LOSARTAN POTASSIUM AND HYDROCHLOROTHIAZIDE

Losartan potassium and hydrochlorothiazide 50 mg/12.5 mg, losartan potassium and hydrochlorothiazide 100 mg/12.5 mg and losartan potassium and hydrochlorothiazide 100 mg/25 mg tablets combine an angiotensin II receptor blocker acting on the AT1 receptor subtype and a diuretic, hydrochlorothiazide. Losartan potassium, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1-[p-(o-1H­- tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt. Its molecular formula is C22 H22 ClKN6 O, and its structural formula is: Losartan Chemical Structure Losartan potassium USP is a white to off-white powder with a molecular weight of 461.01. It is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents, such as acetonitrile and methyl ethyl ketone. Oxidation of the 5-hydroxymethyl group on the imidazole ring results in the active metabolite of losartan. Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its molecular formula is C7 H8 ClN3 O4 S2 and its structural formula is: Hydrochlorothiazide Chemical Structure Hydrochlorothiazide USP is a white or practically white, practically odorless, crystalline powder with a molecular weight of 297.74, which is slightly soluble in water, but freely soluble in sodium hydroxide solution. Losartan potassium and hydrochlorothiazide is available for oral administration in three tablet combinations of losartan and hydrochlorothiazide. Losartan potassium and hydrochlorothiazide tablets USP, 50 mg/12.5 mg contain 50 mg of losartan potassium USP and 12.5 mg of hydrochlorothiazide USP. Losartan potassium and hydrochlorothiazide tablets USP, 100 mg/12.5 mg contain 100 mg of losartan potassium USP and 12.5 mg of hydrochlorothiazide USP. Losartan potassium and hydrochlorothiazide tablets USP, 100 mg/25 mg contain 100 mg of losartan potassium USP and 25 mg of hydrochlorothiazide USP. Inactive ingredients are colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinised starch(maize), and titanium dioxide. Losartan potassium and hydrochlorothiazide 50 mg/12.5 mg and losartan potassium and hydrochlorothiazide 100 mg/25 mg also contain D&C yellow No. 10 aluminum lake. Losartan potassium and hydrochlorothiazide tablets USP, 50 mg/12.5 mg contains 4.24 mg (0.108 mEq) of potassium, losartan potassium and hydrochlorothiazide tablets USP, 100 mg/12.5 mg contains 8.48 mg (0.217 mEq) of potassium, and losartan potassium and hydrochlorothiazide tablets USP, 100 mg/25 mg contains 8.48 mg (0.217 mEq) of potassium. Meets USP Dissolution Test 2.

1 Hypertension Losartan potassium and hydrochlorothiazide tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular (CV) events, primarily strokes and myocardial infarction. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including losartan and hydrochlorothiazide. 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 1 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. This fixed dose combination is not indicated for initial therapy of hypertension, except when the hypertension is severe enough that the value of achieving prompt blood pressure control exceeds the risk of initiating combination therapy in these patients [see CLINICAL STUDIES (14) and DOSAGE AND ADMINISTRATION (2.1)]. Losartan potassium and hydrochlorothiazide tablets may be administered with other antihypertensive agents. 1.2 Hypertensive Patients with Left Ventricular Hypertrophy Losartan potassium and hydrochlorothiazide tablets are indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to Black patients. [See USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3), and DOSAGE AND ADMINISTRATION (2.2)].

