Olmesartan Medoxomil and Hydrochlorothiazide

1 INDICATIONS AND USAGE Olmesartan medoxomil and hydrochlorothiazide tablets are indicated for the treatment of hypertension, to lower blood pressure. Olmesartan medoxomil and hydrochlorothiazide tablets are not indicated for the initial therapy of hypertension [see Dosage and Administration (2) ]. 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 and hydrochlorothiazide 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. Olmesartan medoxomil and hydrochlorothiazide tablets may be used alone, or in combination with other antihypertensive drugs. Olmesartan medoxomil and hydrochlorothiazide tablets are a combination of olmesartan, an angiotensin II receptor blocker and hydrochlorothiazide, a thiazide diuretic 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. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended starting dose of olmesartan medoxomil and hydrochlorothiazide tablets is 40 mg/12.5 mg once daily in patients whose blood pressure is not adequately controlled with olmesartan monotherapy. Dose can be titrated up to 40 mg/25 mg if necessary. The recommended starting dose of olmesartan medoxomil and hydrochlorothiazide tablets is 20 mg/12.5 mg once daily in patients whose blood pressure is not adequately controlled with hydrochlorothiazide monotherapy or who experience dose-limiting adverse reactions with hydrochlorothiazide. Dose can be titrated up to 40 mg/25 mg if necessary. Patients titrated to the individual components (olmesartan and hydrochlorothiazide) may instead receive the corresponding dose of olmesartan medoxomil and hydrochlorothiazide tablets. Recommended starting dose in patients not adequately controlled with olmesartan monotherapy, 40/12.5 mg ( 2 ) Recommended starting dose in patients not adequately controlled with hydrochlorothiazide monotherapy, 20/12.5 mg ( 2 ) Adjust dose after 2 to 4 weeks, as needed, to a maximum of 40 mg / 25 mg olmesartan / hydrochlorothiazide ( 2 )

6 ADVERSE REACTIONS The following adverse reactions with olmesartan medoxomil and hydrochlorothiazide are described elsewhere: Hypotension in Volume- or Salt-Depleted Patients [see Warnings and Precautions (5.2) ] Impaired Renal Function [see Warnings and Precautions (5.3) ] Hypersensitivity Reactions [see Warnings and Precautions (5.4) ] Electrolyte and Metabolic Imbalances [see Warnings and Precautions (5.5) ] Acute Myopia and Secondary Angle-Closure Glaucoma [see Warnings and Precautions (5.6) ] Systemic Lupus Erythematosus [see Warnings and Precautions (5.7) ] Sprue-Like Enteropathy [see Warnings and Precautions (5.8) ] Most common adverse reactions (incidence ≥2%) are nausea, hyperuricemia, dizziness, and upper respiratory infection ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-332-1088 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. Olmesartan medoxomil and hydrochlorothiazide The concomitant use of olmesartan medoxomil and hydrochlorothiazide was evaluated for safety in 1243 hypertensive patients. Treatment with olmesartan medoxomil and hydrochlorothiazide was well tolerated, with an incidence of adverse events similar to that of placebo. Adverse reactions were generally mild, transient and not dependent on the dose of olmesartan medoxomil and hydrochlorothiazide. The rate of withdrawals for adverse events in all trials of hypertensive patients was 2.0% (25/1243) on olmesartan medoxomil plus hydrochlorothiazide and 2.0% (7/342) on placebo. In a placebo-controlled, factorial clinical trial of olmesartan medoxomil (2.5 mg to 40 mg) and hydrochlorothiazide (12.5 mg to 25 mg), the following adverse reactions reported in Table 1 occurred in >2% of patients, and more often on the olmesartan medoxomil and hydrochlorothiazide combination than on placebo. Table 1: Adverse Reactions in a Factorial Trial of Patients with Hypertension Olmesartan/Hydrochlorothiazide (N=247) (%) Olmesartan (N=125) (%) Hydrochlorothiazide (N=88) (%) Placebo (N=42) (%) Nausea 3 2 1 0 Hyperuricemia 4 0 2 2 Dizziness 9 1 8 2 Upper Respiratory Infection 7 6 7 0 Other adverse reactions that have been reported with an incidence of greater than 1.0%, whether or not attributed to treatment, in the more than 1200 hypertensive patients treated with olmesartan medoxomil and hydrochlorothiazide in controlled or open-label trials are listed below. Body as a Whole: chest pain, back pain, peripheral edema Central and Peripheral Nervous System: vertigo Gastrointestinal: abdominal pain, dyspepsia, gastroenteritis, diarrhea Liver and Biliary System: SGOT increased, GGT increased, ALT increased Metabolic and Nutritional: creatine phosphokinase increased Musculoskeletal: arthritis, arthralgia, myalgia Respiratory System: coughing Skin and Appendages Disorders: rash Urinary System: hematuria Facial edema was reported in 2/1243 patients receiving olmesartan medoxomil and hydrochlorothiazide. Angioedema has been reported with angiotensin II receptor antagonists, including olmesartan medoxomil and hydrochlorothiazide. Hydrochlorothiazide Other adverse reactions that have been reported with hydrochlorothiazide are listed below: Body as a Whole: weakness Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia Hypersensitivity: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions Metabolic: glycosuria, hyperuricemia Musculoskeletal: muscle spasm Nervous System/Psychiatric: restlessness Renal: renal dysfunction, interstitial nephritis Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis Special Senses: transient blurred vision, xanthopsia Clinical Laboratory Test Findings Creatinine/blood urea nitrogen (BUN): Minor elevations in creatinine and BUN occurred in 1.7% and 2.5% respectively, of patients taking olmesartan medoxomil and hydrochlorothiazide and 0% and 0% respectively, given placebo in controlled clinical trials. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of olmesartan medoxomil and hydrochlorothiazide. 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 Gastrointestinal: Vomiting Metabolic: Hyperkalemia Musculoskeletal: Rhabdomyolysis Skin and Appendages: Alopecia, pruritus 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. Non-melanoma Skin Cancer Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥50,000 mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.

