13-Drugs 49 (1) 121-142,1995

DRUG EVALUATION Drugs 49 (1): 121-142,1995
0012-6667/95/0001-0121/S2200/0
© Adis International Limited. All rights reserved.
Torasemide
An Update of its Pharmacological Properties and
Therapeutic Efficacy
Christopher J. Dunn, Andrew Fitton and Rex N. Brogden
Adis International Limited, Auckland, New Zealand
Various sections of the manuscript reviewed by:

V.E. Andreucci, Cattedra di Nefrologia Medica, Faculty of Medicine and Surgery, University of Naples,
Naples, Italy; D.C. Brater, Department of Medicine, Indiana Univer.sity Medical Center, Indianapolis,
Indiana, USA; K.S. Channer, Department of Cardiology, Royal Hallamshire Hospital, Sheffield, England;
A.G. Dupont, Department of Pharmacology and Therapeutics, Free University of Brussels, Brussels, Belgium;
T.W.B. Gehr, Division of Nephrology, Medical College of Virginia Hospitals, Virginia Commonwealth
University, Richmond, Virginia, USA; P. Gentilini, Istituto di Medicina Interna, University of Florence,
Florence, Italy; G.D. Johnston, Department of Therapeutics and Pharmacology, Queen's University of
Belfast, Belfast, Northern Ireland; J. Kindler, Department of Internal Medicine, Kreiskrankenhaus
Marienhohe, Wiirselen, Germany; E Kriick, Medizinische Universitiits-Poliklinik, Bonn, Germany;A.E Lant,
Department of Clinical Pharmacology and Therapeutics, Charing Cross and Westminster Medical Schools,
Westminster Hospital, London, England; T.O. Morgan, Department of Physiology, University of Melbourne,
Melbourne, Victoria, Australia; M. Moser, Department of Internal Medicine, Yale University School of
Medicine, New Haven, Connecticut, USA; A.J. Reyes, Institute of Cardiovascular Theory, Montevideo,
Uruguay.
Contents
Summary ............. . 122
1, Overview of Pharmacological Properties . . 125
1.1 Effects on Electrolyte and Water Excretion 125
1.1,1 Diuretic Effects in Acute and Chronic Heart Failure 127
1.1.2 Diuretic Effects in Chronic Renal Failure , , , , , , , 127
1,1.3 Diuretic Effects in Cirrhotic Liver Disease . . . . . . . 128
1.2 Effects on Renal Function and Endogenous Vasoactive Substances 128
1.3 Haemodynamic Effects .. . 128
1.4 Other Effects . . . . . . . . . . . . . . . . . . . . . . . . . 128
1.5 Pharmacokinetic Properties. . . . . . . . ..... . 129
1.5.1 Effects of Age and Disease on Pharmacokinetics 130
2. Therapeutic Use . . . . . . . . . . . . . . . . . . . . . . . . . 130
2.1 Use in Hypertension. .. . ............... . 130
2.1.1 Comparisons with Other Antihypertensive Therapies. 131
2.2 Use in Congestive Heart Failure ... . 131
2.2.1 Comparison with Placebo .. . 132
2.2.2 Comparisons with Furosemide. 132
2.3 Use in Renal Failure . . . . .. 133
2.3.1 Acute Renal Failure . . 133
2.3.2 Chronic Renal Failure . 133
2.3.3 Nephrotic Syndrome 134
2.4 Use in Decompensated Liver Cirrhosis 136
3. Tolerability . . . . . . . . . . . . . . . . . . . 136
122 Dunn et al.
4. Drug Interactions . . . . . . . . . 136

5. Dosage and Administration. . . 137
6. Place of Torasemide in Therapy 137
Summary
Synopsis The pharmacological properties and therapeutic use of the high-ceiling loop
diuretic torasemide (torsemide) were previously reviewed in Drugs in 1991, the
following being a re-examination of the role of the drug in the light of data that
have subsequently become available (particularly in the management of
oedematous disorders).
Torasemide produces a more prolonged water and electrolyte excretion than
equipotent diuretic doses of furosemide (frusemide), but does not increase
kaliuresis to the same extent. Dosages of torasemide of 2.5 to 5 mg/day do not
affect plasma renin activity or aldosterone release to a clinically significant ex-
tent, although torasemide 20mg increases plasma renin levels, angiotensin Il
activity and urinary dopamine and prostaglandin E excretion.
Studies published since the previous review have confirmed the efficacy of low
dosages of torasemide (2.5 to 5 mg/day) in the treatment of hypertension, and
have shown it to be effective when administered orally at a dosage of 5 to 20
mg/day in the management of congestive heart failure. Dosages of up to 400
mg/day increased urinary volume excretion and natriuresis in patients with
chronic renal failure. Bodyweight and peripheral oedema were reduced by tor-
asemide 10 to 200 mg/day as monotherapy, and 5 to 20 mg/day when
coadministered with spironolactone, in patients with nephrotic syndrome. Dos-
ages of 10 to 40 mg/day, either as monotherapy or in conjunction with an aldo-
sterone antagonist, reduced ascites, oedema and bodyweight in patients with
hydropically decompensated liver failure.
Adverse effects due to torasemide are usually mild and transient in nature. No
evidence of ototoxicity has been demonstrated in humans, and torasemide does
not appear to affect blood glucose levels, serum uric acid concentrations, or
serum potassium levels at dosages below 5 mg/day.
Thus, additional evidence has accumulated for the clinical efficacy of tor-
asemide in the management of mild to moderate essential hypertension and
oedematous conditions which require diuretic therapy. Further studies are now
required to confirm the long term efficacy and tolerability of torasemide, and to
investigate the place ofthe drug in therapy relative to cardiovascular agents other
than furosemide and the thiazide diuretics.
Overview of Torasemide is a high-ceiling loop diuretic .which inhibits renal tubular reabsorp-
Pharmacological tion of sodium and chloride in the thick ascending limb of the loop of Henle,
Properties resulting in a pronounced saluresis and diuresis. Urinary volume excretion and
saluresis increase linearly with the logarithm of increasing torasemide dose, with
a dose of torasemide between 10 and 20mg being equivalent in diuretic and
saluretic potency over 24 hours to furosemide (frusemide) 40mg. Torasemide
produces a more prolonged water and electrolyte excretion than furosemide, but
does not increase kaliuresis to the same extent.
At a dosage of 2.5 mg/day, torasemide does not cause any overall increase in
24-hour natriuresis and is therefore nondiuretic. The effective use of torasemide
© Adis International Limited. All rights reserved. Drugs 49 (1) 1995

