients including more than 1000 exposed for at least 6 months and more than 700 exposed for 1 year. Amlodipine and olmesartan medoxomil tablets were studied in one placebo-controlled factorial trial [see Clinical Trials (14.1)]. The population had a mean age of 54 years and included approximately 55% males. Seventy-one percent were Caucasian and 25% were Black. Patients received doses ranging from 5/20 mg to 10/40 mg orally once daily. The overall incidence of adverse reactions on therapy with amlodipine and olmesartan medoxomil tablets were similar to that seen with corresponding doses of the individual components of amlodipine and olmesartan medoxomil tablets, and to placebo. The reported adverse reactions were generally mild and seldom led to discontinuation of treatment (2.6% for amlodipine and olmesartan medoxomil tablets and 6.8% for placebo). Edema Edema is a known, dose-dependent adverse effect of amlodipine but not of olmesartan medoxomil. The placebo-subtracted incidence of edema during the 8-week, randomized, double-blind treatment period was highest with amlodipine 10 mg monotherapy. The incidence was significantly reduced when 20 mg or 40 mg of olmesartan medoxomil was added to the 10 mg amlodipine dose. Placebo-Subtracted Incidence of Edema During the Double-Blind Treatment Period Olmesartan Medoxomil Placebo 20 mg 40 mg Amlodipine Placebo －* -2.4% 6.2% 5 mg 0.7% 5.7% 6.2% 10 mg 24.5% 13.3% 11.2% *12.3% = actual placebo incidence Across all treatment groups, the frequency of edema was generally higher in women than men, as has been observed in previous studies of amlodipine. There was a greater decrease in hemoglobin and hematocrit in patients treated with amlodipine and olmesartan medoxomil tablets as compared to patients receiving either component. Adverse reactions seen at lower rates during the double-blind period also occurred in the patients treated with amlodipine and olmesartan medoxomil tablets at about the same or greater incidence as in patients receiving placebo. These included hypotension, orthostatic hypotension, rash, pruritus, palpitation, urinary frequency, and nocturia. The adverse event profile obtained from 44 weeks of open-label combination therapy with amlodipine plus olmesartan medoxomil was similar to that observed during the 8-week, double-blind, placebo-controlled period. Initial Therapy Analyzing the data described above specifically for initial therapy, it was observed that higher doses of amlodipine and olmesartan medoxomil tablets caused slightly more hypotension and orthostatic symptoms, but not at the recommended starting dose of amlodipine and olmesartan medoxomil tablets 5/20 mg. No increase in the incidence of syncope or near syncope was observed. The incidences of discontinuation because of any treatment emergent adverse events in the double-blind phase are summarized in the table below. Discontinuation for any Treatment Emergent Adverse Event 1 Olmesartan Medoxomil Placebo 10 mg 20 mg 40 mg Amlodipine Placebo 4.9% 4.3% 5.6% 3.1% 5 mg 3.7% 0% 1.2% 3.7% 10 mg 5.5% 6.8% 2.5% 5.6% 1 Hypertension is counted as treatment failure and not as treatment emergent adverse event. N=160 to 163 subjects per treatment group. Amlodipine . Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (N=1730) in doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine due to adverse reactions was required in only about 1.5% of amlodipine-treated patients and about 1% of placebo-treated patients. The most common side effects were headache and edema. The incidence (%) of dose-related side effects was as follows: Adverse Event Placebo N=520 2.5 mg N=275 5 mg N=296 10 mg N=268 Edema 0.6 1.8 3 10.8 Dizziness 1.5 1.1 3.4 3.4 Flushing 0 0.7 1.4 2.6 Palpitation 0.6 0.7 1.4 4.5 For several adverse experiences that appear to be drug- and dose-related, there was a greater incidence in women than men associated with amlodipine treatment as shown in the following table: Adverse Event Placebo Amlodipine Male=% (N=914) Female=% (N=336) Male=% (N=1218) Female=% (N=512) Edema 1.4 5.1 5.6 14.6 Flushing 0.3 0.9 1.5 4.5 Palpitation 0.9 0.9 1.4 3.3 Somnolence 0.8 0.3 1.3 1.6 