TORSEMIDE

1 INDICATIONS AND USAGE Torsemide is a loop diuretic indicated for: the treatment of edema associated with heart failure, renal disease or hepatic disease. ( 1.1 ) 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 ) 1.1 Edema Torsemide tablets are indicated for the treatment of edema associated with heart failure, renal disease or hepatic disease. 1.2 Hypertension Torsemide tablets are 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. 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 torsemide 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. The antihypertensive effects of torsemide tablets are on the average greater in black patients than in nonblack patients [see Clinical Pharmacology (12.2) ]. 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. Torsemide tablets can be used alone or in combination with other antihypertensive agents.

2 DOSAGE AND ADMINISTRATION Edema associated with: Heart failure: Initial dose is 10 mg or 20 mg once daily. Titrate by factors of two; doses above 200 mg have not been studied. ( 2.1 ) Chronic Renal Failure: Initial dose is 20 mg once daily. Titrate by factors of two; doses above 200 mg have not been studied. ( 2.1 ) Hepatic Cirrhosis: Initial dose is 5 mg or 10 mg once daily. Titrate by factors of two; doses above 40 mg have not been studied. ( 2.1 ) Hypertension: The recommended initial dose is 5 mg once daily. After 4 to 6 weeks, increase to 10 mg once daily, if needed. If 10 mg is insufficient, consider adding another agent. ( 2.2 ) 2.1 Treatment of Edema Edema associated with heart failure The recommended initial dose is 10 mg or 20 mg oral torsemide tablets once daily. If the diuretic response is inadequate, titrate upward by approximately doubling until the desired diuretic response is obtained. Doses higher than 200 mg have not been adequately studied. Edema associated with chronic renal failure The recommended initial dose is 20 mg oral torsemide tablets once daily. If the diuretic response is inadequate, titrate upward by approximately doubling until the desired diuretic response is obtained. Doses higher than 200 mg have not been adequately studied. Edema associated with hepatic cirrhosis The recommended initial dose is 5 mg or 10 mg oral torsemide tablets once daily, administered together with an aldosterone antagonist or a potassium-sparing diuretic. If the diuretic response is inadequate, titrate upward by approximately doubling until the desired diuretic response is obtained. Doses higher than 40 mg have not been adequately studied in this population. 2.2 Treatment of Hypertension The recommended initial dose is 5 mg once daily. If the 5 mg dose does not provide adequate reduction in blood pressure within 4 to 6 weeks, increase to 10 mg once daily. If the response to 10 mg is insufficient, add another antihypertensive agent to the treatment regimen.

4 CONTRAINDICATIONS Torsemide tablets are contraindicated in patients with known hypersensitivity to torsemide or to povidone. Torsemide tablets are contraindicated in patients who are anuric. Torsemide tablets are contraindicated in patients with hepatic coma. Hypersensitivity to torsemide or povidone, anuria, and hepatic coma. ( 4 )

5 WARNINGS AND PRECAUTIONS Hypotension and worsening renal function: monitor volume status and renal function periodically ( 5.1 ) Electrolyte and metabolic abnormalities: monitor serum electrolytes and blood glucose periodically. ( 5.2 ) Ototoxicity ( 5.3 , 7.6 ) 5.1 Hypotension and Worsening Renal Function Excessive diuresis may cause potentially symptomatic dehydration, blood volume reduction and hypotension and worsening renal function, including acute renal failure particularly in salt-depleted patients or those taking renin-angiotensin aldosterone inhibitors. Worsening of renal function can also occur with concomitant use of nephrotoxic drugs (e.g., aminoglycosides, cisplatin, and NSAIDs). Monitor volume status and renal function periodically. 5.2 Electrolyte and Metabolic Abnormalities Torsemide can cause potentially symptomatic hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, and hypochloremic alkalosis. Treatment with torsemide can cause an increase in blood glucose levels and hyperglycemia. Asymptomatic hyperuricemia can occur and gout may rarely be precipitated. Monitor serum electrolytes and blood glucose periodically. 5.3 Ototoxicity Tinnitus and hearing loss (usually reversible) have been observed with loop diuretics, including torsemide. Higher than recommended doses, severe renal impairment, and hypoproteinemia, appear to increase the risk of ototoxicity.