Torasemide: An Update 123
at this dosage for the treatment of hypertension has been associated with the
suggestion that increased natriuresis due to diuretic therapy does not playa part
in the reduction of raised blood pressure.
In patients with chronic congestive heart failure (CHF) torasemide 10 to 20mg
appears to produce greater saluresis and diuresis than furosemide 40mg, but uri-
nary potassium excretion does not follow the dose-related increase seen with
sodium and chloride excretion after single doses of torasemide of up to 20mg.
Torasemide 200mg, given intravenously, increased fractional urinary volume
excretion to a greater extent than either intravenous furosemide 250mg or oral
furosemide 500mg in patients with severe chronic renal impairment, and intra-
venous torasemide 60 to 100mg was superior in terms of fractional urinary vol-
ume excretion and fractional sodium excretion to intravenous furosemide 60mg
in patients with moderate renal failure. Single-dose oral torasemide 20mg showed
equivalent saluretic and diuretic potency to furosemide 40mg in a group of pa-
tients with liver cirrhosis and ascites. Torasemide 20mg increased cumulative
24-hour natriuresis and diuresis to a greater extent than furosemide 80mg, and
torasemide 50mg exhibited a longer duration of action than furosemide 100mg
in further studies of patients with hepatic cirrhosis.
Neither glomerular filtration rate nor creatinine clearance is affected by tor-
asemide at dosages of up to 20 mg/day, although plasma renin levels, angiotensin
II activity, urinary dopamine excretion and urinary prostaglandin E excretion are
similarly increased by torasemide 20mg and furosemide 40mg. Torasemide 2.5
to 5 mg/day has no significant effect, however, on plasma renin activity or aldo-
sterone release.
Intravenous torasemide 10 to 20mg is at least as effective as furosemide 20mg
in reducing haemodynamic parameters of cardiac workload in patients with CHF,
and single intravenous doses of torasemide 5 to 10mg reduced mean diastolic
blood pressure by up to 25% in hypertensive patients. Torasemide may increase
fasting plasma glucose levels at dosages above 5 mg/day, but no effects on serum
triglycerides or serum total cholesterol levels are seen at dosages below 20
mg/day and 10 mg/day, respectively.
Torasemide is rapidly absorbed following oral administration, with the peak
plasma concentration achieved within the first hour. Plasma protein binding is 97
to 99%, and the volume of distribution (calculated after intravenous administra-
tion) is 0.09 to 0.31 Llkg. Metabolism of torasemide involves hepatic biotrans-
formation, with up to 25% of an intravenous dose being excreted unchanged in
the urine. Three major metabolites occur in humans, but are not considered to
exert clinically significant diuretic effects. The mean plasma elimination half-life
of torasemide in healthy volunteers ranges from 2.2 to 5.1 hours. Torasemide
exhibits similar pharmacokinetic properties in both young and elderly healthy
volunteers, and no significant accumulation of the parent drug or its metabolites
has occurred following oral administration of torasemide to patients with chronic
renal failure at dosages of up to 200 mg/day for up to 11 days. Linear pharmaco-
kinetics of torasemide have been observed after intravenous and oral administra-
tion of 20 to 200mg, and oral doses of 50 to 200mg to patients with renal failure
and CHF, respectively.
Therapeutic Use Torasemide 2.5 to 5 mg/day has shown equivalent antihypertensive efficacy to
hydrochlorothiazide 25 mg/day, and lacks the adverse metabolic and kaliuretic
effects seen with natriuretic dosages of thiazide diuretics. Monotherapy with

124 Dunn et al.
torasemide at the subdiuretic dosage of 2.5 mg/day normalised diastolic blood

pressure in 60 to 76% of patients with mild to moderate essential hypertension,
compared with 72 to 82% of patients receiving hydrochlorothiazide 25 to 50
mg/day, respectively, in combination with a potassium-sparing diuretic. Torasem-
ide 2.5 mg/day has not been associated with any impairment of quality of life,
based on assessments of daily activity and well-being.
Short term studies have shown orally administered torasemide 5 to 20 mg/day
to decrease the severity of oedema and mean bodyweight to a greater extent than
placebo or furosemide 40mg in patients with chronic CHF. Torasemide 20 mg/day
also achieved a greater reduction in pre-existing oedema than furosemide ;40
mg/day in patients with chronic CHF. Efficacy appeared to be maintained for 11
months in a longer term dose-ranging study using torasemide 5 to 20 mg/day.
Intravenous torasemide 400 to 800mg has shown equivalent diuretic efficacy
to furosemide 1000mg in patients with acute renal failure, whereas oral admin-
istration of torasemide 200 to 400 mg/day increased urine volume and natriuresis
similarly to furosemide 250 to 1000 mg/day in patients with chronic renal failure.
Oral torasemide 50 to 200 mg/day appears to be at least as effective as furosemide
125 to 500 mg/day in reducing interdialysis weight gain and increasing diuresis
and sal uresis in patients with advanced renal impairment. Both torasemide 10 to
200 mg/day as monotherapy, and torasemide 5 to 20 mg/day plus spironolactone
50 to 200 mg/day, significantly reduced bodyweight and peripheral oedema after
up to 13 weeks' treatment in patients with nephrotic syndrome.
Monotherapy with torasemide up to 40 mg/day reduced abdominal girth due
to ascites in patients with hydropic ally decompensated liver failure by up to 5.9%;
furthermore, torasemide 10 to 20 mg/day coadministered with spironolactone 100
to 200 mg/day effectively reduced oedema, ascites and bodyweight in these pa-
tients. Torasemide 10 to 20 mg/day plus potassium canrenoate 200 mg/day de-
creased ascites and oedema in cirrhotic patients to a greater extent than either
monotherapy with potassium canrenoate 400 mg/day for up to 7 days, or furose-
mide 25 to 50 mg/day plus potassium canrenoate 200 mg/day for 3 to 4 days.
Addition of torasemide 10 to 40 mg/day to pre-existing therapy with spironolac-
tone 50 to 400 mg/day improved ascites and oedema in 73% and 67% of patients,
respectively, after 6 months' treatment.
Tolerability The adverse effects attributable to torasemide are usually mild and transient in
nature and inClude fatigue, dizziness, headache, muscle cramps, lower back pain,
skin rash, nausea and orthostatic hypotension. Although other adverse reactions,
including pruritus, paraesthesia and chest pain have been noted after 48 weeks'
therapy with torasemide 2.5 to 5 mg/day, these are rare, and withdrawal from
treatment due to torasemide-related drug reactions is seldom necessary. Analysis
of pooled clinical trial data has shown the rate of occurrence of adverse events to
be significantly less with torasemide than with combinations of hydrochlorothi-
azide and potassium-sparing diuretics in patients with hypertension.
No evidence of ototoxicity has been detected in humans after 4 weeks' oral
administration of torasemide at dosages of up to 400 mg/day. Torasemide does
not appear to affect blood glucose levels, serum uric acid concentrations, or serum
potassium levels at dosages below 5 mg/day.
Drug Interactions Probenecid has been shown to reduce the diuretic and natriuretic effects, and to
increase the plasma elimination half-life, of torasemide. Nonsteroidal anti-
© Adis International Limited, All rights reserved, Drugs 49 (1) 1995

inflammatory drugs are also known to decrease the diuretic and natriuretic re-
sponse to loop diuretics; indomethacin pretreatment appears to reduce diuresis
and natriuresis due to torasemide under conditions of sodium restriction.
No pharmacokinetic interactions have been reported following coadministra-
tion of torasemide with digoxin, spironolactone, carvedilol or cimetidine. Tor-
asemide does not appear to interfere with serum protein binding of either warfarin
or phenprocoumon.
Dosage and An oral dosr.gf' of torasemide 2.5 mg/day, increasing to 5 mg/day if necessary
Administration after 12 weeks is recommended for the management of mild to moderate essential
hypertension. Oral dosages oftorasemide 5 mg/day, increasing to 20 mg/day (the
maximum recommended dosage being 40 mg/day), are recommended for patients
with chronic CHF, and torasemide 5 to 40 mg/day may also be used in conjunction
with an aldosterone antagonist such as spironolactone for the management of
ascites secondary to hepatic cirrhosis. Oedema associated with nephrotic syn-
drome may be treated with torasemide 1OOmg coadministered with an aldosterone
antagonist.
Intravenous administration of torasemide 20 to 200 mg/day is recommended
in advanced chronic renal failure, and no dosage adjustment appears necessary
in patients undergoing haemofiltration or haemodialysis. High-dosage intrave-
nous torasemide (up to 800 mg/day) appears to be effective in converting oliguric
acute renal failure to the polyuric form.
Torasemide (torsemide) is the most active mem- agent, with the addition of data made available
ber of the novel anilinopyridine sulfonylurea deriv- since the last review.
atives (fig. 1). This high-ceiling loop diuretic was The primary site of action of torasemide is the
previously reviewed in Drugs in 1991 ;[1] the pres- thick ascending limb of the loop of Henle, where
ent review re-examines the pharmacological prop- the drug interacts with the sodium/chloride/potas-
erties and therapeutic efficacy of torasemide in the sium cotransport system, thus inhibiting tubular
reabsorption of sodium and chloride)2] This results
light of subsequently available data.
in reduced interstitial hypertonicity, decreased
reabsorption of water and thus a pronounced diure-
1. Overview of Pharmacological sis and saluresis. The high lipophilicity of toras em-
Properties ide may confer some activity at the peritubular side
of the basolateral cells of the nephron, but the main
The pharmacological properties of torasemide pharmacological effect is thought to be exerted on
have been reviewed previously;D] the following is the luminal side (reviewed by Friedel and Buck-
an overview of the most relevant pharmacody- ley[l]). It had previously been concluded that the
namic and pharmacokinetic properties of this proximal tubule was not a site of action for tor-
asemide, but recent data suggest that the drug may
additionally inhibit proximal sodium and water
reabsorption)3]
1.1 Effects on Electrolyte and Water

