Torsemide

Pregnancy

There are no available data on use in pregnant women and the risk of major birth defects or miscarriage; 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 were observed

Lactation

There are no data regarding the presence in human milk or effects on the breastfed child; diuretics can suppress lactation

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

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.

Pharmacodynamics

With oral dosing, the onset of diuresis occurs within 1 hour and the peak effect occurs during the first or second hour and diuresis lasts about 6 to 8 hours. In healthy subjects given single doses, the dose-response relationship for sodium excretion is linear over the dose range of 2.5 mg to 20 mg. The increase in potassium excretion is negligible after a single dose of up to 10 mg and only slight (5 mEq to 15 mEq) after a single dose of 20 mg.

DEMADEX has been studied in controlled trials in patients with New York Heart Association Class II to Class IV heart failure. Patients who received 10 mg to 20 mg of daily DEMADEX in these studies achieved significantly greater reductions in weight and edema than did patients who received placebo.

In patients with essential hypertension, DEMADEX has been shown in controlled studies to lower blood pressure when administered once a day at doses of 5 mg to 10 mg. The antihypertensive effect is near maximal after 4 to 6 weeks of treatment, but it may continue to increase for up to 12 weeks. Systolic and diastolic supine and standing blood pressures are all reduced. There is no significant orthostatic effect, and there is only a minimal peak-trough difference in blood pressure reduction.

The antihypertensive effects of DEMADEX are, like those of other diuretics, on the average greater in black patients (a low-renin population) than in nonblack patients.

When DEMADEX is first administered, daily urinary sodium excretion increases for at least a week. With chronic administration, however, daily sodium loss comes into balance with dietary sodium intake. If the administration of DEMADEX is suddenly stopped, blood pressure returns to pretreatment levels over several days, without overshoot.

DEMADEX has been administered together with β-adrenergic blocking agents, ACE inhibitors, and calcium-channel blockers. Adverse drug interactions have not been observed, and special dosage adjustment has not been necessary.

Pharmacokinetics

The bioavailability of DEMADEX tablets is approximately 80%, with small inter-subject variation; the 90% confidence interval is 75% to 89%. The drug is absorbed with little first-pass metabolism, and the serum concentration reaches its peak (C max ) within 1 hour after oral administration. Cmax and area under the serum concentration-time curve (AUC) after oral administration are proportional to dose over the range of 2.5 mg to 200 mg. Simultaneous food intake delays the time to Cmax by about 30 minutes, but overall bioavailability (AUC) and diuretic activity are unchanged.

The volume of distribution of torsemide is 12 to 15 liters in normal adults or in patients with mild to moderate renal failure or congestive heart failure. In patients with hepatic cirrhosis, the volume of distribution is approximately doubled. Torsemide is extensively bound to plasma protein ( > 99%).

Torsemide is metabolized by the hepatic cytochrome CYP2C9 and, to a minor extent, CYP2C8 and CYP2C18. Three main metabolites have been identified in humans. Metabolite M1 is formed by methyl-hydroxylation of torsemide, metabolite M3 is formed by ring hydroxylation of torsemide, and metabolite M5 is formed by oxidation of M1. The major metabolite in humans is the carboxylic acid derivative M5, which is biologically inactive. Metabolites M1 and M3 possess some pharmacological activity; however, their systemic exposures are much lower when compared to torsemide.

In normal subjects the elimination half-life of torsemide is approximately 3.5 hours. Torsemide is cleared from the circulation by both hepatic metabolism (approximately 80% of total clearance) and excretion into the urine (approximately 20% of total clearance in patients with normal renal function).

Because torsemide is extensively bound to plasma protein ( > 99%), very little enters tubular urine via glomerular filtration. Most renal clearance of torsemide occurs via active secretion of the drug by the proximal tubules into tubular urine.

After a single oral dose, the amounts recovered in urine were: torsemide 21%, metabolite M1 12%, metabolite M3 2%, and metabolite M5 34%.

Renal Impairment In patients with renal failure, renal clearance of torsemide is markedly decreased but total plasma clearance is not significantly altered. A smaller fraction of the administered dose is delivered to the intraluminal site of action, and the natriuretic action of any given dose of diuretic is reduced.

In patients with hepatic cirrhosis, the volume of distribution, plasma half-life, and renal clearance are all increased, but total clearance is unchanged. Geriatric Patients The renal clearance of torsemide is lower in elderly subjects as compared to younger adults, which is related to the decline in renal function that commonly occurs with aging. However, total plasma clearance and elimination half-life remain unchanged.

In patients with decompensated congestive heart failure, hepatic and renal clearance are both reduced, probably because of hepatic congestion and decreased renal plasma flow, respectively. The total clearance of torsemide is approximately 50% of that seen in healthy volunteers, and the plasma half-life and AUC are correspondingly increased. Because of reduced renal clearance, a smaller fraction of any given dose is delivered to the intraluminal site of action, so at any given dose there is less natriuresis in patients with heart failure than in normal subjects.

Drug Interactions

Coadministration of digoxin is reported to increase the AUC for torsemide by 50%, but dose adjustment of DEMADEX is not necessary. Torsemide does not affect the pharmacokinetics of digoxin.