7 DRUG INTERACTIONS Non-steroidal anti-inflammatory drugs (NSAIDs): Reduced diuretic, natriuretic, and antihypertensive effects; risk of renal impairment. ( 7.1 ) CYP2C9: Concomitant use with CYP2C9 inhibitors can decrease torsemide clearance. Torsemide may affect the efficacy and safety of sensitive CYP2C9 substrates or of substrates with a narrow therapeutic range, such as warfarin or phenytoin. ( 7.2 ) Cholestyramine: Decreased exposure of torsemide. ( 7.3 ) Organic anion drugs: may decrease diuretic activity of torsemide. ( 7.4 ) Lithium: Risk of lithium toxicity ( 7.5 ) Renin-angiotensin inhibitors: Increased risk of hypotension and renal impairment. ( 7.7 ) Radiocontrast agents: Increased risk of renal toxicity. ( 7.8 ) Corticosteroids and ACTH: Increased risk of hypokalemia. ( 7.9 ) 7.1 Nonsteroidal Anti-inflammatory Drugs Because torsemide and salicylates compete for secretion by renal tubules, patients receiving high doses of salicylates may experience salicylate toxicity when torsemide is concomitantly administered. Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and torsemide has been associated with the development of acute renal failure. The antihypertensive and diuretic effects of torsemide can be reduced by NSAIDs. Partial inhibition of the natriuretic effect of torsemide by concomitant administration of indomethacin has been demonstrated for torsemide under conditions of dietary sodium restriction (50 mEq/day) but not in the presence of normal sodium intake (150 mEq/day). 7.2 Cytochrome P450 2C9 Inhibitors and Inducers Torsemide is a substrate of CYP2C9. Concomitant use of CYP2C9 inhibitors (e.g., amiodarone, fluconazole, miconazole, oxandrolone) can decrease torsemide clearance and increase torsemide plasma concentrations. Concomitant use of CYP2C9 inducers (e.g., rifampin) increase torsemide clearance and decrease plasma torsemide concentrations. Monitor diuretic effect and blood pressure when used in combination with CYP2C9 inhibitor or inducer. Adjust torsemide dose if necessary. Because of its inhibition of CYP2C9 metabolism, torsemide may affect the efficacy and safety of sensitive CYP2C9 substrates, such as celecoxib, or of substrates with a narrow therapeutic range, such as warfarin or phenytoin. Monitor patients and adjust dosages if necessary. 7.3 Cholestyramine Concomitant use of torsemide and cholestyramine has not been studied in humans but, in a study in animals, coadministration of cholestyramine decreased the absorption of orally administered torsemide. If torsemide and cholestyramine should be coadministered, administer torsemide at least one hour before or 4 to 6 h after cholestyramine administration. 7.4 Organic Anion Drugs Coadministration of organic anion drugs (e.g., probenecid) that undergo significant renal tubular secretion have the potential to reduce secretion of torsemide into the proximal tubule and thereby decreases the diuretic activity of torsemide. Monitor diuretic effect and blood pressure during coadministration. 7.5 Lithium Like other diuretics, torsemide reduces the renal clearance of lithium, inducing a high risk of lithium toxicity. Monitor lithium levels periodically when torsemide is coadministered. 7.6 Ototoxic Drugs Loop diuretics increase the ototoxic potential of other ototoxic drugs, including aminoglycoside antibiotics and ethacrynic acid. This effect has been reported with concomitant use of torsemide and gentamycin. Avoid concomitant use of torsemide and aminoglycoside antibiotics, if possible. 7.7 Renin-angiotensin Inhibitors Coadministration of torsemide with ACE inhibitors or angiotensin receptor blockers can increase the risk of hypotension and renal impairment. 7.8 Radiocontrast Agents Torsemide can increase the risk of renal toxicity related to administration of radiocontrast agents. 7.9 Corticosteroids and ACTH Concomitant use with torsemide may increase risk of hypokalemia