Excretion
A linear relationship has been observed between

Fig. 1. Structural formula of lorasemide. sodium, chloride and urinary volume excretion,
© Adis International Lirnited. All rights reserved. Drugs 49 (1) 1995

126 Dunn et al.
and the logarithm of torasemide dose in healthy 60

• Torasemide 10mg
volunteers for single oral doses of 10 to 100mg, and ~ • Torasemide 5mg
'0 50 o Placebo
intravenous doses of S to 80mgJ4] Torasemide does E
not cause any significant change in phosphate or
g
;;: 40
bicarbonate excretion (which has contributed to the ,g
Q)
30
widely held view that the drug possesses no prox- '0
.§
imal tubular action), and although no significant :c
() 20
~
effects on urinary pH have been reported,lS] oral m
c
10
administration of torasemide 40 mg/day for 3 §
weeks to healthy volunteers raised mean plasma 0
uric acid levels by 40.6% (p < 0.OS)J6] Despite 0 4 8 12 16 20 24
transient increases in plasma calcium and magne- Time (h)
sium levels between the start of this study and day Fig. 2. Urinary chloride flows obtained from a single healthy
10, the changes in plasma levels of these 2 electro- volunteer after separate, randomised, double-blind, crossover
lytes were not significant after 3 weeks. oral administration of placebo, torasemide 5mg, and torasemide
10mg[12)
Intravenous torasemide 20mg was reported to
possess a similar diuretic profile to intravenous fu-
rosemide (frusemide) 40mg, with rapid onset of diuretic. The 24-hour time course of natriuresis
action and maximum effect within IS minutes for seen with torasemide, as with other loop diuretics,
both drugs, in a study of 8 healthy volunteers V] does not change with prolonged administration of
Further studies have shown single intravenous once daily dosages. Lower doses of torasemide
doses of torasemide of between 10 and 20mg to provoke less intense natriuresis and more pro-
have an equivalent natriuretic effect to furosemide tracted urinary sodium excretion, such that tor-
40mg over 6 and 24 hoursJ8,9] At these doses torasemide 2.Smg exhibits a similar 24-hour time
asemide produced a more prolonged excretion of course of sodium excretion to hydrochlorothiazide
water and all electrolytes except potassiumJlO] Ef- 2Smg.[11,12]
fects on urinary calcium excretion appear similar The 24-hour natriuresis and chloruresis seen af-
for both drugs, but single-dose torasemide 20mg ter the first dose of the overtly diuretic Smg and
achieved a greater diuresis and saluresis than furo- 10mg formulations of torasemide decreases to
semide 40mg for up to 6 hours after administration post-placebo levels after 7 days of once daily ad-
to 6 healthy volunteersJlO] ministration in healthy volunteers; this phenome-
Since the publication of the previous review, the non also occurs with furosemide 40mg and hydro-
renal response to torasemide has been more clearly chlorothiazide 2SmgJll] This attenuation of the
defined.D 1,12] Torasemide exhibits biphasic sal- early natriuretic response after prolonged once
uretic and diuretic effects, with sodium and chlor- daily administration has not been observed with
ide excretion increasing in a dose-dependent man- torasemide 2.Smg. It has been suggested[13] that
ner within the first 6 hours of a single oral dose of the natriuretic action of diuretics is not necessary
2.S to lOmg in healthy volunteers; these pro- for these agents to reduce raised blood pressure in
nounced early elev<;ltions in excretory values are essential hypertension, although such an action
followed by an overall decrease in urinary sodium might accelerate the fall in blood pressure seen dur-
and chloride outputs (the 'rebound' effect) due to ing the first few weeks of treatment.
the activation of sodium-conserving processes oc- Doses of torasemide appear to induce smaller
curring 6 to 24 hours after administration (fig. 2). potassium losses than equivalent diuretic doses of
As a result, torasemide 2.Smg does not elevate furosemideJ4,1O] Dosages up to S mg/day have no
overall 24-hour natriuresis, and is therefore non- significant effect on serum potassium levels when

administered to patients with essential hyperten- placebo in these patients. Overall 24-hour urinary
sion for periods of up to 24 weeksJ14] Current volume excretion was higher after intravenous fu-
data[11] confirm earlier observations: oral torasem- rosemide 60mg (32% vs placebo, n = 13) than tor-
ide 2.5 to 5 mg/day does not appear to increase asemide 100mg (26% vs placebo, n = 10) in this
24-hour kaliuresis, and at dosages of up to 10 study, but 24-hour saluresis was greater and cal-
mg/day ceases to augment potassium excretion af- cium excretion less with torasemide 100mg (re-
ter 7 days' treatment (in contrast to hydrochloro- viewed in Friedel and Buckley[1]). A comparative
thiazide 25 mg/day). Oral administration of tor- study of 90 patients with serum creatinine levels of
asemide 20 mg/day for 3 weeks caused a small but at least 265 /lmol/U 21 ] showed similar overall 24-
statistically significant decrease in mean serum po- hour urinary volume and electrolyte excretions
tassium levels in healthy volunteers (4.1 to 3.8 with single-dose intravenous torasemide and furo-
mmollL)J6] A possible inhibitory action of torsemide, using doses of 100mg and 200mg for both
asemide on aldosterone activity has been postu- drugs (reviewed in Friedel and Buckley[1]). It was
lated to account for the relative lack of kaliuresis suggested that the drugs were equipotent at these
with torasemide;[15,16] at present, only animal data higher doses.
are available to support this hypothesis. The duration of action of intravenous torasem-
1. 1. 1 Diuretic Effects in Acute and ide 20mg in both healthy volunteers and patients
Chronic Heart Failure with renal failure (mean CLCR 19.9 ml/min) was
Studies previously reviewed in Drugs[1] approximately 6 hours, and independent of CLCR.
showed that while the onset of diuretic effect of The extent of drug-induced excretion of sodium,
intravenous doses of torasemide and furosemide chloride, potassium, calcium and magnesium was,
was the same, the duration of action of torasemide however, dependent on CLCRJ22]
was longer than that of furosemide after both oral The ability of oral and intravenous torasemide
and intravenous administration to patients with to increase urinary volume and sodium excretion
congestive heart failure (CHF). The pattern of in patients with chronic renal failure has been con-
saluresis and kaluresis differed, however, with tor- firmed in two single-dose studies.[23,24] Oral tor-
asemide 10 to 20 mg/day causing a greater excre- asemide 200mg increased fractional urinary vol-
tion of sodium and chloride ions and a lesser ex- ume excretion (obtained by dividing urinary flow
cretion of potassium ions than furosemide 40 rate by creatinine clearance) by 3.2%, compared
mg/day. The cumulative excretion of sodium and with increases of 2.3% and 2.1 % for intravenous
chloride increased linearly with increasing tor- furosemide 250mg and oral furosemide 500mg, re-
asemide dosage over 12 hours (oral) and 24 hours spectively, in a study of 30 patients with severe
(intravenous), whereas that of potassium was pro- chronic renal impairment (creatinine clearance <
portionately lower (data on file[17,18]). Higher sin- 22 ml/min).[23] Single doses of intravenous tor-
gle intravenous doses of torasemide (60mg) and asemide 20 to 100mg have been compared with
furosemide (l20mg), however, similarly increased intravenous furosemide 60mg and placebo in a
urinary electrolyte and volume excretion over a pe- double-blind, randomised multicentre trial con-
riod of 8 hours in patients with CHF.[19] ducted in 51 patients with moderate renal failure
1. 1.2 Diuretic Effects in Chronic Renal Failure (serum creatinine level> 300 /lmol/L). Fractional
A single intravenous 20mg dose of torasemide urinary volume excretion and fractional sodium
had no significant effect relative to placebo on cu- excretion (urinary sodium concentration/serum so-
mulative 24-hour urinary volume excretion in 11 dium concentration x urinary volume excretion
patients with advanced chronic renal failure (uri- rate) were increased by torasemide therapy in a
nary creatinine clearance [CLCR] ::; 30 ml/min),lZO] dose-dependent manner, with all treatments supe-
Saluresis was, however, significantly greater than rior to placebo, and torasemide 60 to 100mg show-

