SOAANZ

SOAANZ- torsemide tablet, film coated
Sarfez Pharmaceuticals Inc

1 INDICATIONS AND USAGE

SOAANZ is indicated in adults for the treatment of edema associated with heart failure or renal disease.

2 DOSAGE AND ADMINISTRATION

The recommended initial dose is 20 mg oral SOAANZ 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.

3 DOSAGE FORMS AND STRENGTHS

Tablets:

• 20 mg, yellow, round, film-coated tablet debossed with “T20” on one side
• 40 mg, orange, round, film-coated tablet debossed with “T40” on one side
• 60 mg, pink, round, film-coated tablet debossed with “T60” on one side

4 CONTRAINDICATIONS

SOAANZ is contraindicated in patients with known hypersensitivity to SOAANZ.

SOAANZ is contraindicated in patients who are anuric.

SOAANZ is contraindicated in patients with hepatic coma.

5 WARNINGS AND PRECAUTIONS

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. Monitor volume status and renal function periodically.

5.2 Electrolyte and Metabolic Abnormalities

SOAANZ can cause potentially symptomatic hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, and hypochloremic alkalosis. Treatment with SOAANZ 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.

6 ADVERSE REACTIONS

The following risks are discussed in more detail in other 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)]

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, SOAANZ has been evaluated for safety in 65 subjects. Discontinuation of therapy due to adverse reactions occurred in 4 out of the 65 of subjects (6%) treated with SOAANZ.

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

7 DRUG INTERACTIONS

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 SOAANZ is concomitantly administered.

Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and torsemide has been associated with the development of acute renal failure. The 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 SOAANZ 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 SOAANZ and cholestyramine should be coadministered, administer SOAANZ 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 which thereby decreases the diuretic activity of SOAANZ. 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 SOAANZ 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 SOAANZ and aminoglycoside antibiotics, if possible.

7.7 Renin-angiotensin Inhibitors

Coadministration of SOAANZ with ACE inhibitors or angiotensin receptor blockers can increase the risk of hypotension and renal impairment.

7.8 Radiocontrast Agents

SOAANZ can increase the risk of renal toxicity related to administration of radiocontrast agents.

7.9 Corticosteroids and ACTH

Concomitant use with SOAANZ may increase risk of hypokalemia.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on use of SOAANZ in pregnant women and the risk of major birth defects or miscarriage. In pregnant rats and rabbits dosed, on a mg/m² basis, with 2.4 and 1.6 times a human starting 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 2-4%, and 15-20%, respectively.

Animal Data

There was no fetotoxicity or teratogenicity in rats treated with up to 5 mg/kg/day of torsemide (on a mg/m² basis, the animal dose is 2.4 times the human starting dose of 20 mg/day), or in rabbits, treated with 1.6 mg/kg/day (on a mg/m² basis, the animal dose is 1.6 times the human starting dose of 20 mg/day 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.