Laboratory Values
Potassium: See WARNINGS.
Calcium
Single doses of
torsemide 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 torsemide for an average of 11 months,
hypocalcemia was not reported as an adverse event.
Magnesium
Single doses of
torsemide 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 torsemide 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 torsemide 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 torsemide,
respectively.
Blood Urea Nitrogen
(BUN), Creatinine and Uric Acid
Torsemide produces small
dose-related increases in each of these laboratory values. In hypertensive
patients who received 10 mg of torsemide 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 torsemide, but its incidence has been
similar to that seen in patients receiving placebo.
Glucose
Hypertensive patients
who received 10 mg of daily torsemide 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 torsemide 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 torsemide 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 torsemide daily, no clinically significant differences from
baseline lipid values were observed after 1 year of therapy.
Other
In long-term studies in
hypertensive patients, torsemide 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.
Drug Interactions
In patients with
essential hypertension, torsemide has been administered together with
beta-blockers, ACE inhibitors and calcium-channel blockers. In patients with
congestive heart failure, torsemide 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 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 torsemide 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 torsemide and
salicylates compete for secretion by renal tubules, patients receiving high
doses of salicylates may experience salicylate toxicity when torsemide 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 torsemide (like that of many other diuretics) is partially inhibited by the
concomitant administration of indomethacin. This effect has been demonstrated
for torsemide under conditions of dietary sodium restriction (50 mEq/day) but
not in the presence of normal sodium intake (150 mEq/day).
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 torsemide 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 torsemide and cholestyramine are used concomitantly,
simultaneous administration is not recommended.
Coadministration of
probenecid reduces secretion of torsemide into the proximal tubule and thereby
decreases the diuretic activity of torsemide.
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 torsemide 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 torsemide have not been studied.
Carcinogenesis and Mutagenesis and Impairment of
Fertility
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
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.
Labor and Delivery
The effect of torsemide
on labor and delivery is unknown.
Nursing Mothers
It is not known whether
torsemide is excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when torsemide is administered to a nursing
woman.
Pediatric Use
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 torsemide in such
patients has not been studied.
Geriatric Use
Of the total number of
patients who received torsemide 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.