128 Dunn et al.
ing greater efficacy than furosemide 60mg)24] the subdiuretic nature of this dosage range).[1!]
Data are lacking on the effects of higher doses of Studies of isolated canine coronary arteries have
furosemide (>60mg) relative to the same dose suggested a possible inhibition by torasemide of
range of torasemide. the vasoconstriction induced by thromboxane
A2)33] Further work is required to define the clin-
1. 1.3 Diuretic Effects in Cirrhotic Liver Disease
ical relevance of the effect of torasemide and the
A single oral dose of torasemide 20mg had a
other loop diuretics on renal prostaglandins and re-
similar effect to that of furosemide 40mg on 24-
lated vasoactive substances.
hour water, sodium and chloride excretion in pa-
tients with liver cirrhosis and ascites.l25] The same 1.3 Haemodynamic Effects
dose of torasemide induced a significantly greater
cumulative 24-hour diuresis (2.86 versus 2.11L) A single intravenous dose of torasemide 20mg
and a greater 6- to 24-hour natriuresis (38 versus decreased pulmonary capillary wedge pressure to
17 mmol) than furosemide 80mg in patients with a similar extent to furosemide 20mg, but reduced
ascitic cirrhosis.l2 6] Single-dose torasemide 50mg median left ventricular end-diastolic pressure (20
exhibited a longer duration of diuretic action than vs 12%) to a greater extent than furosemide 20mg
furosemide 100mg in patients with hepatic cirrho- 12 minutes after intravenous administrationJ34]
sis, natriuresis being significantly greater with tor- Similar reductions in cardiac work have also been
asemide than with furosemide at 3 to 24 hours after reported with single intravenous doses of torasem-
oral administration.[27] ide lOmg and furosemide 20mg in patients with
heart failure undergoing stepwise ergometric exer-
1.2 Effects on Renal Function and ciseJ35] Oral treatment with torasemide 10 mg/day
Endogenous Vasoactive Substances for 4 weeks reduced parameters of left ventricular
preload and afterload, and improved cardiac per-
Torasemide does not appear to have a clinically
formance in 12 patients with chronic heart failure
significant effect on glomerular filtration rate
[New York Heart Association (NYHA) class II to
(GFR) or CLCR at dosages of up to 20 mg/day. [7 ,28-30]
III])36] Right atrial and pulmonary vascular pres-
Decreased CLCR was observed after a 200mg in-
sures were significantly reduced, both at rest and
travenous dose in patients with chronic renal fail-
after exercise, in 24 men with mild chronic conges-
ure;[2!] the authors suggested that this may have
tive heart failure after 12 weeks of therapy with
been secondary to a reduction in blood pressure and
oral torasemide 5 mg/day)37] Single intravenous
consequently reduced GFR. A single dose of
doses of torasemide 5 to 10mg reduced mean dias-
100mg administered to a comparator group had no
tolic blood pressure by up to 25% in 44 hyperten-
such effect. Conversely, increased urinary creati-
sive patients,[32] and 7 days' treatment with intra-
nine excretion seen after single doses of torasemide
venous torasemide (mean initial dosage 0.9
10 to 20mg in patients with cardiac failure has been
mg/kg/day) reduced mean diastolic blood pressure
attributed to improved renal perfusion)3!]
by 39.3% in 9 patients with chronic renal fail-
Oral and intravenous doses of torasemide 5 to ure)38]
20mg increase plasma renin activity and angioten-
sin II leve1s,[28,29,32] with single intravenous doses
1.4 Other Effects
of torasemide 20mg and furosemide 40mg produc-
ing similar increases in plasma renin activity, uri- Preliminary animal data have shown that intra-
nary prostaglandin E and dopamine excretionV] venous torasemide 1 to 100mg reduces intracranial
Recent data indicate that lower dosages of torasem- pressure and cytotoxic brain oedemaJ39,40] These
ide (2.5 to 5 mg/day) do not significantly stimulate observations indicate that torasemide may have a
plasma renin activity or aldosterone release rela- role in the management of brain oedema and in-
tive to placebo after 7 days' treatment (reflecting tracranial hypertension.

Table I. Summary of pharmacokinetic parameters of torasemide and its major metabolites in healthy volunteers
Parameter Route of administration References
oral intravenous
Absolute bioavailability (F) [%J 76-96 a 42,43,10,44,45
t max (h) 0.86-1.0 43,45
AUC (mg/L· h) 20mg dose 5.7 6.2-10.5 46,47,10
AUC (mg/L • h) 1Omg dose 3.7 4.5 45
Vd (Ukg) 0.09-0.31 43
Vd (L) 11.7-16.5 47,45
CL(Uh) 3.4b 2.2-2.6 47,48,45
CLR (Uh) 0.43 0.38-0.53 47,45
Ae (% of dose) 22-34 22-34 43
t1/2~ (h) 2.2-3.8 2.2-5.1 10,47,45
Pharmacokinetic parameters of major metabolites of torasemide (M1, M3 and MS)C

t1;2~ (h)
M1 2.9 2.9 44
M3 2.8 4.4
M5 2.5 2.4
Cumulative urinary excretion after single dose (%)
torasemide 21 25 44
M1 12 11
M3 2 3
M5 34 44
a 90 to 100% in 24 patients with moderate to severe renal failure.149]
b Based on clearance after 20mg dose.l48]
c After a single 20mg dose.
Abbreviations and symbols: Ae = amount of drug excreted unchanged via the urine; AUC = area under the plasma drug concentration-time
curve; CL = total clearance; CLR = renal clearance; t1;2~ = plasma elimination half-life; t max = time to reach maximum plasma drug concentration
after a single oral dose; Vd = apparent volume of distribution (figures obtained following intravenous administration).
The effects of torasemide and other diuretics on ment open model. [46] Plasma protein binding is 97
carbohydrate tolerance and lipid metabolism have to 99%,[44] but the pattern of tissue distribution
been reviewed[41J and current data indicate that remains unclear. The volume of distribution of tor-
fasting plasma glucose levels are significantly in- asemide in healthy volunteers is 0.09 to 0.31
creased by torasemide at dosages above 5 mg/day. Llkg[43] and is reported to be of the same order as
Dosages of torasemide below 20 mg/day do not the extracellular fluid volume)44]
significantly increase serum triglyceride levels, Torasemide is metabolised by the hepatic cyto-
and dosages below 10 mg/day have not been re-
chrome P450 system (unlike furosemide, which
ported to increase serum total cholesterol lev-
els)41] undergoes glucuronide conjugation), with up to
25% of an intravenous dose appearing in the urine
as unchanged drug)43,44] Of the 3 major metabo-
1.5 Pharmacokinetic Properties
lites, M1 (formed by hydroxylation at the aromatic
A summary of the main pharmacokinetic prop- methyl group) possesses one-tenth of the diuretic
erties of torasemide is given in table I. Torasemide potency of torasemide, M3 (formed by para-
is rapidly absorbed following oral administration hydroxylation of the methyl phenyl amino moiety)
(peak plasma concentration is achieved within the is equipotent with the parent compound, and M5
first hour) and elimination follows a 2-compart- (Ml oxidised to the corresponding carboxylic