Olmesartan medoxomil. Olmesartan medoxomil has been evaluated for safety in more than 3825 patients/subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least 6 months and more than 525 treated for at least 1 year. Treatment with olmesartan medoxomil was well tolerated, with an incidence of adverse events similar to that seen with placebo. Events were generally mild, transient, and without relationship to the dose of olmesartan medoxomil. The overall frequency of adverse events was not dose related. Analysis of gender, age, and race groups demonstrated no differences between olmesartan medoxomil- and placebo-treated patients. The rate of withdrawals due to adverse events in all trials of hypertensive patients was 2.4% (i.e., 79/3278) of patients treated with olmesartan medoxomil and 2.7% (i.e., 32/1179) of control patients. In placebo-controlled trials, the only adverse event that occurred in more than 1% of patients treated with olmesartan medoxomil and at a higher incidence in olmesartan medoxomil treated patients vs. placebo was dizziness (3% vs 1%). 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of the individual components of amlodipine and olmesartan medoxomil tablets. 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. Amlodipine. The following post-marketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In post-marketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine. Postmarketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine. Olmesartan medoxomil. The following adverse reactions have been reported in post-marketing experience: Body as a Whole: asthenia, angioedema, anaphylactic reactions, peripheral edema Gastrointestinal: vomiting, diarrhea, sprue-like enteropathy [see Warnings and Precautions (5.6)] Metabolic and Nutritional Disorders: hyperkalemia Musculoskeletal: rhabdomyolysis Urogenital System: acute renal failure, increased blood creatinine levels Skin and Appendages: alopecia, pruritus, urticaria Data from one controlled trial and an epidemiologic study have suggested that high-dose olmesartan may increase cardiovascular (CV) risk in diabetic patients, but the overall data are not conclusive. The randomized, placebo-controlled, double-blind ROADMAP trial (Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention trial, n=4447) examined the use of olmesartan, 40 mg daily, vs. placebo in patients with type 2 diabetes mellitus, normoalbuminuria, and at least one additional risk factor for CV disease. The trial met its primary endpoint, delayed onset of microalbuminuria, but olmesartan had no beneficial effect on decline in glomerular filtration rate (GFR). There was a finding of increased CV mortality (adjudicated sudden cardiac death, fatal myocardial infarction, fatal stroke, revascularization death) in the olmesartan group compared to the placebo group (15 olmesartan vs. 3 placebo, HR 4.9, 95% confidence interval [CI], 1.4, 17), but the risk of non fatal myocardial infarction was lower with olmesartan (HR 0.64, 95% CI 0.35, 1.18). The epidemiologic study included patients 65 years and older with overall exposure of > 300,000 patient-years. In the sub-group of diabetic patients receiving high-dose olmesartan (40 mg/d) for > 6 months, there appeared to be an increased risk of death (HR 2, 95% CI 1.1, 3.8) compared to similar patients taking other angiotensin receptor blockers. In contrast, high-dose olmesartan use in non-diabetic patients appeared to be associated with a decreased risk of death (HR 0.46, 95% CI 0.24, 0.86) compared to similar patients taking other angiotensin receptor blockers. No differences were observed between the groups receiving lower doses of olmesartan compared to other angiotensin blockers or those receiving therapy for < 6 months. Overall, these data raise a concern of a possible increased CV risk associated with the use of high-dose olmesartan in diabetic patients. There are, however, concerns with the credibility of the finding of increased CV risk, notably the observation in the large epidemiologic study for a survival benefit in non-diabetics of a magnitude similar to the adverse finding in diabetics.

