Fluoxetin-ratiopharm may be available in the countries listed below.
Fluoxetine hydrochloride (a derivative of Fluoxetine) is reported as an ingredient of Fluoxetin-ratiopharm in the following countries:
International Drug Name Search
Kanavit may be available in the countries listed below.
Phytomenadione is reported as an ingredient of Kanavit in the following countries:
International Drug Name Search
Demadex®
(torsemide)
TABLETS
IN-0455-03 Rev. 2/10
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 C16H20N4O3S, 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.
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+/2CI--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.
The bioavailability of Demadex tablets is approximately 80%, with little intersubject 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 (Cmax) 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. Absorption is essentially unaffected by renal or hepatic dysfunction.
The volume of distribution of torsemide is 12 liters 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.
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). The major metabolite in humans is the carboxylic acid derivative, which is biologically inactive. Two of the lesser metabolites possess some diuretic activity, but for practical purposes metabolism terminates the action of the drug.
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.
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 congestive heart failure than in normal subjects.
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. A diuretic response in renal failure may still be achieved if patients are given higher doses. The total plasma clearance and elimination half-life of torsemide remain normal under the conditions of impaired renal function because metabolic elimination by the liver remains intact.
In patients with hepatic cirrhosis, the volume of distribution, plasma half-life, and renal clearance are all increased, but total clearance is unchanged.
The pharmacokinetic profile of torsemide in healthy elderly subjects is similar to that in young subjects except for a decrease in renal clearance related to the decline in renal function that commonly occurs with aging. However, total plasma clearance and elimination half-life remain unchanged.
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.
Congestive Heart Failure
Demadex has been studied in controlled trials in patients with New York Heart Association Class II to Class IV congestive 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.
Nonanuric Renal Failure
In single-dose studies in patients with nonanuric renal failure, high doses of Demadex (20 mg to 200 mg) caused marked increases in water and sodium excretion. In patients with nonanuric renal failure, severe enough to require hemodialysis, chronic treatment with up to 200 mg of daily Demadex has not been shown to change steady-state fluid retention. When patients in a study of acute renal failure received total daily doses of 520 mg to 1200 mg of Demadex, 19% experienced seizures. Ninety-six patients were treated in this study; 6/32 treated with torsemide experienced seizures, 6/32 treated with comparably high doses of furosemide experienced seizures, and 1/32 treated with placebo experienced a seizure.
Hepatic Cirrhosis
When given with aldosterone antagonists, Demadex also caused increases in sodium and fluid excretion in patients with edema or ascites due to hepatic cirrhosis. Urinary sodium excretion rate relative to the urinary excretion rate of Demadex is less in cirrhotic patients than in healthy subjects (possibly because of the hyperaldosteronism and resultant sodium retention that are characteristic of portal hypertension and ascites). However, because of the increased renal clearance of Demadex in patients with hepatic cirrhosis, these factors tend to balance each other, and the result is an overall natriuretic response that is similar to that seen in healthy subjects. Chronic use of any diuretic in hepatic disease has not been studied in adequate and well-controlled trials.
Essential Hypertension
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.
Demadex is indicated for the treatment of edema associated with congestive heart failure, renal disease, or hepatic disease. Use of torsemide has been found to be effective for the treatment of edema associated with chronic renal failure. Chronic use of any diuretic in hepatic disease has not been studied in adequate and well-controlled trials.
Demadex is indicated for the treatment of hypertension alone or in combination with other antihypertensive agents.
Demadex is contraindicated in patients with known hypersensitivity to Demadex or to sulfonylureas.
Demadex is contraindicated in patients who are anuric.
Hepatic Disease With Cirrhosis and Ascites
Demadex 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 Demadex (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 Demadex.
Ototoxicity
Tinnitus and hearing loss (usually reversible) have been observed after rapid intravenous injection of other loop diuretics and have also been observed after oral Demadex. It is not certain that these events were attributable to Demadex. Ototoxicity has also been seen in animal studies when very high plasma levels of torsemide were induced.
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, Demadex should be discontinued until the situation is corrected; Demadex may be restarted at a lower dose.
In controlled studies in the United States, Demadex 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 essentially the same in patients who received Demadex (1.5%) as in those who received placebo (3%). In patients followed for 1 year, there was no further change in mean serum potassium levels. In patients with congestive heart failure, hepatic cirrhosis, or renal disease treated with Demadex at doses higher than those studied in United States antihypertensive trials, hypokalemia was observed with greater frequency, in a dose-related manner.