130 Dunn et al.
acid) is inactive. The active metabolites, however, hepatic cirrhosis than that seen in healthy volun-
are not considered to exert clinically significant di- teersP5] and the mean plasma elimination half-life
uretic effectsJ43,50] The mean plasma elimination of torasemide (following a single oral dose of
half-life of torasernide in healthy volunteers is re- 20mg) was 4.8 hours in cirrhotic patients and 3
ported to range from 2.2 t05.1 hours (table 1),[10,45,47] hours in healthy volunteersJ25] The renal clearance
compared with approximately 1 hour for furose- of intravenous and oral torasemide 10mg was also
mide, bumetanide and piretanide; this is consistent increased (by 46%) in patients with hepatic cirrho-
with the longer duration of action of torasemide sis (n = 12))45] overall natriuresis in this latter
after intravenous administration (6 hours, com- group, however, was reported to be similar to that
pared with 2 to 2.5 hours for the other agents in healthy volunteers.
quoted[43]).
2. Therapeutic Use
1.5.1 Effects of Age and Disease on
Pharmacokinetics 2.1 Use in Hypertension
The pharmacokinetic properties of intravenous
and oral torasemide in healthy elderly volunteers Current data indicate that the older loop diuret-
(65 to 83 years) were similar to those observed in ics such as furosemide are inferior to thiazide di-
young volunteers (19 to 28 years).[51] uretics in the management of mild to moderate es-
Dose-dependent linear pharmacokinetics have sential hypertension,l56,57] whereas comparative
been observed after intravenous or oral administra- studies have confirmed the antihypertensive effi-
tion of torasemide 20 to 200mg to patients with cacy of torasemide monotherapy compared with
severe renal failure (CLCR::; 30 mllmin);[49,50] this both placebo and thiazidesJ56,58-60] Results of
contrasts with furosemide, whose total clearance studies made available since the original review in
and plasma elimination half-life may be prolonged Drugs[1] have continued to show torasemide 2.5 to
in patients with renal diseaseJ21,52] Treatment with 5 mg/day administered orally to reduce diastolic
oral torasemide 200 mg/day for up to 11 days re- blood pressure (DBP) to a significantly greater ex-
sulted in no clinically significant accumulation of tent than placebo,l56,58] without adverse effects on
the parent drug or metabolites Ml, M3 and MS in carbohydrate and lipid metabolism.[61]
12 patients with a mean residual urine volume of 2. 1. 1 Comparisons with Other Antihypertensive
less than 1000 ml/dayJ53] Therapies
A lower mean renal clearance value for torasem- Thiazide diuretics are usually regarded as first-
ide was observed in patients with CHF (4 mllmin) line antihypertensive agents, but are associated
than in healthy volunteers (10 mllmin) after a sin- with dose-dependent metabolic adverse effects
gle oral dose oftorasemide 20mgJ54] Results from such as hypokalaemia, hypomagnesaemia, hyper-
a further study[55] showed linear pharmacokinetics uricaemia, impaired glucose tolerance, and alter-
for single oral doses of torasemide 50 to 200mg in ations of lipid metabolismJ62] Preliminary com-
16 patients with CHF (NYHA class II to III), with parative studies showed torasemide 2.S to 5
a maximum urinary sodium excretion rate approx- mg/day to be as effective in the management of
imately 20% of that seen in healthy individuals. A essential hypertension as natriuretic dosages of thi-
dose ceiling of SOmg was apparent in this group of azides, while lacking the adverse metabolic and
patients. 20mg of torasemide administered orally kaliuretic effects associated with the latterJ62-64]
increased the area under the plasma concentration- Further trials have continued to focus upon the
time curve (AUC) in patients with CHF relative to comparative efficacy of subdiuretic dosages of tor-
that in healthy volunteers (10.8 mg/L.h vs 6.3 asemide against thiazide diuretics in combination
mg/L • h)J54] The mean AUC after the same dose with a potassium-sparing agent (triamterene or
of torasemide was 2.S times higher in patients with amiloride »)59,60]

Torasemide 2.5 mg/day for 12 weeks normal- Changes in quality of life have been evaluated
ised diastolic blood pressure (DBP ::;90mm Hg) in in 24 elderly patients with mild to moderate essen-
76% of 41 patients with mild to moderate essential tial hypertension undergoing monotherapy with ei-
ther torasemide 2,5 mg/day or hydrochlorothiazide
hypertension, compared with 72% of 43 patients
25 mg/day for 19 weeks.l 65 ] No deterioration was
who had received a combination of hydrochloro- ,
noted for either drug, based on subjective assess-
thiazide 25mg and triamterene 50mg daily, in a ments (by patients) and answers to a questionnaire
double-blind, randomised trial;[60] these data con- relating to well-being and daily activity.
firmed results obtained in 58 patients in a 24-week
study.[14] In a further trial,,[59] 60% of a group of
2.2 Use in Congestive Heart Failure
72 patients with mild to moderate essential hyper-
tension who had received torasemide 2.5 mg/day Diuretic treatment is usually initiated in chronic
for 10 weeks achieved DBP ::;90mm Hg, compared heart failure when congestive symptoms are appar-
with 82% of 71 patients who had received hydro- ent (NYHA class 11); loop diuretics are more effec-
chlorothiazide 50mg and amiloride 5mg daily. tive than thiazides in this condition because of their
high ceiling of action and maintenance of potency
Treatment was continued for a further 14 weeks,
in the presence of renal dysfunction.l 66 ]
with doubling of dosages (torasemide 5 mg/day
A noncomparative dose-ranging study of tor-
and hydrochlorothiazide 100mg with amiloride 10
asemide 5 to 20 mg/day for 11 months in 111 pa-
mg/day) in those patients who had failed to re-
tients with CHF [following ~4 weeks' (mean 3
spond adequately to the initial regimens; decreases months) pretreatment with furosemide 40
in DBP and normotensive response rates were not mg/day][67] (reviewed by Friedel and Buckley[l])
significantly different between the 2 treatment showed torasemide to reduce bodyweight signifi-
groups after 24 weeks (table II). cantly at all dosages studied, and to maintain this
Table II. Summary of clinical studies comparing the antihypertensive efficacy of oral torasemide (T) with thiazide diuretics
Reference No. of Study Study Dosage Clinical parameter Percentage of Overall
evaluable design duration (mg) (mean % decrease patients achieving efficacy
patients (weeks) from baseline) target DBP
SBP DBP (,,90mm Hg)
Achhammer& 29 db, pw, r 24 T2.50d a 10.4 12.7 72 T"HfTR
Eberhard[14) 29 H 25fTR 50 od a 10.6 10.9 79
Boike et al. [60) 41 db, pw, r 12 T2.50d 8.2 13.7 76 T"HfTR
43 H 25fTR 50 od 13.4 13.7 72
Boike et al. [59) 72 db, pw, r 10b T 2.5 od 10.7 11.7 60 T"H/A
71 H 50/A5 od 15.3 15.5 82
Spannbrucker et alJ63) 23 db, pw, r 12 T 2.5 od 17.7c 21.0c 94c T"I
24 12.50d 15.8c 22.0c 88c
a Eight patients in the torasemide group and 6 patients in the hydrochlorothiazide/triamterene group did not achieve target DBP at 12
weeks and therefore received double dosages from week 12 to week 24. Percentages given for patients achieving target DBP are
based on results after 12 weeks' treatment.
b Hydrochlorothiazide/amiloride showed a greater antihypertensive effect than torasemide at 10 weeks, but after doubling of dosages in
each group where necessary, no significant difference was observed between groups at 24 weeks.
c Figures quoted include only patients who responded to 2.5 mg/day, except figures for patients achieving DBP ,,90mm Hg, which
include an additional 9 patients on torasemide and 10 patients on indapamide who required 5 mg/day after week 4.
Abbreviations and symbols: A = amiloride; db = double-blind; DBP = diastolic blood pressure; H = hydrochlorothiazide; I = indapamide;
od =daily; pw =placebo washout; r =randomised; SBP =systolic blood pressure; TR =triamterene; " indicates equivalent efficacy. All blood
pressure changes indicated were statistically significant versus baseline (p < 0.05).
© Adis International Limited, All rights reserved. Drugs 49 (1) 1995

132 Dunn et al.
Table III. Summary of clinical studies comparing the efficacy of oral torasemide (T) with oral furosemide (frusemide; F) in the management
of chronic congestive heart failure
Reference No. of Study design Study Dosage Mean decrease Patients with Overall
evaluable duration (mg/day) in bodyweight improvement of efficacy
patients from baseline pre-existing oedema
(kg) (%)
Dusing & Piesche[68[ 34 db, mc, pll, r 4 weeks T5 1.0 (1.3%)a 54 T= Fb
34 T10 1.1 (1.4%)a 55
36 F 40 1.5 (1.9%)a 74
Goebel[69] 24c db, mc, pll, r 6 weeks T10 2.1 (2.7%) 46 T> Fd
23c T20 3.0 (3.9%) 74
23c F 40 1.3(1.8%) 48
Lehnert et al. [70] 23e db, p[l, r 14 weeks T5 NAf 809 T=F
26e F 40 739
Piesche & B6[ke[71] 24 db, mc, pll, r 8 days T20 1.3(1.9%) NA T>F
22 F 40 H
Stauch & Stiehl[72] 34 db, mc, pll, r 4 weeks T5 NAh 94 T= Fb