6 ADVERSE REACTIONS The following risks are discussed in more detail in others sections: Hypotension and Worsening Renal Function [see Warnings and Precautions (5.1) ] Electrolyte and Metabolic Abnormalities [see Warnings and Precautions (5.2) ] Ototoxicity [see Warnings and Precautions (5.3) ] The most common adverse reaction is excessive urination (6.7%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 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. In pre-approval studies, torsemide has been evaluated for safety in approximately 4000 subjects; over 800 of these subjects received torsemide for at least 6 months, and over 380 were treated for more than 1 year. Among these subjects were 564 who received torsemide during United States-based trials in which 274 other subjects received placebo. Discontinuation of therapy due to adverse reactions occurred in 3.5% of United States patients treated with torsemide and in 4.4% of patients treated with placebo. In United States placebo-controlled trials excessive urination occurred in 6.7% of patients compared with 2.2% of patients receiving placebo. The daily doses of torsemide used in these trials ranged from 1.25 mg to 20 mg, with most patients receiving 5 mg to 10 mg; the duration of treatment ranged from 1 to 52 days, with a median of 41 days. In the placebo-controlled hypertension studies excessive urination was dose related; 1% of patients receiving placebo, 4% of those treated with 5 mg of daily torsemide, and 15% of those treated with 10 mg. Excessive urination was generally not reported as an adverse event among patients who received torsemide for cardiac, renal, or hepatic failure. There was no effect of age or sex on the incidence of adverse reactions. Laboratory Parameters Potassium In controlled studies in the United States, torsemide was administered to hypertensive patients at doses of 5 mg or 10 mg daily. After 6 weeks at these doses, the mean decrease in serum potassium was approximately 0.1 mEq/L. The percentage of patients who had a serum potassium level below 3.5 mEq/L at any time during the studies was 1.5% on torsemide and 3% on placebo. In patients followed for 1 year, there was no progressive change in mean serum potassium levels. In patients with congestive heart failure, hepatic cirrhosis, or renal disease treated with torsemide at doses higher than those studied in United States antihypertensive trials, hypokalemia was observed with greater frequency, in a dose-related manner. Blood Urea Nitrogen (BUN), Creatinine and Uric Acid Torsemide produces small dose-related increases in each of these laboratory values. In hypertensive patients who received 10 mg of torsemide daily for 6 weeks, the mean increase in blood urea nitrogen was 1.8 mg/dL (0.6 mmol/L), the mean increase in serum creatinine was 0.05 mg/dL (4 mmol/L), and the mean increase in serum uric acid was 1.2 mg/dL (70 mmol/L). Little further change occurred with long-term treatment, and all changes reversed when treatment was discontinued. Glucose Hypertensive patients who received 10 mg of daily torsemide experienced a mean increase in serum glucose concentration of 5.5 mg/dL (0.3 mmol/L) after 6 weeks of therapy, with a further increase of 1.8 mg/dL (0.1 mmol/L) during the subsequent year. In long-term studies in diabetics, mean fasting glucose values were not significantly changed from baseline. Serum Lipids Torsemide 20 mg caused small increases in total cholesterol and triglycerides in short term hypertension studies. The changes subsided with chronic therapy. 6.2 Postmarketing Experience The following adverse reactions have been identified during the post-approval use of torsemide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or establish a causal relationship to drug exposure. Gastrointestinal system: Pancreatitis, abdominal pain Nervous System: Paresthesia, confusion, visual impairment, loss of appetite Hematologic: Leucopenia, thrombocytopenia, anemia Hepatobiliary: Increase in liver transaminases, gamma-glutamyltransferase Metabolism: Thiamine (vitamin B1) deficiency Skin/hypersensitivity: Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity reaction, pruritus Urogenital: Acute urinary retention

8.1 Pregnancy Risk Summary There are no available data on use of torsemide in pregnant women and the risk of major birth defects or miscarriage. In pregnant rats and rabbits dosed, on a mg/m 2 basis, with 10 and 1.7 times a human dose of 20 mg/day, respectively, there was no fetotoxicity or teratogenicity. However, in pregnant rats and rabbits administered 50 and 6.8 times the human dose, respectively, decreases in body weight, decreased fetal resorption and delayed fetal ossification was observed. 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 malformations and miscarriage in clinically recognized pregnancies is 2 to 4%, and 15 to 20%, respectively. Data There was no fetotoxicity or teratogenicity in rats treated with up to 5 mg/kg/day of torsemide (on a mg/kg basis, this is 15 times a human dose of 20 mg/day; on a mg/m 2 basis, the animal dose is 10 times the human dose), or in rabbits, treated with 1.6 mg/kg/day (on a mg/kg basis, 5 times the human dose of 20 mg/kg/day; on a mg/m 2 basis, 1.7 times this dose). Fetal and maternal toxicity (decrease in average body weight, increase in fetal resorption and delayed fetal ossification) occurred in rabbits and rats given doses 4 (rabbits) and 5 (rats) times larger.