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 Demadex.
Potassium: See WARNINGS
Calcium
Single doses of Demadex increased the urinary excretion of calcium by normal subjects, but serum calcium levels were slightly increased in 4- to 6-week hypertension trials. In a long-term study of patients with congestive heart failure, the average 1-year change in serum calcium was a decrease of 0.10 mg/dL (0.02 mmol/L). Among 426 patients treated with Demadex for an average of 11 months, hypocalcemia was not reported as an adverse event.
Magnesium
Single doses of Demadex caused healthy volunteers to increase their urinary excretion of magnesium, but serum magnesium levels were slightly increased in 4- to 6-week hypertension trials. In long-term hypertension studies, the average 1-year change in serum magnesium was an increase of 0.03 mg/dL (0.01 mmol/L). Among 426 patients treated with Demadex for an average of 11 months, one case of hypomagnesemia (1.3 mg/dL [0.53 mmol/L]) was reported as an adverse event.
In a long-term clinical study of Demadex in patients with congestive heart failure, the estimated annual change in serum magnesium was an increase of 0.2 mg/dL (0.08 mmol/L), but these data are confounded by the fact that many of these patients received magnesium supplements. In a 4-week study in which magnesium supplementation was not given, the rate of occurrence of serum magnesium levels below 1.7 mg/dL (0.70 mmol/L) was 6% and 9% in the groups receiving 5 mg and 10 mg of Demadex, respectively.
Blood Urea Nitrogen (BUN), Creatinine and Uric Acid
Demadex produces small dose-related increases in each of these laboratory values. In hypertensive patients who received 10 mg of Demadex 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.
Symptomatic gout has been reported in patients receiving Demadex, but its incidence has been similar to that seen in patients receiving placebo.
Glucose
Hypertensive patients who received 10 mg of daily Demadex 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. Cases of hyperglycemia have been reported but are uncommon.
Serum Lipids
In the controlled short-term hypertension studies in the United States, daily doses of 5 mg, 10 mg, and 20 mg of Demadex 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.
In the same short-term hypertension studies, daily doses of 5 mg, 10 mg and 20 mg of Demadex were associated with mean increases in plasma triglycerides of 16, 13 and 71 mg/dL (0.15 to 0.80 mmol/L), respectively.
In long-term studies of 5 mg to 20 mg of Demadex daily, no clinically significant differences from baseline lipid values were observed after 1 year of therapy.
Other
In long-term studies in hypertensive patients, Demadex 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. Although statistically significant, all of these changes were medically inconsequential. No significant trends have been observed in any liver enzyme tests other than alkaline phosphatase.
In patients with essential hypertension, Demadex has been administered together with beta-blockers, ACE inhibitors, and calcium-channel blockers. In patients with congestive heart failure, Demadex 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 Demadex 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 Demadex and salicylates compete for secretion by renal tubules, patients receiving high doses of salicylates may experience salicylate toxicity when Demadex is concomitantly administered. Also, although possible interactions between torsemide and nonsteroidal 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 Demadex (like that of many other diuretics) is partially inhibited by the concomitant administration of indomethacin. This effect 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).
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 Demadex 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 Demadex and cholestyramine are used concomitantly, simultaneous administration is not recommended.
Coadministration of probenecid reduces secretion of Demadex into the proximal tubule and thereby decreases the diuretic activity of Demadex.
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 Demadex 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. These potential interactions with Demadex have not been studied.
No overall increase in tumor incidence was found when torsemide was given to rats and mice throughout their lives at doses up to 9 mg/kg/day (rats) and 32 mg/kg/day (mice). On a body-weight basis, these doses are 27 to 96 times a human dose of 20 mg; on a body-surface-area basis, they are 5 to 8 times this dose. In the rat study, the high-dose female group demonstrated renal tubular injury, interstitial inflammation, and a statistically significant increase in renal adenomas and carcinomas. The tumor incidence in this group was, however, not much higher than the incidence sometimes seen in historical controls. Similar signs of chronic non-neoplastic renal injury have been reported in high-dose animal studies of other diuretics such as furosemide and hydrochlorothiazide.
No mutagenic activity was detected in any of a variety of in vivo and in vitro tests of torsemide and its major human metabolite. The tests included the Ames test in bacteria (with and without metabolic activation), tests for chromosome aberrations and sister-chromatid exchanges in human lymphocytes, tests for various nuclear anomalies in cells found in hamster and murine bone marrow, tests for unscheduled DNA synthesis in mice and rats, and others.