12.3 Pharmacokinetics The pharmacokinetics of amlodipine and olmesartan medoxomil from amlodipine and olmesartan medoxomil tablets are equivalent to the pharmacokinetics of amlodipine and olmesartan medoxomil when administered separately. The bioavailability of both components is well below 100%, but neither component is affected by food. The effective half-lives of amlodipine (45 ± 11 hours) and olmesartan (7 ± 1 hours) result in a 2- to 3- fold accumulation for amlodipine and negligible accumulation for olmesartan with once-daily dosing. Amlodipine. After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability is estimated as between 64% and 90%. Olmesartan medoxomil. Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. The absolute bioavailability of olmesartan medoxomil is approximately 26%. After oral administration, the peak plasma concentration (C max ) of olmesartan is reached after 1 to 2 hours. Food does not affect the bioavailability of olmesartan medoxomil. Distribution Amlodipine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing. Olmesartan medoxomil. The volume of distribution of olmesartan is approximately 17 L. Olmesartan is highly bound to plasma proteins (99%) and does not penetrate red blood cells. The protein binding is constant at plasma olmesartan concentrations well above the range achieved with recommended doses. In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan passed across the placental barrier in rats and was distributed to the fetus. Olmesartan was distributed to milk at low levels in rats. Metabolism and Excretion Amlodipine. Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Ten percent of the parent compound and 60% of the metabolites are excreted in the urine. Olmesartan medoxomil. Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption, there is virtually no further metabolism of olmesartan. Total plasma clearance of olmesartan is 1.3 L/h, with a renal clearance of 0.6 L/h. Approximately 35% to 50% of the absorbed dose is recovered in urine while the remainder is eliminated in feces via the bile. Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination half-life of approximately 13 hours. Olmesartan shows linear pharmacokinetics following single oral doses of up to 320 mg and multiple oral doses of up to 80 mg. Steady-state levels of olmesartan are achieved within 3 to 5 days and no accumulation in plasma occurs with once-daily dosing. Specific Populations Geriatric Patients The pharmacokinetic properties of amlodipine and olmesartan medoxomil tablets in the elderly are similar to those of the individual components. Amlodipine. Elderly patients have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%, and a lower initial dose may be required. Olmesartan medoxomil. The pharmacokinetics of olmesartan medoxomil were studied in the elderly (≥65 years). Overall, maximum plasma concentrations of olmesartan were similar in young adults and the elderly. Modest accumulation of olmesartan was observed in the elderly with repeated dosing; AUC ѕѕ,τ was 33% higher in elderly patients, corresponding to an approximate 30% reduction in CL R . Pediatric Patients Amlodipine. Sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults. Olmesartan medoxomil. The pharmacokinetics of olmesartan medoxomil have not been investigated in patients <18 years of age. Male and Female Patients Population pharmacokinetic analysis indicated that female patients had approximately 15% smaller clearances of olmesartan than male patients. Gender had no effect on the clearance of amlodipine. Olmesartan medoxomil. Minor differences were observed in the pharmacokinetics of olmesartan medoxomil in women compared to men. AUC and C max were 10% to 15% higher in women than in men. Patients with Renal Impairment Amlodipine. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose. Olmesartan medoxomil. In patients with renal insufficiency, serum concentrations of olmesartan were elevated compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). The pharmacokinetics of olmesartan medoxomil in patients undergoing hemodialysis has not been studied. No initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min). Patients with Hepatic Impairment Amlodipine. Patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%. Olmesartan medoxomil. Increases in AUC 0-∞ and C max were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%. Heart Failure Amlodipine. Patients with heart failure have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%. Drug Interaction Studies Simvastatin: Co-administration 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 [see Drug Interactions (7.1)] . CYP3A inhibitors : Co-administration 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 co-administration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of amlodipine to a greater extent [see Drug Interactions (7.1)] . Cyclosporine: In a prospective study in renal transplant patients, an average 40% increase in trough cyclosporine levels was observed in the presence of amlodipine [see Drug Interactions (7.1)] . Colesevelam: Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy subjects resulted in 28% reduction in C max and 39% reduction in AUC of olmesartan. Lesser effects, 4% and 15% reduction in C max and AUC respectively, were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride [see Drug Interactions (7.2)] . Cimetidine: Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine. Grapefruit juice: Co-administration 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): Co-administration 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: Co-administration 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: Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers. No significant drug interactions were reported in studies in which olmesartan medoxomil was coadministered with digoxin in healthy volunteers. Ethanol (alcohol) : Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol. Warfarin : Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time. No significant drug interactions were reported in studies in which olmesartan medoxomil was coadministered with warfarin in healthy volunteers. Antacids : The bioavailability of olmesartan medoxomil was not significantly altered by the co-administration of antacids [Al(OH) 3 /Mg(OH) 2 ].