WARNINGS Hepatic Disease with Cirrhosis and AscItes: -TORSERETIC should be used with caution in patients with hepatic disease with cirrhosis and ascites, since sudden alterations of fluid and electrolyte balance may precipitate hepatic coma. In these patients, diuresis with TORSERETIC (or any other diuretic) is best initiated in the hospital. To prevent hypokalemia and metabolic alkalosis, an aldosterone antagonist or potassium-sparing drug should be used concomitantly with TORSERETIC. Ototoxlcity: -Tinnitus and hearing loss (usually reversible) have been observed after rapid intravenous injection of other loop diuretics and have also been observed after oral TORSERETIC. It is not certain that these events were attributable to TORSERETIC. Administered intravenously, TORSERETIC should be injected slowly over 2 minutes, and single doses should not exceed 200 mg. Volume and Electrolyte Depletion: -Patients receiving diuretics should be observed for clinical evidence of electrolyte imbalance, hypovolemia, or prerenal azotemia. Symptoms of these disturbances may include one or more of the following,
dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, and vomiting.Excessive diuresis may cause dehydration, blood-volume reduction, and possibly thrombosis and embolism, especially in elderly patients. In patients who develop fluid and electrolyte imbalances, hypovolemia, or prerenal azotemia, the observed laboratory changes may include hyper- or hyponatremia, hyper- or hypochloremia, hyper- or hypokalemia, acid-base abnormalities, and increased blood urea nitrogen (BUN). If any of these occur, TORSERETIC should be discontinued until the situation is corrected; TORSERETIC may be restarted at a lower dose. -In patients with cardiovascular disease, especially those receiving digitalis glycosides, diuretic-induced hypokalemia may be a risk factor for the development of arrhythmias. The risk of hypokalemia is greatest in patients with cirrhosis of the liver, in patients experiencing a brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes, and in patients receiving concomitant therapy with corticosteroids or ACTH. -Periodic monitoring of serum potassium and other electrolytes is advised in patients treated with TORSERETIC. PRECAUTIONS Laboratory Values -Potassium :See WARNINGS. -Calcium: Single doses of TORSERETIC increased the urinary excretion of calcium by normal subjects, but serum calcium levels were slightly increased in 4- to 6-week hypertension trials. -Magnesium: Single doses of TORSERETIC caused healthy volunteers to increase their urinary excretion of magnesium, but serum magnesium levels were slightly increased in 4- to 6-week hypertension trials. -Blood Urea Nitrogen (BUN), Creatinine and Uric Acid: TORSERETIC produces small dose-related increases in each of these laboratory values. -Symptomatic gout has been reported in patients receiving TORSERETIC, but its incidence has been similar to that seen in patients receiving placebo. -Glucose: Hypertensive patients who received 10 mg of daily TORSERETIC experienced a mean increase in serum glucose concentration of 5.5 mg/dL (0.3 mmol/L) after 6 weeks of therapy. In long-term studies in diabetics, mean fasting glucose values were not significantly changed from baseline. Cases of hyperglycemia have been reported but are uncommon. -Serum Lipids : Daily doses of 5 mg, 10 mg, and 20 mg of TORSERETIC were associated with increases in total plasma cholesterol of 4. 4, and 8 mg/dL (0.10 to 0.20 mmol/L), respectively. The changes subsided during chronic therapy. -Other: TORSERETIC has been associated with small mean decreases in hemoglobin, hematocrit, and erythrocyte count and small mean increases in white blood cell count, platelet count, and serum alkaline phosphatase. -This product contains lactose which must be used for patients with lactose- galactose intolerance. DRUG INTERACTIONS: -In patients with essential hypertension, TORSERETIC has been administered together with beta-blockers, ACE inhibitors, and calcium-channel blockers. In patients with congestive heart failure, TORSERETIC has been administered together with digitalis glycosides, ACE inhibitors, and organic nitrates. None of these combined uses was associated with new or unexpected adverse events. -Torsemide does not affect the protein binding of glyburide or of warfarin, the anticoagulant effect of phenprocoumon (a related coumarin derivative), or the pharmacokinetics of digoxin or carvedilol (a vasodilator/beta-blocker). -In healthy subjects, coadministration of TORSERETIC was associated with significant reduction in the renal clearance of spironolactone, with corresponding increases in the AUC. However, clinical experience indicates that dosage adjustment of either agent is not required. -Because TORSERETIC and salicylates compete for secretion by renal tubules, patients receiving high doses of salicylates may experience salicylate toxicity when TORSERETIC is concomitantly administered. Also, although possible interactions between torsemide and non steroidal anti-inflammatory agents (including aspirin) have not been studied, coadministration of these agents with another loop diuretic (furosemide) has occasionally been associated with renal dysfunction. -The natriuretic effect of TORSERETIC (like that of many other diuretics) is partially inhibited by the concomitant administration of indomethacin. This effect has been demonstrated for TORSERETIC under conditions of dietary sodium restriction (50 mEq/day) but not in the presence of normal sodium intake (150 mEq/day). -The pharmacokinetic profile and diuretic activity of torsemide are not altered by cimetidine or spironolactone. Coadministration of digoxin is reported to increase the area under the curve for torsemide by 50%, but dose adjustment of TORSERETIC is not necessary. -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 TORSERETIC and cholestyramine are used concomitantly, simultaneous administration is not recommended. -Coadministration of probenecid reduced secretion of TORSERETIC into the proximal tubule and thereby decreases the diuretic activity of TORSERETIC. -Other diuretics are known to reduce the renal clearance of lithium, inducing a high risk of lithium toxicity, so coadministration of lithium and diuretics should be undertaken with great caution, if at all. Coadministration of lithium and TORSERETIC has not been studied. -Other diuretics have been reported to increase the ototoxic potential of aminoglycoside antibiotics and of ethacrynic acid, especially in the presence of impaired renal function. PREGNANCY: This drug should be used during pregnancy only if clearly needed. Labor and Delivery The effect of TORSERETIC on labor and delivery is unknown. Nursing Mothers It is not known whether TORSERETIC is excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when TORSERETIC is administered to a nursing woman
PEDIATRIC USE: Safety and effectiveness in pediatric patients have not been established.