In doses up to 25 mg/kg/day (75 times a human dose of 20 mg on a body-weight basis; 13 times this dose on a body-surface-area basis), torsemide had no adverse effect on the reproductive performance of male or female rats.
Pregnancy Category B
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/m2 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/m2 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. Adequate and well-controlled studies have not been carried out in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
The effect of Demadex on labor and delivery is unknown.
It is not known whether Demadex is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Demadex is administered to a nursing woman.
Safety and effectiveness in pediatric patients have not been established.
Administration of another loop diuretic to severely premature infants with edema due to patent ductus arteriosus and hyaline membrane disease has occasionally been associated with renal calcifications, sometimes barely visible on X-ray but sometimes in staghorn form, filling the renal pelves. Some of these calculi have been dissolved, and hypercalciuria has been reported to have decreased, when chlorothiazide has been coadministered along with the loop diuretic. In other premature neonates with hyaline membrane disease, another loop diuretic has been reported to increase the risk of persistent patent ductus arteriosus, possibly through a prostaglandin-E-mediated process. The use of Demadex in such patients has not been studied.
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.
To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
At the time of approval, Demadex had been evaluated for safety in approximately 4000 subjects: over 800 of these subjects received Demadex for at least 6 months, and over 380 were treated for more than 1 year. Among these subjects were 564 who received Demadex during United States-based trials in which 274 other subjects received placebo.
The reported side effects of Demadex were generally transient, and there was no relationship between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy due to side effects occurred in 3.5% of United States patients treated with Demadex and in 4.4% of patients treated with placebo. In studies conducted in the United States and Europe, discontinuation rates due to side effects were 3.0% (38/1250) with Demadex and 3.4% (13/380) with furosemide in patients with congestive heart failure, 2.0% (8/409) with Demadex and 4.8% (11/230) with furosemide in patients with renal insufficiency, and 7.6% (13/170) with Demadex and 0% (0/33) with furosemide in patients with cirrhosis.
The most common reasons for discontinuation of therapy with Demadex were (in descending order of frequency) dizziness, headache, nausea, weakness, vomiting, hyperglycemia, excessive urination, hyperuricemia, 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 or probably related to study drug that occurred in United States placebo-controlled trials in more than 1% of patients treated with Demadex are shown in Table 1.
| Demadex (N=564) | Placebo (N=274) | |
|---|---|---|
| Headache | 7.3 | 9.1 |
| Excessive Urination | 6.7 | 2.2 |
| Dizziness | 3.2 | 4.0 |
| Rhinitis | 2.8 | 2.2 |
| Asthenia | 2.0 | 1.5 |
| Diarrhea | 2.0 | 1.1 |
| ECG Abnormality | 2.0 | 0.4 |
| Cough Increase | 2.0 | 1.5 |
| Constipation | 1.8 | 0.7 |
| Nausea | 1.8 | 0.4 |
| Arthralgia | 1.8 | 0.7 |
| Dyspepsia | 1.6 | 0.7 |
| Sore Throat | 1.6 | 0.7 |
| Myalgia | 1.6 | 1.5 |
| Chest Pain | 1.2 | 0.4 |
| Insomnia | 1.2 | 1.8 |
| Edema | 1.1 | 1.1 |
| Nervousness | 1.1 | 0.4 |
The daily doses of Demadex 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. Of the side effects listed in the table, only “excessive urination” occurred significantly more frequently in patients treated with Demadex than in patients treated with placebo. In the placebo-controlled hypertension studies whose design allowed side-effect rates to be attributed to dose, excessive urination was reported by 1% of patients receiving placebo, 4% of those treated with 5 mg of daily Demadex, and 15% of those treated with 10 mg. The complaint of excessive urination was generally not reported as an adverse event among patients who received Demadex for cardiac, renal, or hepatic failure.
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 Demadex who was later found to be allergic to sulfa drugs.
Of the adverse reactions during placebo-controlled trials listed without taking into account assessment of relatedness to drug therapy, arthritis and various other nonspecific musculoskeletal problems were more frequently reported in association with Demadex than with placebo, even though gout was somewhat more frequently associated with placebo. These reactions did not increase in frequency or severity with the dose of Demadex. One patient in the group treated with Demadex withdrew due to myalgia, and one in the placebo group withdrew due to gout.