In healthy subjects, coadministration of torsemide was associated with significant reduction in the renal clearance of spironolactone, with corresponding increases in the AUC. However, the pharmacokinetic profile and diuretic activity of torsemide are not altered by spironolactone.

Torsemide does not affect the protein binding of glyburide or warfarin.

The pharmacokinetic profile and diuretic activity of torsemide are not altered by cimetidine.

Torsemide is a prescription medication used to treat high blood pressure and fluid retention caused by congestive heart failure and other conditions. Torsemide belongs to a group of drugs called diuretics ("water pills") which help the body get rid of excess fluid by increasing the amount of salt and water the kidneys remove from the blood.

This medication comes in tablet form and is taken once daily, with or without food. Torsemide also comes in an injectable form to be given directly into a vein (IV) by a healthcare provider. This article will focus on the oral form.

Common side effects of torsemide include nausea, weakness, and runny nose. This medication can cause dizziness. Do not drive or operate heavy machinery until you know how it affects you.

Torsemide is part of the drug class:

• High Ceiling Sulfonamide Diuretics

Serious side effects can occur. See "Drug Precautions" section.

Common side effects include:

• dizziness
• runny nose
• weakness
• diarrhea
• faintness
• arrhythmia (irregular heart beat)
• fatigue
• muscle weakness or spasm
• constipation
• chest or joint pain
• nausea
• nervousness or restlessness

This is not a complete list of torsemide side effects. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• Take torsemide exactly as prescribed.
• This medication comes in tablet form and is usually taken once daily.
• Torsemide can be taken with or without food.
• Because torsemide increases urination, it is best taken in the morning to avoid having to get up in the night to urinate. 
• If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Do not take two doses at the same time.

Take torsemide exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The torsemide dose your doctor recommends will be based on:

• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication

The recommended oral dose range for torsemide is 5 mg to 200 mg daily.

Many drugs can interact with torsemide. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any you start or stop using, especially:

• cholestyramine, lithium, phenytoin, probenecid, warfarin (Coumadin, Jantoven);

• an intravenous (IV) antibiotic medicine;

• any other diuretic medicine;

• antifungal medicine--fluconazole, voriconazole;

• heart or blood pressure medicine--amiodarone, candesartan, digoxin, enalapril, lisinopril, olmesartan, valsartan, and others;

• NSAIDs (nonsteroidal anti-inflammatory drugs)--ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others;

• salicylates--aspirin, Nuprin Backache Caplet, Kaopectate, KneeRelief, Pamprin Cramp Formula, Pepto-Bismol, Tricosal, Trilisate, and others or

• steroid medicine--oxandrolone, prednisone, and others.

This list is not complete and many other drugs can interact with torsemide. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Contraindications

• Anuria.1 12 13 14

• Known hypersensitivity to torsemide or to sulfonylureas.1 12 13 14

Warnings/Precautions

Warnings

Sudden alterations of electrolyte balance in patients with cirrhosis may precipitate hepatic coma; use with caution in patients with hepatic cirrhosis and ascites.1 12 13 14

Therapy in such patients is best initiated in the hospital.1 14 Use an aldosterone antagonist or potassium-sparing agent concomitantly with torsemide to prevent hypokalemia and metabolic alkalosis in such patients.1 12 13 14

Tinnitus and hearing loss, usually reversible, have been observed following rapid IV injection of other loop diuretics and following oral torsemide administration.1 12 13 14 Administer IV slowly (over 2 minutes); do not exceed 200 mg as a single dose.1 12 14

Observe carefully for manifestations of fluid and electrolyte depletion (e.g., dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, vomiting).1 12 13 14

Excessive diuresis may cause dehydration and blood volume reduction with circulatory collapse and possibly vascular thrombosis and embolism, particularly in geriatric patients.1 12 13 14

Laboratory changes may include altered serum concentrations of sodium, chloride, and potassium; acid-base abnormalities; and increased BUN.1 12 If electrolyte imbalance, hypovolemia, or prerenal azotemia develops, torsemide should be discontinued until the abnormality is corrected; treatment then may be restarted at a reduced dosage.1 12 13 14

Risk of hypokalemia, especially with brisk diuresis, with inadequate oral electrolyte intake, in those with cirrhosis, or during concomitant use of corticosteroids or ACTH.1 12 Risk of arrhythmias secondary to hypokalemia in patients with cardiovascular disease, especially those receiving concomitant therapy with a cardiac glycoside.1 12 13

Periodically monitor serum potassium and other electrolyte concentrations.1 12 13 14

General Precautions

Possible increased blood glucose concentrations; hyperglycemia occurred rarely. 1 12 13 14

Small, dose-related, reversible increases in BUN, Scr, and uric acid concentrations reported.1 14 12 Symptomatic gout reported at an incidence similar to placebo.1 12 13 14

Slight alterations in calcium and magnesium concentrations.1 12 13

Increases in total plasma cholesterol concentrations may occur; usually subside during chronic therapy.1 12 13 14

