Losartan Potassium and Hydrochlorothiazide

1 INDICATIONS AND USAGE Losartan potassium and hydrochlorothiazide tablet is a combination of losartan, an angiotensin II receptor blocker (ARB) and hydrochlorothiazide, a diuretic indicated for: • Treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. ( 1.1) • Reduction of the risk of stroke in patients with hypertension and left ventricular hypertrophy. There is evidence that this benefit does not apply to Black patients. ( 1.2 ) 1.1 Hypertension Losartan potassium and hydrochlorothiazide tablet is 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 tablet may be administered with other antihypertensive agents. 1.2 Hypertensive Patients with Left Ventricular Hypertrophy Losartan potassium and hydrochlorothiazide tablet is 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 ).]

2 DOSAGE AND ADMINISTRATION Hypertension • Usual starting dose: 50/12.5 mg once daily. ( 2.1 ) • Titrate as needed to a maximum dose of 100/25 mg. ( 2.1 ) Hypertensive Patients with Left Ventricular Hypertrophy • Not controlled on monotherapy: Initiate with 50/12.5 mg. Titrate as needed to a maximum of 100/25 mg. ( 2.2 ) 2.1 Hypertension The usual starting dose of losartan potassium and hydrochlorothiazide tablet is 50/12.5 (losartan 50 mg/hydrochlorothiazide 12.5 mg) once daily. The dosage can be increased after 3 weeks of therapy to a maximum of 100/25 (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 tablet 50/12.5 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 tablet 50/12.5 once daily or one tablet of losartan potassium and hydrochlorothiazide tablet 100/25 once daily. Initiate a patient whose blood pressure is not adequately controlled with losartan 100 mg monotherapy with losartan potassium and hydrochlorothiazide tablet 100/12.5 (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 tablet 50/12.5 once daily or one tablet of losartan potassium and hydrochlorothiazide tablet 100/25 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 tablet 50/12.5 once daily, reducing the dose of hydrochlorothiazide without reducing the overall expected antihypertensive response. Evaluate the clinical response to losartan potassium and hydrochlorothiazide tablet 50/12.5 and, if blood pressure remains uncontrolled after about 3 weeks of therapy, increase the dose to two tablets of losartan potassium and hydrochlorothiazide tablet 50/12.5 once daily or one tablet of losartan potassium and hydrochlorothiazide tablet 100/25 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 tablet 50/12.5. If additional blood pressure reduction is needed, increase the dose to losartan potassium and hydrochlorothiazide tablet 100/12.5, followed by losartan potassium and hydrochlorothiazide tablet 100/25. For further blood pressure reduction add other antihypertensives [see CLINICAL STUDIES ( 14 )].

5 WARNINGS AND PRECAUTIONS • Hypotension: Correct volume or salt depletion prior to administration of losartan and hydrochlorothiazide. ( 5.2 ) • Monitor renal function and potassium in susceptible patients. ( 5.3 ) • Observe for clinical signs of fluid or electrolyte imbalance. ( 5.5 ) • Acute angle-closure glaucoma. ( 5.6 ) • Exacerbation of systemic lupus erythematosus. ( 5.7 ) 5.1 Fetal Toxicity Losartan and hydrochlorothiazide can cause fetal harm when administered to a pregnant woman. 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 losartan and hydrochlorothiazide as soon as possible. Thiazides cross the placental barrier and appear in cord blood. Adverse reactions include fetal or neonatal jaundice, thrombocytopenia [see USE IN SPECIFIC POPULATIONS ( 8.1 )]. 5.2 Hypotension 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 losartan and hydrochlorothiazide .Correct volume or salt depletion prior to administration of losartan and hydrochlorothiazide. Do not use losartan and hydrochlorothiazide as initial therapy in patients with intravascular volume depletion. 5.3 Impaired 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 losartan and hydrochlorothiazide .Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on losartan and hydrochlorothiazide [see DRUG INTERACTIONS ( 7.3 ) and USE IN SPECIFIC POPULATIONS ( 8.8 )]. 5.4 Hypersensitivity 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 [see ADVERSE REACTIONS ( 6.2 )] . 5.5 Electrolyte and Metabolic Effects In double-blind clinical trials of various doses of losartan potassium and hydrochlorothiazide, the incidence of hypertensive patients who developed hypokalemia (serum potassium <3.5 mEq/L) was 6.7% versus 3.5% for placebo; the incidence of hyperkalemia (serum potassium >5.7 mEq/L) was 0.4% versus 0% for placebo. Losartan potassium and hydrochlorothiazide tablet contains hydrochlorothiazide which can cause hypokalemia, hyponatremia and hypomagnesemia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. Losartan potassium and hydrochlorothiazide tablet also contains losartan which can cause hyperkalemia. Monitor serum electrolytes periodically [see DRUG INTERACTIONS ( 7.1 )]. Concomitant use of other drugs that may increase serum potassium may lead to hyperkalemia [see DRUG INTERACTIONS ( 7.1 )]. 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. Because losartan decreases uric acid, losartan in combination with hydrochlorothiazide attenuates the diuretic-induced hyperuricemia. Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations o…

