OLMESARTAN MEDOXOMIL and HYDROCHLOROTHIAZIDE 20 mg; 12.5 mg Tablet, 60-count

5 WARNINGS AND PRECAUTIONS • Hypotension: Correct volume-depletion prior to administration. ( 5.2 ) • Monitor renal function and potassium in susceptible patients ( 5.3 ) • Observe for signs of fluid or electrolyte imbalance. ( 5.4 ) • Acute angle-closure glaucoma ( 5.5 ) • Sprue-like enteropathy has been reported. Consider discontinuation of olmesartan medoxomil and hydrochlorothiazide tablets in cases where no other etiology is found ( 5.7 )

5.1Fetal Toxicity Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is detected, discontinue olmesartan medoxomil and hydrochlorothiazide tablets as soon as possible [see Use in Specific Populations ( 8.1 )]. Thiazides cross the placental barrier and appear in cord blood. Adverse reactions include fetal or neonatal jaundice and thrombocytopenia [see Use in Specific Populations ( 8.1 )].

5.2Hypotension in Volume or Salt-Depleted Patients In patients with an activated renin-angiotensin system, such as volume-or salt-depleted patients ( e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with olmesartan medoxomil and hydrochlorothiazide tablets. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. When electrolyte and fluid imbalances have been corrected, olmesartan medoxomil and hydrochlorothiazide tablets usually can be continued without difficulty.

A transient hypotensive response is not a contraindication to further treatment.

5.3Impaired Renal Function Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system ( e.g. , patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on olmesartan medoxomil and hydrochlorothiazide tablets. Monitor renal function periodically in these patients.

Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on olmesartan medoxomil and hydrochlorothiazide tablets [see Drug Interactions ( 7 )].

5.4Hypersensitivity Reactions Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.

5.5Electrolyte and Metabolic Imbalances Olmesartan medoxomil and hydrochlorothiazide tablets contain hydrochlorothiazide which can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. Olmesartan medoxomil and hydrochlorothiazide tablets also contain olmesartan, a drug that inhibits the renin-angiotensin system (RAS).

Drugs that inhibit the RAS can cause hyperkalemia. Monitor serum electrolytes periodically. Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.

Hyperuricemia may occur or frank gout may be precipitated in patients receiving thiazide therapy. Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels.

5.6Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocu…

6 ADVERSE REACTIONS The following adverse reactions with olmesartan medoxomil and hydrochlorothiazide tablets 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 Solco Healthcare US, LLC at 1-866-257-2597 or FDA at 1-800-332-1088 or www.fda.gov/medwatch.

6.1Clinical 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/HCTZ Olmesartan HCTZ Placebo (N=247) (N=125) (N=88) (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 tablets. 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 Nerv…

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 )

7.1Agents Increasing Serum Potassium Coadministration of olmesartan medoxomil and hydrochlorothiazide tablets with other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients.

7.2Lithium 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.

7.3Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-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.

7.4Dual 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 tablets and other agents that affect the RAS. Do not co-administer aliskiren with olmesartan medoxomil and hydrochlorothiazide tablets in patients with diabetes [see Contraindications ( 4 )]. Avoid use of aliskiren with olmesartan medoxomil and hydrochlorothiazide tablets in patients with renal impairment (GFR <60 ml/min).

7.5Colesevelam 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 )] .

7.6The 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 – 6 hours after the administration of resins would potentially minimize the interaction [see Clinical Pharmacology ( 12.3 )].

Corticosteroids, AC…