34 T10 97
36 F40 92
a Not stated whether or not statistically significant.
b Also based upon number of patients showing improved NYHA classification after treatment.
c 61 % of patients received concomitant cardiac g[ycosides.
d Taken as torasemide 20 mg/day and furosemide 40 mg/day.
e All patients had concomitant non-insulin-dependent diabetes mellitus, controlled with g[ibenclamide.
'Slight decrease' (not quantified) reported for both groups.
g Percentage of patients with abolition of oedema.
h Percentages of patients achieving a reduction in bodyweight 22.5kg were 70.6% for T 5 mg/day, 76.5% for T 10 mg/day and
61.1 % for F 40 mg/day.
Abbreviations and symbols: db = double-blind; mc = ml;llticentre; NA= not available; pll = parallel groups; r = randomised; = indicates equivalent
efficacy; > indicates greater efficacy; H indicates no statistically significant change. Decreases in bodyweight were statistically significant
(p < 0.05) unless stated otherwise.
reduction throughout the study period; 82% of pa- icantly greater extent with torasemide, compared
tients with residual oedema following pretreatment with placebo.
with furosemide were free from oedema by the end
2.2.2 Comparisons with Furosemide
of the study. This trial contains the only currently
Oral torasemide 5 to 20 mg/day has shown effi-
available data on the long term efficacy of torasem- cacy equivalent to or greater than that of oral furo-
ide in CHF. semide 40 mg/day, over periods ranging from 8
days to 14 weeks in the management of chronic
2.2. 1 Comparison with Placebo
CHF (table III). Torasemide 10 to 20 mg/day was
A double-blind, randomised trial in 66 patients
associated with a decrease in bodyweight of 1.4 to
with chronic CHF (NYHA class II to III) has dem- 3.9% after 1 to 6 weeks' treatment, compared with
onstrated the efficacy of oral torasemide 5 to 20 a decrease of up to 1.9% with furosemide 40
mg/day against placebo (data on file[l7l). Mean de- mg/dayJ68,69, 71 1 In one of these studies[ 69 l all pa-
crease in body weight from baseline was 0.21kg af- tients had been maintained on furosemide 40
ter 7 days' placebo treatment, compared with de- mg/day for at least 2 weeks prior to randomisation,
creases of 0.82 to 1.75kg after torasemide 5 to 20 and 61 % were receiving concomitant therapy with
mg/day. Severity of oedema decreased to a signif- cardiac glycosides; in another,[ 71 l patients had re-
© Adis International limited. All rights reserved. Drugs 49 (1) 1995

ceived furosemide 40 mg/day for at least 1 week uresis in patients with ARF in a small (n = 24)
prior to inclusion. Torasemide 5 to 10 mg/day and double-blind study (data on file[77]).
furosemide 40 mg/day decreased pre-existing oe-
2.3.2 Chronic Renal Failure
dema, pulmonary congestion and cardiac enlarge-
Clinical studies have indicated orally adminis-
ment to a similar extent;[69,70] these observations
tered torasemide 200 to 400 mg/day and furose-
are concordant with those of studies previously re-
mide 250 to 1000 mg/day to be of comparable ef-
viewed in Drugs,c6S,72] whereas at the higher dos-
ficacy in increasing urine volume and natriuresis
age of 20 mg/day, torasemide produced a signifi-
in patients with chronic renal failure. In contrast to
cantly greater reduction in pre-existing oedema
furosemide, torasemide did not affect the rate of
than furosemide 40 mg/day[69]. Studies comparing
urinary calcium excretion or plasma renin activity
high intravenous doses of torasemide with other
at any dosageJ78,79] Additionally, torasemide 50 to
loop diuretics in the management of acute cardiac
200 mg/day has been shown to be at least as effec-
failure have yet to be performed, as have trials
tive as furosemide 125 to 500 mg/day in reducing
comparing torasemide with oral agents other than
interdialysis weight gain and increasing water, so-
furosemide and with oral furosemide at dosages
dium and chloride excretion in patients with ad-
greater than 40 mg/day.
vanced renal disease[SO,Sl] (reviewed by Friedel
and Buckley[l]).
2.3 Use in Renal Failure Patients who require haemodialysis may benefit
from therapy with loop diuretics if they have a re-
High dose loop diuretics are the drugs of choice sidual urine output of 200 to 500 ml/day; urinary
in the management of both acute and chronic renal output can be increased, thus permitting an in-
failure, promoting negative sodium and water bal- crease in fluid intake and a consequent improve-
ance and alleviating hypertensionJ73,74] In con- ment in quality of lifeV 4] Interim data (14-week)
trast to the other loop diuretics, the plasma elimina- presented by Schulz et al,csO] showed oral torasem-
tion half-life and duration of action of torasemide ide 200 mg/day to cause an increase urinary vol-
are not dependent on renal function, and accumu- ume, sodium and chloride excretion which was of
lation of the parent compound does not occur in greater clinical significance than that seen with
patients with renal failure,c74] oral furosemide 500 mg/day or placebo. Published
results of the second phase of this trial (reported at
2.3. 1 Acute Renal Failure
week 26) showed no significant change in pre-
Acute renal failure (ARF) is characterised by a
dialytic body weight for any of the treatment
rapid deterioration in renal function resulting from
groups, but a decrease in mean sitting predialytic
severe hypoperfusion of the kidney (ischaemic
blood pressure (from 157/83 to 147/8lmm Hg)
ARF), or the effect of nephrotoxic substances
was observed in the torasemide group only)73]
(toxic ARF). High intravenous dosages of loop di-
Maintenance of neurological status noted in the in-
uretics are used to convert oliguric ARF into the
terim report was sustained to week 26 in all treat-
prognostically better, easier to manage, polyuric
ment groups . .Furthermore, Schulz et alJsO] re-
formJ75] Torasemide 250 mg/day administered in-
ported that torasemide 100 mg/day was at least as
travenously for 4 to 13 days induced a clinically
effective as furosemide 250 mg/day in reducing
significant diuresis in 5 of 6 patients (mean in-
interdialysis weight gain following 4 weeks' oral
crease in urine output of 1780 ml/day), but failed
to improve renal function (in terms of reduced se- treatment of 44 patients with chronic renal failure.
rum creatinine concentrations) in a series of case 2.3.3 Nephrotic Syndrome
studies of patients with oliguric ARFJ76] Torasem- Nephrotic syndrome is characterised by a se-
ide 400 to 800mg has also shown similar clinical vere, prolonged increase in glomerular permeabil-
efficacy to furosemide 1000mg in increasing di- ity to protein. The resulting proteinuria may cause