Hypokalemia: See WARNINGS
Postmarketing Experience
The following adverse reactions have been identified during the post approval use of Demadex. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported include the following: leucopenia, thrombocytopenia.
Serious skin reactions (i.e., Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported in association with torsemide use.
There is no human experience with overdoses of Demadex, but the signs and symptoms of overdosage can be anticipated to be 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.
Demadex tablets may be given at any time in relation to a meal, as convenient. Special dosage adjustment in the elderly is not necessary.
The usual initial dose of Demadex is 10 mg or 20 mg of once-daily oral Demadex. 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.
The usual initial dose of Demadex is 20 mg of once-daily oral Demadex. 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.
The usual initial dose is 5 mg or 10 mg of once-daily oral Demadex, 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 mg have not been adequately studied.
Chronic use of any diuretic in hepatic disease has not been studied in adequate and well-controlled trials.
The usual 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, 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.
Demadex for oral administration is available as white, scored tablets containing 5 mg, 10 mg, 20 mg, or 100 mg of torsemide. The tablets are supplied in bottles of 100 as follows:
| Dose | Shape | Bottle |
|---|---|---|
| 5 mg | elliptical | NDC 0037-5005-01 |
| 10 mg | elliptical | NDC 0037-5010-01 |
| 20 mg | elliptical | NDC 0037-5020-01 |
| 100 mg | capsule shaped | NDC 0037-5001-01 |
Each tablet is debossed on the scored side with the logo BM and 102, 103, 104, or 105 (for 5 mg, 10 mg, 20 mg, or 100 mg, respectively). On the opposite side, the tablet is debossed with 5, 10, 20, or 100 to indicate the dose.
Storage
Store at 15° to 30°C (59° to 86°F).
Rx Only
Manufactured By: Roche Farma S.A., Leganes Spain
For: Meda Pharmaceuticals
Meda Pharmaceuticals Inc.
Somerset, NJ 08873-4120
To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Printed in USA
©2010 Meda Pharmaceuticals Inc.
IN-0455-03 Rev. 2/10
Package Label - Principal Display Panel – 100-Count Bottle, 5 mg Tablets
NDC 0037-5005-01
100 Tablets
Demadex®
(torsemide)
5 mg Rx only
Meda Pharmaceuticals®
LB-455050-02 Rev. 5/09
Usual dosage: See accompanying
full prescribing information.
Dispense in a tight container.
Store at 15°-30°C (59°-86°F).
Manufactured by:
Roche Farma S.A. Leganes, Spain
for: Meda Pharmaceuticals®
Meda Pharmaceuticals Inc.
Somerset, New Jersey 08873-4120
Package Label - Principal Display Panel – 100-Count Bottle, 10 mg Tablets
NDC 0037-5010-01
100 Tablets
Demadex ®
(torsemide)
10 mg Rx only
Meda Pharmaceuticals ®
LB-455101-02 Rev. 5/09
Usual dosage: See accompanying
full prescribing information.
Dispense in a tight container.
Store at 15°-30°C (59°-86°F).
Manufactured by:
Roche Farma S.A. Leganes, Spain
for: Meda Pharmaceuticals®
Meda Pharmaceuticals Inc.
Somerset, New Jersey 08873-4120
Package Label - Principal Display Panel – 100-Count Bottle, 20 mg Tablets
NDC 0037-5020-01
100 Tablets
Demadex ®
(torsemide)
20 mg Rx only
Meda Pharmaceuticals ®
LB-455201-02 Rev. 5/09
Usual dosage: See accompanying
full prescribing information.
Dispense in a tight container.
Store at 15°-30°C (59°-86°F).
Manufactured by:
Roche Farma S.A. Leganes, Spain
for: Meda Pharmaceuticals®
Meda Pharmaceuticals Inc.
Somerset, New Jersey 08873-4120
Package Label - Principal Display Panel – 100-Count Bottle, 100 mg Tablets
NDC 0037-5001-01
100 Tablets
Demadex ®
(torsemide)
100 mg Rx only
Meda Pharmaceuticals ®
LB-455100-02 Rev. 5/09
Usual dosage: See accompanying
full prescribing information.
Dispense in a tight container.
Store at 15°-30°C (59°-86°F).
Manufactured by:
Roche Farma S.A. Leganes, Spain
for: Meda Pharmaceuticals®
Meda Pharmaceuticals Inc.