1 Hypertension The usual starting dose of losartan potassium and hydrochlorothiazide tablets is 50 mg/12.5 mg (losartan 50 mg/hydrochlorothiazide 12.5 mg) once daily. The dosage can be increased after 3 weeks of therapy to a maximum of 100 mg/25 mg (losartan 100 mg/hydrochlorothiazide 25 mg) once daily as needed to control blood pressure [see CLINICAL STUDIES (14.2)]. Initiate a patient whose blood pressure is not adequately controlled with losartan 50 mg monotherapy with losartan potassium and hydrochlorothiazide tablets 50 mg/12.5 mg once daily. If blood pressure remains uncontrolled after about 3 weeks of therapy, the dosage may be increased to two tablets of losartan potassium and hydrochlorothiazide 50 mg/12.5 mg once daily or one tablet of losartan potassium and hydrochlorothiazide 100 mg/25 mg once daily. Initiate a patient whose blood pressure is not adequately controlled with losartan 100 mg monotherapy with losartan potassium and hydrochlorothiazide tablets 100 mg/12.5 mg (losartan 100 mg/hydrochlorothiazide 12.5 mg) once daily. If blood pressure remains uncontrolled after about 3 weeks of therapy, increase the dose to two tablets of losartan potassium and hydrochlorothiazide 50 mg/12.5 mg once daily or one tablet of losartan potassium and hydrochlorothiazide 100 mg/25 mg once daily. Initiate a patient whose blood pressure is inadequately controlled with hydrochlorothiazide 25 mg once daily, or is controlled but who experiences hypokalemia with this regimen, on losartan potassium and hydrochlorothiazide tablets 50 mg/12.5 mg once daily, reducing the dose of hydrochlorothiazide without reducing the overall expected antihypertensive response. Evaluate the clinical response to losartan potassium and hydrochlorothiazide tablets 50 mg/12.5 mg and, if blood pressure remains uncontrolled after about 3 weeks of therapy, increase the dose to two tablets of losartan potassium and hydrochlorothiazide 50 mg/12.5 mg once daily or one tablet of losartan potassium and hydrochlorothiazide 100 mg/25 mg once daily. 2.2 Hypertensive Patients with Left Ventricular Hypertrophy In patients whose blood pressure is not adequately controlled on 50 mg losartan potassium, initiate treatment with losartan potassium and hydrochlorothiazide tablets 50 mg/12.5 mg. If additional blood pressure reduction is needed, increase the dose to losartan potassium and hydrochlorothiazide tablets 100 mg/12.5 mg, followed by losartan potassium and hydrochlorothiazide tablets 100 mg/25 mg. For further blood pressure reduction add other antihypertensives [see CLINICAL STUDIES (14)].

Losartan potassium and hydrochlorothiazide tablets are contraindicated: • In patients who are hypersensitive to any component of this product. • In patients with anuria • For coadministration with aliskiren in patients with diabetes

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. Losartan potassium-hydrochlorothiazide has been evaluated for safety in 858 patients treated for essential hypertension and 3889 patients treated for hypertension and left ventricular hypertrophy. Most adverse reactions have been mild and transient in nature and have not required discontinuation of therapy. In controlled clinical trials, discontinuation of therapy due to clinical adverse events was required in only 2.8% and 2.3% of patients treated with the combination and placebo, respectively. In these double-blind controlled clinical trials, adverse reactions occurring in greater than 2% of subjects treated with losartan-hydrochlorothiazide and at a greater rate than placebo were: back pain (2.1% vs 0.6%), dizziness (5.7% vs 2.9%), and upper respiratory infection (6.1% vs 4.6%). The following additional adverse reactions have been reported in clinical trials with losartan potassium and hydrochlorothiazide and/or the individual components: Blood and the lymphatic system disorders: Anemia, aplastic anemia, hemolytic anemia, leukopenia, agranulocytosis. Metabolism and nutrition disorders: Anorexia, hyperglycemia, hyperuricemia, electrolyte imbalance including hyponatremia and hypokalemia. Psychiatric disorders: Insomnia, restlessness. Nervous system disorders: Dysgeusia, headache, migraine, paraesthesias. Eye disorders: Xanthopsia, transient blurred vision. Cardiac disorders: Palpitation, tachycardia. Vascular disorders: Dose-related orthostatic effects, necrotizing angiitis (vasculitis, cutaneous vasculitis). Respiratory, thoracic and mediastinal disorders: Nasal congestion. Gastrointestinal disorders: Dyspepsia, abdominal pain, gastric irritation, cramping, nausea, vomiting, pancreatitis, sialoadenitis. Hepato-biliary disorders: Jaundice (intrahepatic cholestatic jaundice). Skin and subcutaneous tissue disorders: Rash, pruritus, purpura, toxic epidermal necrolysis, urticaria, photosensitivity, cutaneous lupus erythematosus. Musculoskeletal and connective tissue disorders: Muscle cramps, muscle spasm. Renal and urinary disorders: Glycosuria, renal dysfunction, interstitial nephritis, renal failure. Reproductive system and breast disorders: Erectile dysfunction/impotence. General disorders and administration site conditions: Chest pain, malaise, weakness. Investigations: Liver function abnormalities. Cough Persistent dry cough has been associated with ACE-inhibitor use and in practice can be a cause of discontinuation of ACE-inhibitor therapy. Two prospective, parallel-group, double-blind, randomized, controlled trials were conducted to assess the effects of losartan on the incidence of cough in hypertensive patients who had experienced cough while receiving ACE-inhibitor therapy. Patients who had typical ACE-inhibitor cough when challenged with lisinopril, whose cough disappeared on placebo, were randomized to losartan 50 mg, lisinopril 20 mg, or either placebo (one study, n=97) or 25 mg hydrochlorothiazide (n=135). The double-blind treatment period lasted up to 8 weeks. The incidence of cough is shown in Table 1 below. Table 1: *Demographics = (89% Caucasian, 64% female) † Demographics = (90% Caucasian, 51% female) Study 1* HCTZ Losartan Lisinopril Cough 25% 17% 69% Study 2† Placebo Losartan Lisinopril Cough 35% 29% 62% These studies demonstrate that the incidence of cough associated with losartan therapy, in a population that all had cough associated with ACE-inhibitor therapy, is similar to that associated with hydrochlorothiazide or placebo therapy. Cases of cough, including positive re-challenges, have been reported with the use of losartan in postmarketing experience. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of losartan potassium and hydrochlorothiazide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Digestive: Hepatitis has been reported rarely in patients treated with losartan. Hematologic: Thrombocytopenia. Hypersensitivity: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue has been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Vasculitis, including Henoch-Schönlein purpura, has been reported with losartan. Anaphylactic reactions have been reported. Musculoskeletal: Rhabdomyolysis. Skin: Erythroderma. 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.

