Olmesartan Medoxomil

1 INDICATIONS & USAGE Olmesartan medoxomil tablets are indicated for the treatment of hypertension in adults and children six years of age and older, 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 the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with 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. It may be used alone or in combination with other antihypertensive agents. • Olmesartan medoxomil tablets is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension in adult and pediatric patients six years of age and older,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.

2 DOSAGE & ADMINISTRATION Indication Starting Dose Dose Range Adult Hypertension (2.1) 20 mg once daily 20 to 40 mg once daily Pediatric Hypertension (6 years of age and older) ( 2.2 ) 20 to <35 kg 10 mg once daily ≥35 kg 20 mg once daily 20 to <35 kg 10 to 20 mg once daily ≥35 kg 20 to 40 mg once daily. 2.1 Adult Hypertension Dosage must be individualized. The usual recommended starting dose of olmesartan medoxomil tablets is 20 mg once daily when used as monotherapy in patients who are not volume-contracted. For patients requiring further reduction in blood pressure after 2 weeks of therapy, the dose of olmesartan medoxomil tablets may be increased to 40 mg. Doses above 40 mg do not appear to have greater effect. Twice-daily dosing offers no advantage over the same total dose given once daily. For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics, particularly those with impaired renal function), initiate olmesartan medoxomil tablets under close medical supervision and give consideration to use of a lower starting dose [see Warnings and Precautions ( 5.3 )] 2.2 Pediatric Hypertension (6 Years of Age and Older) Dosage must be individualized. For children who can swallow tablets, the usual recommended starting dose of olmesartan medoxomil tablets is 10 mg once daily for patients who weigh 20 to <35 kg (44 to 77 lb), or 20 mg once daily for patients who weigh ≥35 kg. For patients requiring further reduction in blood pressure after 2 weeks of therapy, the dose of olmesartan medoxomil tablets may be increased to a maximum of 20 mg once daily for patients who weigh <35 kg or 40 mg once daily for patients who weigh ≥35 kg. Use of olmesartan medoxomil tablets in children less than 1 year of age is not recommended [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.4 )] . For children who cannot swallow tablets, the same dose can be given using an extemporaneous suspension as described below [see Clinical Pharmacology ( 12.3 ) ]. Follow the suspension preparation instructions below to administer olmesartan medoxomil tablets as a suspension. Preparation of Suspension (for 200 mL of a 2 mg/mL suspension) Add 50 mL of Purified Water to an amber polyethylene terephthalate (PET) bottle containing twenty olmesartan medoxomil tablets 20 mg and allow to stand for a minimum of 5 minutes. Shake the container for at least 1 minute and allow the suspension to stand for at least 1 minute. Repeat 1-minute shaking and 1-minute standing for four additional times. Add 100 mL of ORA-Sweet ® and 50 mL of ORA-Plus ®* to the suspension and shake well for at least 1 minute. The suspension should be refrigerated at 2 to 8°C (36 to 46°F) and can be stored for up to 4 weeks. Shake the suspension well before each use and return promptly to the refrigerator. * ORA-Sweet ® and ORA-Plus ® are registered trademarks of Paddock Laboratories, Inc.

6 ADVERSE REACTIONS The most common adverse reaction in adults was dizziness (3%) ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 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. Adult Hypertension Olmesartan medoxomil tablets 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 for at least 1 year. Events generally were mild, transient and had no relationship to the dose of olmesartan medoxomil tablets. Analysis of gender, age and race groups demonstrated no differences between olmesartan medoxomil tablets and placebo-treated patients. The rate of withdrawals due to adverse reactions in all trials of hypertensive patients was 2.4% (i.e., 79/3278) of patients treated with olmesartan medoxomil tablets and 2.7% (i.e., 32/1179) of control patients. In placebo-controlled trials, the only adverse reaction that occurred in more than 1% of patients treated with olmesartan medoxomil tablets and at a higher incidence versus placebo was dizziness (3% vs. 1%). Facial edema was reported in five patients receiving olmesartan medoxomil tablets. Angioedema has been reported with angiotensin II antagonists. Pediatric Hypertension No relevant differences were identified between the adverse experience profile for pediatric patients aged 1 to 16 years and that previously reported for adult patients. 6.2 Post-Marketing Experience The following adverse reactions have been reported in post-marketing 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. Body as a Whole : Asthenia, angioedema, anaphylactic reactions Gastrointestinal : Vomiting, sprue-like enteropathy [see Warnings and Precautions ( 5.5 )] 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 2.0, 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 Absorption Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. Olmesartan medoxomil tablets and the suspension formulation prepared from olmesartan medoxomil tablets are bioequivalent [see Dosage and Administration ( 2.2 )] . The absolute bioavailability of olmesartan is approximately 26%. After oral administration, the peak plasma concentration (Cmax) of olmesartan is reached after 1 to 2 hours. Food does not affect the bioavailability of olmesartan. Olmesartan medoxomil tablets may be administered with or without food. Distribution 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 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 pharmacokinetics of olmesartan 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; AUCss, τ was 33% higher in elderly patients, corresponding to an approximate 30% reduction in CLR [see Dosage and Administration ( 2.1 ) and Use in Specific Populations ( 8.5 )] . Pediatric Patients The pharmacokinetics of olmesartan were studied in pediatric hypertensive patients aged 1 to16 years. The clearance of olmesartan in pediatric patients was similar to that in adult patients when adjusted by the body weight [see Use in Specific Populations ( 8.4 )] . Olmesartan pharmacokinetics have not been investigated in pediatric patients less than 1 year of age [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.4 )]. Male and Female Patients Minor differences were observed in the pharmacokinetics of olmesartan in women compared to men. AUC and Cmax were 10-15% higher in women than in men. Patients with Hepatic Impairment Increases in AUC0-∞ and Cmax were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60% [see Dosage and Administration ( 2.1 ) and Use in Specific Populations ( 8.6 )] . Patients with Renal Impairment 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 in patients undergoing hemodialysis has not been studied [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.4 ) and Use in Specific Populations ( 8.7 )] . Drug Interaction Studies Bile Acid Sequestering Agent 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 (7.5)]. Other Studies No significant drug interactions were reported in studies in which olmesartan medoxomil was co-administered with digoxin or warfarin in healthy volunteers. The bioavailability of olmesartan was not significantly altered by the co-administration of antacids [Al(OH)3/Mg(OH)2]. Olmesartan medoxomil is not metabolized by the cytochrome P450 system and has no effects on P450 enzymes; thus, interactions with drugs that inhibit, induce, or are metabolized by those enzymes are not expected.