Somerset, New Jersey 08873-4120
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Simvastatina Cinfa may be available in the countries listed below.
Simvastatin is reported as an ingredient of Simvastatina Cinfa in the following countries:
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Lispine may be available in the countries listed below.
Disopyramide is reported as an ingredient of Lispine in the following countries:
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Trombopirin may be available in the countries listed below.
Ticlopidine is reported as an ingredient of Trombopirin in the following countries:
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See also: Generic Humalog Mix 50/50, Generic Humalog Mix 50/50 KwikPen, Generic Humalog Mix 50/50 Pen, Generic Humalog Mix 75/25, Generic Humalog Mix 75/25 Pen
Humalog Mix 75/25 KwikPen is a brand name of insulin lispro/insulin lispro protamine, approved by the FDA in the following formulation(s):
No. There is currently no therapeutically equivalent version of Humalog Mix 75/25 KwikPen available.
Note: Fraudulent online pharmacies may attempt to sell an illegal generic version of Humalog Mix 75/25 KwikPen. These medications may be counterfeit and potentially unsafe. If you purchase medications online, be sure you are buying from a reputable and valid online pharmacy. Ask your health care provider for advice if you are unsure about the online purchase of any medication.
See also: About generic drugs.
There are no current U.S. patents associated with Humalog Mix 75/25 KwikPen.
Torlasporin may be available in the countries listed below.
Cefalexin is reported as an ingredient of Torlasporin in the following countries:
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Generic Name: morphine (Oral route)
MOR-feen
Kadian(R): Capsule contains morphine sulfate, an opioid agonist and Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. Kadian(R) is indicated for the management of moderate-to-severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. The 100-mg and 200-mg capsules are for use in opioid-tolerant patients only. Kadian(R) capsules should be swallowed whole or the contents sprinkled on applesauce. Do not crush, chew, or dissolve capsule pellets due to the risk of rapid release and absorption of a potentially fatal dose of morphine .
Avinza(R): Capsules are a modified-release formulation of morphine sulfate indicated for once daily administration for the relief of moderate to severe pain requiring continuous, around-the-clock opioid therapy for an extended period of time. Avinza(R) capsules should be swallowed whole or the contents sprinkled on applesauce. Do not crush, chew, or dissolve capsule beads due to the risk of rapid release and absorption of a potentially fatal dose of morphine. Avoid alcohol and alcohol-containing medications as consumption of alcohol may result in the rapid release and absorption of a potentially fatal dose of morphine .
Morphine oral solution is available in 10 mg/5 mL, 20 mg/5 mL and 100 mg/5 mL (20 mg/mL) concentrations. The 100 mg/5 mL (20 mg/mL) concentration is indicated for use in opioid-tolerant patients only. Take care to avoid dosing errors due to confusion between different concentrations and between mg and mL, which could result in accidental overdose and death. Keep morphine oral solution out of the reach of children .
MS Contin(R): 100 mg and 200 mg tablets are for use in opioid-tolerant patients only. MS Contin(R) tablets are a controlled-release formulation, should be swallowed whole and are not to be broken, chewed, dissolved, or crushed due to the risk of rapid release and absorption of a potentially fatal dose of morphine . Oramorph(R) SR: This is a sustained-release dosage form. Swallow the tablet whole; the tablet should not be broken in half, nor should it be crushed or chewed .
In the U.S.
Available Dosage Forms:
Therapeutic Class: Analgesic
Chemical Class: Opioid
Morphine is used to relieve moderate to severe pain. It belongs to the group of medicines called narcotic analgesics (pain medicines). Morphine acts on the central nervous system (CNS) to relieve pain.
When morphine is used for a long time, it may become habit-forming, causing mental or physical dependence. However, people who have continuing pain should not let the fear of dependence keep them from using narcotics to relieve their pain. Mental dependence (addiction) is not likely to occur when narcotics are used for this purpose. Physical dependence may lead to withdrawal side effects if treatment is stopped suddenly. However, severe withdrawal side effects can usually be prevented by gradually reducing the dose over a period of time before treatment is stopped completely.
This medicine is available only with your doctor's prescription.
In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:
Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.
Appropriate studies have not been performed on the relationship of age to the effects of morphine in the pediatric population. Safety and efficacy have not been established.
Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of morphine in the elderly. However, elderly patients are more likely to have age-related liver, kidney, or heart problems, which may require caution and an adjustment in the dose for patients receiving morphine.
| Pregnancy Category | Explanation | |
|---|---|---|
| All Trimesters | C | Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. |
Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.
Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.
Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.
The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:
This section provides information on the proper use of a number of products that contain morphine. It may not be specific to Roxanol. Please read with care.
Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. This is especially important for elderly patients, who may be more sensitive to the effects of pain medicines. If too much of this medicine is taken for a long time, it may become habit-forming (causing mental or physical dependence).
You may take this medicine with or without food.
Morphine extended-release capsules and tablets should only be used by patients who have already been taking narcotic pain medicines, also called opioids. These patients are called opioid-tolerant. If you are uncertain whether or not you are opioid-tolerant, check with your doctor before using this medicine.
Swallow the extended-release capsules and tablets whole. Do not break, crush, dissolve, or chew them. Do not use extended-release tablets that are broken.
If you cannot swallow the extended-release capsule, you may open it and pour the medicine into a small amount of applesauce. Stir this mixture well and swallow it right away without chewing.
While taking the extended-release tablet, part of the tablet may pass into your stool. This is normal and nothing to worry about.
Morphine extended-release capsules or tablets work differently from the regular morphine oral solution or tablets, even at the same dose. Do not switch from one brand or form to the other unless your doctor tells you to.
Measure the oral liquid with a marked measuring spoon, oral syringe, or medicine cup. The average household teaspoon may not hold the right amount of liquid.
The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Morphine can cause serious unwanted effects if taken by adults who are not used to strong narcotic pain medicines, children, or pets. Make sure you store the medicine in a safe and secure place to prevent others from getting it.
Flush the unused capsules, liquid, and tablets down the toilet.
It is very important that your doctor check your progress while you are taking this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it.
This medicine will add to the effects of alcohol and other CNS depressants (medicines that can make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for allergies or colds; sedatives, tranquilizers, or sleeping medicine; other prescription pain medicine or narcotics; medicine for seizures or barbiturates; muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before taking any of these medicines while you are using this medicine.
This medicine may be habit-forming. If you feel that the medicine is not working as well, do not use more than your prescribed dose.
Dizziness, lightheadedness, or fainting may occur when you get up suddenly from a lying or sitting position. Getting up slowly may help lessen this problem. Also, lying down for a while may relieve the dizziness or lightheadedness.
This medicine may make you dizzy, drowsy, confused, or disoriented. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.
Using narcotics for a long time can cause severe constipation. To prevent this, your doctor may direct you to take laxatives, drink a lot of fluids, or increase the amount of fiber in your diet. Be sure to follow the directions carefully, because continuing constipation can lead to more serious problems.
This medicine may cause a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash; itching; hoarseness; trouble breathing; trouble swallowing; or any swelling of your hands, face, or mouth while you are using this medicine.
If you have been using this medicine regularly for several weeks or longer, do not change your dose or suddenly stop using it without checking with your doctor. Your doctor may want you to gradually reduce the amount you are using before stopping it completely. This may help prevent worsening of your condition and reduce the possibility of withdrawal symptoms, such as abdominal or stomach cramps, anxiety, fever, nausea, runny nose, sweating, tremors, or trouble with sleeping.
Using this medicine while you are pregnant may cause serious unwanted effects in your newborn baby. Tell your doctor right away if you think you are pregnant or if you plan to become pregnant while using this medicine.
Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:
Get emergency help immediately if any of the following symptoms of overdose occur:
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
See also: Roxanol side effects (in more detail)
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Padrax may be available in the countries listed below.
Piperazine hexahydrate (a derivative of Piperazine) is reported as an ingredient of Padrax in the following countries:
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Beclometason-ratiopharm may be available in the countries listed below.
Beclometasone 17α,21-dipropionate (a derivative of Beclometasone) is reported as an ingredient of Beclometason-ratiopharm in the following countries:
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Zeloxim may be available in the countries listed below.
Meloxicam is reported as an ingredient of Zeloxim in the following countries:
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Sandoz Spironolactone may be available in the countries listed below.
Spironolactone is reported as an ingredient of Sandoz Spironolactone in the following countries:
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Prosogan may be available in the countries listed below.
Lansoprazole is reported as an ingredient of Prosogan in the following countries:
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Desalex may be available in the countries listed below.
Desloratadine is reported as an ingredient of Desalex in the following countries:
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