4 CONTRAINDICATIONS Losartan potassium and hydrochlorothiazide tablet is contraindicated: • In patients who are hypersensitive to any component of this product. • In patients with anuria • For coadministration with aliskiren in patients with diabetes • Hypersensitivity to any component of losartan potassium and hydrochlorothiazide tablets. ( 4 ) • Anuria. ( 4 ) • Coadministration with aliskiren in patients with diabetes. ( 4 )

7 DRUG INTERACTIONS • Agents increasing serum potassium: Risk of hyperkalemia. ( 7.1 ) • Lithium: Risk of lithium toxicity. ( 7.2 ) • Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): increased risk of renal impairment and reduced diuretic, natriuretic, and antihypertensive effects. ( 7.3 ) • Dual inhibition of the renin-angiotensin system: increased risk of renal impairment, hypotension, syncope, and hyperkalemia. ( 7.4 ) • Antidiabetic drugs: dosage adjustment of antidiabetic may be required. ( 7.5 ) • Cholestyramine and colestipol: Reduced absorption of thiazides. ( 7.5 ) 7.1 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 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 tablets and other agents that affect the RAS. Do not coadminister aliskiren with losartan potassium and hydrochlorothiazide tablets in patients with diabetes. Avoid use of aliskiren with losartan and hydrochlorothiazide in patients with renal impairment (GFR <60 mL/min). 7.5 The Use of Hydrochloro…

8.1 Pregnancy Risk Summary Losartan and hydrochlorothiazide can cause fetal harm when administered to a pregnant woman. 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. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. When pregnancy is detected, discontinue losartan and hydrochlorothiazide as soon as possible (see Clinical Considerations) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal Adverse Reactions Losartan: Use of drugs that act on the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: oligohydramnios, reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue losartan and hydrochlorothiazide, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of gestation. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe neonates with histories of in utero exposure to losartan and hydrochlorothiazide for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to losartan and hydrochlorothiazide, if oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function. Hydrochlorothiazide: Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma. Hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion. It accumulates in the amniotic fluid, with reported concentrations up to 19 times higher than in umbilical vein plasma. Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since they do not alter the course of pre-eclampsia, these drugs should not be used to treat hypertension in pregnant women. The use of hydrochlorothiazide for other indications in pregnancy should be avoided. Data Animal Data There was no evidence of teratogenicity in rats or rabbits treated with a maximum losartan potassium dose of 10 mg/kg/day in combination with 2.5 mg/kg/day of hydrochlorothiazide. At these dosages, respective exposures (AUCs) of losartan, its active metabolite, and hydrochlorothiazide in rabbits were approximately 5, 1.5, and 1.0 times those achieved in humans with 100 mg losartan in combination with 25 mg hydrochlorot…

8.2 Lactation Risk Summary It is not known whether losartan is excreted in human milk, but significant levels of losartan and its active metabolite were shown to be present in rat milk. Thiazides appear in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥2% and greater than placebo) are dizziness, upper respiratory infection, cough, and back pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 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 Study 1 Demographics = (89% Caucasian, 64% female) HCTZ Losartan Lisinopril Cough 25 % 17 % 69 % Study 2 Demographics = (90% Caucasian, 51% female) 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-i…