134 Dunn et al.
82 a dosage of torasemide 5 mg/day plus spironolac-

25
tone 50 mg/day, increasing to torasemide 20
. i
80
o ii 20 mg/day plus spironolactone 200 mg/day where
Oi
C
78 (I)
necessary over 4 weeks. Mean bodyweight de-
.E C
'"
'iii
15 .!l! clined significantly by 3.2kg over this period, with
0;
~
>.
"tl
76 c. no further change over a subsequent 9 weeks' treat-
0 (;
.0 10 ment with a mean dosage of 10 mg/day torasemide
c: 74 0
(b) z
~
'"
Q>
5
plus 100 mg/day spironolactone. Peripheral oe-
72 dema was abolished in 77% of patients by week 13
70 0 (fig. 3).
0 6 12 The apparent efficacy of the low dosage of tor-
Time (weeks) asemide used in this study may have been attribut-
Fig. 3. Mean bodyweight (left axis) of 2 groups of patients with
able to the synergistic effect of spironolactone, al-
nephrotic syndrome during an initial dosage titration period of 4 dosterone antagonists being indicated in nephrotic
to 5 weeks (a) and following a subsequent fixed-dosage period syndrome if secondary hyperaldosteronism is pres-
of 7 to 9 weeks (b): i. 33 patients receiving oral torasemide ~200
mg/day (mean final dosage 66 mg/day)J82] ii. 13 patients receiv-
ent (whether any patients were affected by this is
ing oral torasemide ~20 mg/day + spironolactone 200 mg/day unclear).
(mean final dosage 10 mg/day + 100 mg/day).1831Bars indicate
the number of patients (right axis), from an original sample of
33, free from pre-existing oedema at the study intervals indi- 2,4 Use in Decompensated Liver Cirrhosis
cated after treatment with torasemide ~200 mg/day.[82[
Most patients with hepatic cirrhosis develop so-
dium and water retention, extracellular fluid vol-
hypoalbuminaemia (<30 giL) which lowers the ume expansion, ascites and peripheral oedema. The
oncotic pressure of plasma, giving rise to physiological mechanisms underlying these
generalised oedema. changes are complex and incompletely understood,
Treatment with torasemide 10 to 200 mg/day but current evidence suggests that splanchnic va-
orally for up to 13 weeks reduced bodyweight and sodilation and high portal venous pressure, accom-
peripheral oedema in two nonblind dose titration panied by peripheral vasodilation, result in reduced
studies in patients with nephrotic syndrome.l 82 ,83] effective arterial blood volume. This causes a baro-
In the first study,r82] 33 patients (glomerular filtra- receptor-mediated stimulation of the renin-angio-
tion rate ~30 ml/min) were given torasemide at an tensin system (with a consequent increase in circu-
initial dosage of 10 mg/day, increasing over 5 lating aldosterone) and non osmotic hypersecretion
weeks to up to 200 mg/day in order to maintain a of antidiuretic hormone. Treatment of cirrhotic as-
cites is based on bed rest and dietary sodium re-
mean weight loss of 2 to 5 kg/week. This dosage
striction; if :this fails, aldosterone antagonists are
(mean 66 mg/day) was continued for a further 7
effective in inducing diuresis and natriuresis in
weeks, each patient's fluid intake being maintained
nonazotaemic cirrhotic patients, with the addition
at a constant level throughout. Mean body weight
of a loop or thiazide diuretic where necessary to
decreased by 5.6kg in the first 5 weeks, and by
achieve the desired response (ideally a weight loss
l.lkg over the subsequent 7 weeks; bodyweight of 0.3 to 0.5 kg/day).l84,85]
was reduced by at least 4kg in 61 % of patients, and Torasemide monotherapy reduced body weight
a clinically significant improvement in oedema sta- in a dose-dependent manner when administered at
tus was evident overall (elimination of oedema in dosages of up to 40 mg/day for 3 weeks to patients
61 % of patients). The second study[83] used a com- with hydropic ally decompensated liver failure par-
bination of torasemide and spironolactone in 13 ticipating in a double-blind, randomised dose find-
patients (serum creatinine :::::2 mg/dl), starting with ing study (table IV).l86] Abdominal girth was re-
© Adis International Lirnited. All rights reserved, Drugs 49 (1) 1995

Table IV. Summary of noncomparative and comparative clinical studies of torasemide (T) in the management of hydropically decompensated
liver failure
Reference No. of Study Study Dosage Mean decrease in Overall efficacy

evaluable design duration (mg/day) bodyweight from
patients baseline
(kg)
Torasemide monotherapy
Brunner et al. [86] 36" db, mc, pll, r 3 weeks 5-20c 3.0 Dose-dependent
34b 10-40c 4.3 effect
Torasemide + aldosterone antagonist

Fiaccadori et al. [87] 14 db, pll, r 10 weeks F 50 PO + S 200 PO H T",F
14 T20PO+S200PO H
Gentilini et al. [85]d 7 db, co 4 days F 50· + KCan 200 IV 0.2 T>F
7 4 days T 20· + KCan 200 IV 2.5
Laffi et al. [88] 12 db, r 3 days F 25 PO + KCan 200 IV 1.3 T>F
12 T 10 PO + KCan 200 IV 2.5
Long term study

Knauf & Mutschler[89] 95 nb 6 months T 10-40 POf + S 50-400 9 PO 3.1 Long term
efficacy confirmed
a 9 patients also received spironolactone.
b 3 patients also received spironolactone.
c Week 1: lowest intravenous dosage necessary for satisfactory therapeutic effect in each patient established for each treatment group.
Week 2: above dosage given orally. Week 3: above dosage reduced by half; oral administration continued. Mean dosages at week 3:
group 1 = 8.2 mg/day; group 2 = 16.7 mg/day.
d Crossover trial: patients received first treatment for 4 days, then a 3-day break with no treatment, then second treatment for 4 days.
Potassium canrenoate was coadministered with torasemide to all patients.
e Route of administration not stated.
Mean dosage = t 5 mg/day.
g Pre-existing therapy continued throughout study period.
Abbreviations and symbols: co = crossover; db = double-blind; F = furosemide; KCan = potassium canrenoate; mc = multicentre; nb = non blind;
pll = parallel groups; PO = oral[y; r = randomised; S = spirono[actone;H indicates no statistically significant change; > indicates greater
efficacy; '" indicates equivalent efficacy. Decreases in bodyweight were all statistically significant (p < 0.05).
duced by 3.9% with torasemide 5 to 20 mg/day, Further trials[85,88] have indicated superior effi-
and by 5.9% with torasemide 10 to 40 mg/day; cacy of torasemide 10 to 20 mg/day over furose-
these reductions were considered clinically signif- mide 25 to 50 mg/day, when coadministered with
icant. intravenous potassium canrenoate 200 mg/day for
Previously reviewed studies[90,91] have shown 3 or 4 days in cirrhotic patients showing an inade-
torasemide 10 to 20 mg/day coadministered with quate response (defined as loss of body weight <0.3
spironolactone 100 to 200 mg/day to decrease oe- kg/day) to sodium restriction and bed rest (table
dema, ascites and bodyweight in patients with IV). Intravenous administration of torasemide 10
hydropic ally decompensated liver failure unre- to 20 mg/day plus potassium canrenoate 200
sponsive to sodium and water restriction. When mg/day for 7 days decreased ascites and oedema to
used at the upper end of this dosage range, the com- a greater extent (stated to be clinically significant)
bination of torasemide and spironolactone appears than monotherapy with potassium canrenoate 400
at least as effective as that of furosemide 50 mg/day in a double-blind trial of 30 patients with
mg/day and spironolactone 200 mg/day. hydropicaUy decompensated liver cirrhosis (data

