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.

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 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 can be used alone or in combination with other antihypertensive agents.

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 Avet Pharmaceuticals Inc.

at 1-866-901-DRUG (3784) 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 4,000 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