GERIATRIC USE: No specific age-related differences in effectiveness or safety were observed between younger patients and elderly patients. ADVERSE REACTIONS The most common is dizziness, headache, nausea, weakness, vomiting, hyperglycemia, excessive urination, hyperuricernia, hypokalemia, excessive thirst, hypovolemia, impotence, esophageal hemorrhage, and dyspepsia. Dropout rates for these adverse events ranged from 0.1% to 0.5%. The side effects considered possibly Headache, Excessive Urination, Dizziness, Rhinitis, Asthenia, Diarrhea, ECG Abnormality, Cough Increase, Constipation, Nausea, Arthralgia, Dyspepsia, Sore Throat, Myalgia, Chest Pain, Insomnia, Edema, Nervousness. Serious adverse events reported in the clinical studies for which a drug relationship could not be excluded were atrial fibrillation, chest pain, diarrhea, digitalis intoxication, gastrointestinal hemorrhage, hyperglycemia, hyperuricemia, hypokalemia, hypotension, hypovolemia, shunt thrombosis, rash, rectal bleeding, syncope, and ventricular tachycardia. Angioedema has been reported in a patient exposed to TORSERETIC who was later found to be allergic to sulfa drugs.Arthritis and various other nonspecific musculoskeletal problems were reported . OVERDOSAGE There is no human experience with overdoses of TORSERETIC, but the signs and symptoms of over dosage can be anticipated to be those of excessive pharmacologic effect: dehydration, hypovolemia, hypotension, hyponatremia, hypokalemia, hypochloremic, alkalosis, and hemoconcentration. Treatment of over dosage should consist of fluid and electrolyte replacement DOSAGE AND ADMINISTRATION General -TORSERETIC tablets may be given at any time in relation to a meal, as convenient. Special dosage adjustment in the elderly is not necessary. -Because of the high bioavailability of TORSERETIC, oral and intravenous doses are therapeutically equivalent, so patients may be switched to and from the intravenous form with no change in dose. -TORSERETIC intravenous injection should be administered either slowly as a bolus over a period of 2 minutes or administered as a continuous infusion. -If TORSERETIC is administered through an IV line, it is recommended that, as with other IV injections, the IV line be flushed with Normal Saline (Sodium Chloride Injection, USP) before and after administration. TORSERETIC injection is formulated above pH 8.3.Flushing the line is recommended to avoid the potential for incompatibilities caused by differences in pH which could be indicated by color change, haziness or the formation of a precipitate in the solution. -If TORSERETIC is administered as a continuous infusion, stability has been demonstrated through 24 hours at room temperature in plastic containers for the following fluids and concentrations: 200 mg TORSERETIC (10 mg/mL) added to: 250 mL Dextrose 5% in water 250 mL 0.9% Sodium Chloride 500 mL 0.45% Sodium Chloride 50 mg TORSERETIC (10 mg/mL) added to: 500 mL Dextrose 5% in water 500 mL 0.9% Sodium Chloride 500 mL 0.45% Sodium Chloride Before administration, the solution of TORSERETIC should be visually inspected for discoloration and particulate matter. If either is found, the ampoule should not be used. Congestive Heart Failure The usual initial dose is 10 mg or 20 mg of once-daily oral or intravenous TORSERETIC. If the diuretic response is inadequate, the dose should be titrated upward by approximately doubling until the desired diuretic response is obtained. Single doses higher than 200 mg have not been adequately studied. Chronic Renal Failure The usual initial dose of TORSERETIC is 20 mg of once-daily oral or Intravenous TORSERETIC. If the diuretic response is inadequate, the dose should be titrated upward by approximately doubling until the desired diuretic response is obtained. Single doses higher than200 mg have not been adequately studied. Hepatic Cirrhosis The usual initial dose is 5 mg or 10 mg of once-daily oral or intravenous TORSERETIC, administered together with an aldosterone antagonist or a potassium-sparing diuretic. If the diuretic response is inadequate, the dose should be titrated upward by approximately doubling until the desired diuretic response is obtained. Single doses higher than 40 should not be used. Hypertension The usual initial dose is 5mg once daily. If the 5mg dose does not provide adequate reduction in blood pressure within 4 to 6 weeks, the dose may be increased to 10 mg once daily. If the response to 10 mg is insufficient, an additional antihypertensive agent should be added to the treatment regimen. PACKAGE: For TORSERETIC 5mg & 10 mg & 20 mg Tablets Carton box containing 1 or 3 transparent PVDC/ AL strips, each strip of 10 tablets insert leaflet For TORSERETIC 20 mg/2ml ampoule Carton box containing 3 clear colorless glass ampoules type II of 2 ml solution with an insert leaflet. PRODUCED BY: Tablets : Future Pharmaceutical Industries for Utopia Pharmaceuticals Ampoules :Sigmatec pharmaceutical industries for utopia pharmaceuticals