Approved Drug Label (PDF)
4
Contraindications
Additions and/or revisions underlined:
- DEMADEX is contraindicated
in patients with known hypersensitivity to DEMADEX or to povidone.
- DEMADEX is contraindicated
in patients with hepatic coma.
5
Warnings and Precautions
Physician
Labeling Rule (PLR) conversion; revised as below:
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.
6
Adverse Reactions
PLR Conversion; additions and/or revisions underlined:
The
following risks are discussed in more detail in others sections:
- Hypotension and Worsening
Renal Function
- Electrolyte and Metabolic
Abnormalities
- Ototoxicity
6.1
Clinical Trials Experience
Because
clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to
rates in the clinical trials of another drug and may not reflect the rates
observed in practice.
In
pre-approval
studies, DEMADEX has 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.
Discontinuation
of therapy due to adverse reactions occurred in 3.5% of United States patients
treated with DEMADEX and in 4.4% of patients treated with placebo.
In
United States eplacebo-controlled trials excessive urination occurred in
6.7% of patients compared with 2.2% of
patients receiving placebo. 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.
In
the placebo-controlled hypertension studies excessive urination was dose
related; 1% of patients receiving placebo, 4% of those treated with 5 mg of
daily DEMADEX, and 15% of those treated with 10 mg. Excessive urination was
generally not reported as an adverse event among patients who received DEMADEX
for cardiac, adrenal, or hepatic failure.
There
was no effect of age or sex on the incidence of adverse reactions.
Laboratory
Parameters
Potassium
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 1.5% on DEMADEX and 3% on placebo. In patients followed
for 1 year, there was no progressive 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.
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.
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.
Serum Lipids
DEMADEX
20 mg caused small increases in total cholesterol and triglycerides in short
term hypertension studies. The changes subsided with chronic therapy.
6.2
Postmarketing Experience
Gastrointestinal
system: Pancreatitis, abdominal pain
Nervous
System:
Paresthesia, confusion, visual impairment, loss of appetite
Hematologic: Leucopenia,
thrombocytopenia, anemia
Hepatobiliary:
Increase in liver transaminases, gamma-glutamyltransferase
Metabolism:
Thiamine (vitamin B1) deficiency
Skin/hypersensitivity:
Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity
reaction, pruritus
Urogenital:
Acute urinary retention
7
Drug Interactions
PLR conversion,
as below:
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.
8
Use in Specific Populations
8.1 Pregnancy
PLLR conversion:
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/m2
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/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.
8.2 Lactation
PLLR conversion:
Risk
Summary
There
are no data regarding the presence of DEMADEX in human milk or the effects of
DEMADEX on the breastfed child. Diuretics can suppress lactation.
8.4 Pediatric Use
Additions and/or revisions underlined:
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.
8.6 Use in Renal Impairment
Newly added subsection:
In single-dose studies in patients with
non-anuric renal failure, high doses of DEMADEX (20 mg to 200 mg) caused marked
increases in water and sodium excretion. In patients with non-anuric 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.
8.7 Use in Hepatic Impairment
Newly added subsection:
DEMADEX can cause sudden alterations of
fluid and electrolyte balance which may precipitate hepatic coma in patients
with hepatic disease with cirrhosis and ascites. In these patients, diuresis with
DEMADEX is best initiated in the hospital.
Diuretic treatment can cause or
contribute to the development of hypovolemia, hypokalemia, metabolic alkalosis,
hyponatremia or azotemia which can lead to new or worsening hepatic
encephalopathy. Consider suspending or discontinuing DEMADEX.
To prevent hypokalemia and metabolic
alkalosis, use an aldosterone antagonist or potassium-sparing drug with DEMADEX
in patients with hepatic disease.
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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING NFORMATION
PLR conversion; newly added section:
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.
Non-Steroidal Anti-inflammatory Drugs (NSAID): Advise patients to discuss with their physician
before taking NSAID
medications concomitantly.
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