7 DRUG INTERACTIONS Lithium: Risk of lithium toxicity ( 7.2 ) Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Reduced diuretic, natriuretic and antihypotensive effects; increased risk of renal toxicity ( 7.3 ) Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia ( 7.4 ) Colesevelam hydrochloride: Consider administering olmesartan at least 4 hours before colesevelam hydrochloride dose ( 7.5 ) Antidiabetic drugs: Dosage adjustment may be required ( 7.6 ) Cholestyramine and colestipol: Reduced absorption of thiazides ( 7.6 ) 7.1 Agents Increasing Serum Potassium Coadministration of olmesartan medoxomil and hydrochlorothiazide with other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients. 7.2 Lithium Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists or hydrochlorothiazide. Monitor serum lithium levels during concomitant use. 7.3 Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) Olmesartan medoxomil In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists (including olmesartan medoxomil) may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving olmesartan medoxomil and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including olmesartan medoxomil may be attenuated by NSAIDs including selective COX-2 inhibitors. Hydrochlorothiazide In some patients the administration of a NSAID can reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics. Therefore, monitor blood pressure closely. 7.4 Dual Blockade of the Renin Angiotensin System 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 olmesartan medoxomil and hydrochlorothiazide and other agents that affect the RAS. Do not co-administer aliskiren with olmesartan medoxomil and hydrochlorothiazide in patients with diabetes [see Contraindications (4) ]. Avoid use of aliskiren with olmesartan medoxomil and hydrochlorothiazide in patients with renal impairment (GFR <60 mL/min). 7.5 Colesevelam Hydrochloride Concurrent administration of bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan. Administration of olmesartan at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Consider administering olmesartan at least 4 hours before the colesevelam hydrochloride dose [see Clinical Pharmacology (12.3) ]. 7.6 The Use of Hydrochlorothiazide with Other Drugs When administered concurrently the following drugs may interact with thiazide diuretics: Antidiabetic drugs (oral agents and insulin): Dosage adjustment of the antidiabetic drug may be required. Ion exchange resins: Staggering the dosage of hydrochlorothiazide and ion exchange resins (e.g., cholestyramine, colestipol) such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of resins would potentially minimize the interaction [see Clinical Pharmacology (12.3) ]. Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia.

16 HOW SUPPLIED/STORAGE AND HANDLING Olmesartan medoxomil and hydrochlorothiazide tablets 40 mg/12.5 mg are reddish-yellow, oval shaped, biconvex film-coated tablets, debossed with ‘K’ on one side and ‘53’ on the other side. NDC 71335-0845-1: 30 Tablets in a BOTTLE NDC 71335-0845-2: 90 Tablets in a BOTTLE NDC 71335-0845-3: 28 Tablets in a BOTTLE Storage Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504