torsemide 5 MG Oral Tablet
DRUG INTERACTIONS
7 • 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 DEMADEX.
( 7.3 ) • Organic anion drugs: may decrease diuretic activity of DEMADEX.
( 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 DEMADEX and salicylates compete for secretion by renal tubules, patients receiving high doses of salicylates may experience salicylate toxicity when DEMADEX 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 DEMADEX can be reduced by NSAIDs.
Partial inhibition of the natriuretic effect of DEMADEX by concomitant administration of indomethacin has been demonstrated for DEMADEX 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 DEMADEX and cholestyramine should be coadministered, administer DEMADEX 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 DEMADEX into the proximal tubule and thereby decreases the diuretic activity of DEMADEX.
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 DEMADEX and aminoglycoside antibiotics, if possible.
7.7 Renin-angiotensin Inhibitors Coadministration of DEMADEX with ACE inhibitors or angiotensin receptor blockers can increase the risk of hypotension and renal impairment.
7.8 Radiocontrast Agents DEMEDEX can increase the risk of renal toxicity related to administration of radiocontrast agents.
7.9 Corticosteroids and ACTH Concomitant use with DEMEDEX may increase risk of hypokalemia.
OVERDOSAGE
10 The signs and symptoms of overdosage can be anticipated to include those of excessive pharmacologic effect: dehydration, hypovolemia, hypotension, hyponatremia, hypokalemia, hypochloremic alkalosis, and hemoconcentration.
Treatment of overdosage should consist of fluid and electrolyte replacement.
Laboratory determinations of serum levels of torsemide and its metabolites are not widely available.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of torsemide and its metabolites.
Torsemide is not dialyzable, so hemodialysis will not accelerate elimination.
DESCRIPTION
11 DEMADEX ® (torsemide) is a diuretic of the pyridine-sulfonylurea class.
Its chemical name is 1-isopropyl-3-[(4- m -toluidino-3-pyridyl) sulfonyl] urea and its structural formula is: Its empirical formula is C 16 H 20 N 4 O 3 S, its pKa is 7.1, and its molecular weight is 348.43.
Torsemide is a white to off-white crystalline powder.
The tablets for oral administration also contain lactose NF, crospovidone NF, povidone USP, microcrystalline cellulose NF, and magnesium stearate NF.
Torsemide Structural Formula
HOW SUPPLIED
16 /STORAGE AND HANDLING DEMADEX for oral administration is available as white, scored tablets as follows: Dose Shape Debossing NDC 0037-xxxx-xx Side 1 Side 2 Bottle/100 5 mg elliptical 5 5005 3505-01 10 mg elliptical 10 5010 3510-01 20 mg elliptical 20 5020 3520-01 100 mg capsule shaped 100 5001 3500-01 Store at 15° to 30°C (59° to 86°F).
GERIATRIC USE
8.5 Geriatric Use Of the total number of patients who received DEMADEX in United States clinical studies, 24% were 65 or older while about 4% were 75 or older.
No specific age-related differences in effectiveness or safety were observed between younger patients and elderly patients.
DOSAGE FORMS AND STRENGTHS
3 DEMADEX is available as white scored tablets in 5-, 10-, 20-, and 100-mg strengths.
Tablets: 5 mg, 10 mg, 20 mg and 100 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Micropuncture studies in animals have shown that torsemide acts from within the lumen of the thick ascending portion of the loop of Henle, where it inhibits the Na + /K + /2Cl – -carrier system.
Clinical pharmacology studies have confirmed this site of action in humans, and effects in other segments of the nephron have not been demonstrated.
Diuretic activity thus correlates better with the rate of drug excretion in the urine than with the concentration in the blood.
Torsemide increases the urinary excretion of sodium, chloride, and water, but it does not significantly alter glomerular filtration rate, renal plasma flow, or acid-base balance.
INDICATIONS AND USAGE
1 DEMADEX 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 DEMADEX is indicated for the treatment of edema associated with heart failure, renal disease or hepatic disease.
1.2 Hypertension DEMADEX is 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 DEMADEX.
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 DEMADEX 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.
DEMADEX can be used alone or in combination with other antihypertensive agents.
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Administration of another loop diuretic to premature infants has been associated with the precipitation of nephrocalcinosis/nephrolithiasis.
Nephrocalcinosis/nephrolithiasis has also been observed in children under 4 years of age with no history of prematurity who have been treated chronically with the other loop diuretic.
The other loop diuretic, when administered during the first weeks of life, has also been reported to increase the risk of persistent patent ductus arteriosus.
The use of DEMADEX in such patients has not been studied.
PREGNANCY
8.1 Pregnancy Risk Summary There are no available data on use of DEMADEX 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 2-4%, and 15-20%, 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.
WARNING AND CAUTIONS
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 DEMADEX can cause potentially symptomatic hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, and hypochloremic alkalosis.
Treatment with DEMADEX 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 DEMADEX.
Higher than recommended doses, severe renal impairment, and hypoproteinemia, appear to increase the risk of ototoxicity.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Symptomatic Hypotension: Advise patients receiving DEMADEX that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician.
The patients should be told that if syncope occurs, DEMADEX should be discontinued until the physician has been consulted.
All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope [see Warnings and Precautions (5.1) ].
Non-Steroidal Anti-inflammatory Drugs (NSAID): Advise patients to discuss with their physician before taking NSAID medications concomitantly [see Drug Interactions (7.1) ].
MEDA PHARMACEUTICALS and DEMADEX are registered trademarks of Meda AB.
Any other trademarks are the property of their respective owners.
Manufactured By: Meda Manufacturing GmbH, Cologne, Germany For: Meda Pharmaceuticals Meda Pharmaceuticals Inc.
Somerset, NJ 08873-4120 Made in Germany Printed in USA © 2017 Meda Pharmaceuticals Inc.
IN-3500-02
DOSAGE AND ADMINISTRATION
2 Edema associated with: • Heart failure: Initial dose is 10 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 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 4-6 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 DEMADEX 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 DEMADEX 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 DEMADEX 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.