Increases in plasma triglyceride concentrations reported.1 12 13

In long-term studies, no clinically important differences in lipid profiles compared to baseline.1 12 14

No clinically important effects on hemoglobin; hematocrit; WBC, erythrocyte, or platelet counts; or serum alkaline phosphatase concentrations.1 12 13 14

Specific Populations

Category B.1 12 13

Not known whether torsemide is distributed into milk.1 12 13 14 Caution if used in nursing women.1 12 13 14

Safety and efficacy not established.1 12 13 14

Renal calcifications reported in severely premature infants with edema secondary to patent ductus arteriosus and hyaline membrane disease receiving another loop diuretic.1 12 14 Increased risk of persistent patent ductus arteriosus in premature neonates with hyaline membrane disease receiving another loop diuretic also has been reported.1 12 13 14

No substantial differences in safety and efficacy relative to younger adults.1 12 13 14

Seizures reported in patients with acute renal failure receiving higher than recommended dosages of torsemide.1 12 13

Common Adverse Effects

Headache, excessive urination, dizziness, rhinitis, asthenia, diarrhea, ECG abnormality, increased cough.1 12 13 14

Specific Drugs

Torsemide USP 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 C16H20N4O3S, its pKa is 7.1, and its molecular weight is 348.43.

Torsemide USP is a white to off-white crystalline powder. The tablets for oral administration also contain: crospovidone, lactose (anhydrous), magnesium stearate, microcrystalline cellulose and povidone.

Diuresis: Oral, IV: ~6 to 8 hours

Half-Life Elimination

~3.5 hours

Protein Binding

Plasma: >99%

Heart failure: Hepatic and renal clearance are decreased. Total clearance is ~50% of that seen in healthy volunteers, and the plasma half-life and AUC are correspondingly increased.

Note: Torsemide injection has been discontinued in the US for more than 1 year.

Note: IV and oral dosing are equivalent. Dose equivalency for patients with normal renal function (approximate): Torsemide 20 mg = Bumetanide 1 mg = furosemide 40 mg = ethacrynic acid 50 mg

Edema:

Chronic renal failure: Oral, IV: Initial: 20 mg once daily; may increase gradually by doubling dose until the desired diuretic response is obtained; doses >200 mg/day have not been adequately studied.

Heart failure:

Oral: Initial: 10 to 20 mg once daily; may increase gradually by doubling dose until the desired diuretic response is obtained. Maximum dose: 200 mg/day (ACCF/AHA [Yancy 2013]).

IV: Initial: 10 to 20 mg; may repeat every 2 hours with double the dose as needed.

Continuous IV infusion (off-label dose): Initial: 20 mg IV load, then 5 to 20 mg/hour; repeat loading dose before increasing infusion rate. Note: With lower baseline creatinine clearance (eg, CrCl <25 mL/minute), the upper end of the initial infusion dosage range should be considered (ACCF/AHA [Yancy 2013]; Brater 1998)

Hepatic cirrhosis: Oral: Initial: 5 to 10 mg once daily; may increase gradually by doubling dose until the desired diuretic response is obtained (maximum recommended single dose: 40 mg). Note: Administer with an aldosterone antagonist or a potassium-sparing diuretic.

Hypertension: Oral: Initial: 5 mg once daily; may increase to 10 mg once daily after 4 to 6 weeks if adequate antihypertensive response is not apparent; if still not effective, an additional antihypertensive agent may be added. Usual dosage (ASH/ISH [Weber 2014]): 10 mg daily.

IV: Store at 15°C to 30°C (59°F to 86°F). If torsemide is to be administered via continuous infusion, stability has been demonstrated through 24 hours at room temperature in plastic containers for the following fluids and concentrations:

200 mg torsemide (10 mg/mL) added to 250 mL D5W, 250 mL NS or 500 mL 0.45% sodium chloride

50 mg torsemide (10 mg/mL) added to 500 mL D5W, 500 mL NS, or 500 mL 0.45% sodium chloride

Tablets: Store at 15°C to 30°C (59°F to 86°F).

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache. Have patient report immediately to prescriber signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or nausea or vomiting), signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), severe dizziness, passing out, severe diarrhea, hearing impairment, tinnitus, or shortness of breath (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Commonly reported side effects of torsemide include: polyuria. See below for a comprehensive list of adverse effects.

Edema Associated with Congestive Heart Failure:
IV and oral: 10 to 20 mg once a day; if diuresis remains inadequate, titrate upward by approximately doubling the dose until desired response is achieved; single doses higher than 200 mg have not been adequately studied.

Edema Associated with Renal Disease:
IV and oral: 20 mg once a day; if diuresis remains inadequate, titrate upward by approximately doubling the dose until desired response is achieved; single doses higher than 200 mg have not been adequately studied.

Edema Associated with Hepatic Disease:
IV and oral: 5 to 10 mg once a day together with an aldosterone antagonist or a potassium-sparing diuretic; if diuresis remains inadequate, titrate upward by approximately doubling the dose until desired response is achieved; single doses higher than 40 mg have not been adequately studied.

Comments: Chronic use of any diuretic in hepatic disease has not been studied adequately.

Use with caution

Data not available