1 Agents Increasing Serum Potassium Coadministration of losartan 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 with concomitant use of angiotensin II receptor antagonists or thiazide diuretics. Monitor lithium levels in patients receiving losartan potassium and hydrochlorothiazide and lithium. 7.3 Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors Losartan Potassium In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists (including losartan) may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving losartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including losartan, may be attenuated by NSAIDs, including selective COX-2 inhibitors. Hydrochlorothiazide The administration of a non-steroidal anti-inflammatory agent including a selective COX-2 inhibitor can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when losartan potassium and hydrochlorothiazide and non-steroidal anti-inflammatory agents including selective COX-2 inhibitors are used concomitantly, observe closely to determine if the desired effect of the diuretic is obtained. In patients receiving diuretic therapy, coadministration of NSAIDs with angiotensin receptor blockers, including losartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving hydrochlorothiazide, losartan, and NSAID therapy. 7.4 Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial enrolled 1448 patients with type 2 diabetes, elevated urinary-albumin-to-creatinine ratio, and decreased estimated glomerular filtration rate (GFR 30 to 89.9 mL/min), randomized them to lisinopril or placebo on a background of losartan therapy and followed them for a median of 2.2 years. Patients receiving the combination of losartan and lisinopril did not obtain any additional benefit compared to monotherapy for the combined endpoint of decline in GFR, end-stage renal disease, or death, but experienced an increased incidence of hyperkalemia and acute kidney injury compared with the monotherapy group. Closely monitor blood pressure, renal function, and electrolytes in patients on losartan potassium and hydrochlorothiazide and other agents that affect the RAS. Do not coadminister aliskiren with losartan potassium and hydrochlorothiazide in patients with diabetes. Avoid use of aliskiren with losartan potassium and hydrochlorothiazide in patients with renal impairment (GFR <60 mL/min). 7.5 The Use of Hydrochlorothiazide with Other Drugs When administered concurrently, the following drugs may interact with thiazide diuretics [see CLINICAL PHARMACOLOGY (12.3)]: Antidiabetic drugs (oral agents and insulin) — dosage adjustment of the antidiabetic drug may be required. Cholestyramine and colestipol resins — Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively. Stagger the dosage of hydrochlorothiazide and the resin such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of the resin.