136 Dunn et al.
on file[92]). A double-blind, randomised compari- hearing has, however, been demonstrated in cats
son of torasemide 20 mg/day plus spironolactone receiving doses of up to 32 mg/kg torasemide[9S]
200 mg/day and furosemide 50 mg/day plus spiro- [toxic dose causing defined hearing loss in 50% of
nolactone 200 mg/day, however, showed no signif- animals (TDso) = 20.8 mg/kg].
icant effect on bodyweight after 10 weeks' treat- Single oral doses of torasemide 20 to 100mg and
ment for either combination (table IV)J87] This intravenous doses of torasemide of 20 to 80mg
may be attributed to the sole inclusion in this study were associated with statistically significant in-
of patients previously satisfactorily controlled with creases in serum uric acid levels in healthy volun-
aldosterone antagonists and the loop diuretics fu- teers;[4] increased serum uric acid[6,96] and serum
rosemide and muzolimine. triglyceride levels[96] have also been noted follow-
The long term clinical efficacy of torasemide in ing oral administration of torasemide 40 mg/day
liver failure has yet to be clearly established. How- for 3 weeks. Torasemide does not appear to affect
ever, addition of torasemide 10 to 40 mg/day to blood glucose levels,l56,60,70] serum uric acid con-
pre-existing therapy with spironolactone 50 to 400 centrations, or serum potassium levels at dosages
mg/day produced a statistically significant reduc- below 5 mg/dayJS6,60]
tion in bodyweight after 6 months, with improve-
ment of ascites and oedema in 73% and 67% of 4. Drug Interactions
patients, respectively. [89]
Administration of probenecid 1 g/day for 3 days
3. Tolerability before a single intravenous dose of torasemide
20mg significantly reduced urinary volume excre-
As previously reported in Drugs,D] adverse ef- tion and natriuresis, and increased the elimination
fects observed during treatment with torasemide half-life of torasemide by 34.5%, relative to tor-
are usually mild and transient in nature and include asemide administered aloneJ9] Probenecid is
fatigue, dizziness, headache, muscle cramps, lower known to block the active renal tubular secretion
back pain, skin rash, nausea and orthostatic hypo- of loop diuretics, and these data imply that the di-
tensionJ14,68,80,82,93] Cumulative 4-week adverse uretic response to torasemide is determined by lu-
event rates (the cumulative number of patients ex- minal concentration of the drug. Nonsteroidal anti-
periencing at least 1 adverse event expressed as a inflammatory drugs are known to decrease the
percentage of the total number of patients), deter- diuretic and natriuretic response to loop diuretics
mined by analysis of pooled clinical trial data (dos- (possibly by inhibiting renal prostaglandin synthe-
ages not specified), were 9.1 % for placebo and sis, and thus preventing the stimulation of plasma
24.8% for hydrochlorothiazide plus potassium- renin activity usually seen with loop diuretics)J28]
sparing diuretic combinations in patients with hy- Pretreatment with indomethacin abolished the nor-
pertension, and 14.6% for furosemide in patients mally expected increases in plasma renin activity
with CHF; these figures compared with an overall and angiotensin II levels, but did not affect urinary
(mean) rate of 10% for torasemide (data on volume or sodium excretion following intravenous
file[94]). Other adverse effects noted after 48 administration of torasemide 20mgJ28] Further
weeks' therapy with oral torasemide 2.5 to 5 data, however, indicate that indomethacin pretreat-
mg/day, [S6] included pruritus, paraesthesia and ment (150 mg/day) can reduce the diuretic and na-
chest pain (each in 1 of 98 patients). Withdrawal triuretic effects of torasemide (single doses of 10
from treatment due to torasemide-related drug re- to 20mg) in healthy volunteers who have been
actions is seldom necessaryJS] maintained on a sodium-restricted diet «50
Oral dosages of torasemide up to 400 mg/day mEq/day)J29]
for 28 days have not shown any evidence of oto- No pharmacokinetic interactions have been re-
toxicity in humansJ78] Temporary impairment of ported following coadministration of torasemide

with digoxin,[97] spironolactone (data on file[98]) natriuresis has recently been reported to be 50mg
or the p-adrenoreceptor antagonist carvedilol (data in patients with moderate chronic renal failure
on file[99]). Inhibition or induction of the micro- (creatinine clearance 30 to 60 ml/min), and 100mg
somal enzymes of the cytochrome P450 system in patients with severe chronic renal failure «30
may be a theoretical source of drug interactions ml/min)].[102] No dosage adjustment appears nec-
with torasemide, but 3 days' pretreatment with ci- essary in patients undergoing haemofiltration or
metidine 1.2 g/day had no effect on the pharmaco- haemodialysis.l 103 ] High intravenous dosages of
kinetic or pharmacodynamic properties of single torasemide (up to 800 mg/day) appear to be effec-
lOmg oral doses of torasemide.l lOO ] tive in converting oliguric acute renal failure to the
Torasemide was reported not to interfere with polyuric form.
warfarin binding to plasma proteins in vitro,[71]
and torasemide 20 mg/day for 1 week failed to in- 6. Place of Torasemide in Therapy
teract with phenprocoumon therapy in 24 patients
with CHFJ71] Preliminary animal data, however, Torasemide appears to be at least as effective as
have shown reduced bioavailability of radio- furosemide in terms of its diuretic and saluretic
labelled torasemide following coadministration of activity; both drugs have a rapid onset of action
the cholesterol-binding agent cholestyramine (data when given intravenously, but torasemide pro-
on file[lOl]). . duces a more prolonged water and electrolyte ex-
cretion, and has a less pronounced kaliuretic effect
5. Dosage and Administration than furosemide. Thus, at doses below 5mg tor-
asemide does not appear to increase urinary potas-
An initial oral dosage of torasemide 2.5 mg/day sium excretion, while at dosages of up to 10
is recommended for the management of mild to mg/day it produces only a transient (1 week)
moderate essential hypertension; this may be in- kaliuresis. Torasemide has a lower propensity to
creased to 5 mg/day if a satisfactory response is not cause metabolic disturbance than the conventional
obtained after 12 weeks' treatment.l 13 ] dosages of thiazide diuretics used in hypertension,
A starting oral dosage of torasemide 5 mg/day, and does not alter carbohydrate or lipid metabo-
increasing to 20 mg/day, is recommended for pa- lism at dosages below 5 mg/day.
tients with chronic CHF. Oedema secondary to Low dosages of torasemide (2.5 to 5 mg/day)
CHF or hepatic dysfunction may be treated with possess antihypertensive efficacy equivalent to
intravenous torasemide 10 to 20 mg/day (the max- that of combinations of thiazides and potassium-
imum recommended dosage being 40 mg/day). sparing agents. Subdiuretic dosages of torasemide
Oral torasemide 5 to 40 mg/day may also be used may therefore be used to reduce blood pressure
in conjunction with an aldosterone antagonist such without producing orthostatic symptoms, metabo-
as spironolactone for the management of ascites lic disturbance or increased kaliuresis in patients
secondary to hepatic cirrhosis (sufficient time with mild to moderate essential hypertension. It
should be allowed for the maximal response to the has, however, been suggested[104,105] that dosages
aldosterone antagonist to be achieved before ad- of thiazide diuretics traditionally recommended
ministering torasemide, in order to avoid severe for the treatment of hypertension may be higher
electrolyte imbalance). Dosages of torasemide up than necessary, and data are available[105-107]
to 100 mg/day, coadministered with an aldosterone which indicate that low dosages of these drugs con-
antagonist, may also be effective in controlling oe- trol blood pressure without causing the metabolic
dema secondary to nephrotic syndrome. changes and adverse reactions that have been asso-
Intravenous administration of torasemide 20 to ciated with their use at conventional dosages. Fur-
200 mg/day is recommended in advanced chronic thermore, the clinical significance of these bio-
renal failure [although the dose ceiling in terms of chemical changes has been questioned in the

138 Dunn et al.
literature.[108] Therefore torasemide, in common are currently unavailable. Well controlled clinical
with low dose thiazides, would appear to confer studies are required to compare the efficacy of tor-
metabolic advantages in the management of mild asemide against dosages of furosemide greater than
to moderate essential hypertension. 40 mg/day in chronic CHF, and published data
Monotherapy with torasemide is effective in the comparing torasemide with loop diuretics other
management of CHF, reducing both clinical symp- than furosemide in all oedematous conditions are
toms and haemodynamic parameters of cardiac also lacking. A wide range of cardiovascular drugs,
workload. The clinical efficacy of torasemide has in addition to those mentioned in this review, is
been demonstrated for up to 11 months in this in- available for the management of the conditions dis-
dication, and in comparative trials, torasemide 20 cussed; it is expected that relevant comparative
mg/day appeared superior to furosemide 40 clinical data will become available as experience
mg/day. These properties, together with the potas- with torasemide develops.
sium-neutral nature of torasemide relative to equi- In summary, currently available clinical data in-
potent diuretic doses of furosemide, make torasem- dicate torasemide to be an effective agent in the
ide a useful alternative to furosemide in the treatment of mild to moderate hypertension, CHF,
treatment of CHF. acute and chronic renal failure, nephrotic syn-
In patients with chronic renal failure torasemide drome and cirrhotic ascites. Torasemide appears at
has demonstrated clinical efficacy equivalent to least as effective as other diuretic treatments dis-
cussed, with potential advantages in terms of its
that of equipotent diuretic doses of furosemide,
duration of action, bioavailability and metabolic
while lacking the latter's effects on calciuresis and
effects. Further clinical studies are needed to estab-
plasma renin activity. Torasemide may also be used
lish more fully the long term efficacy and tolerabil-
in the management of severe oedema associated
ity of torasemide, and to define its positioning rel-
with nephrotic syndrome and ascitic cirrhosis of
ative to a wider range of treatments.
the liver. Coadministration of torasemide with an
aldosterone antagonist is at least as effective as
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New York: Gustav Fischer Verlag, 1990: 39-46 Correspondence: Christopher J. Dunn, Adis International
98. von Mollendorff E, Kaufmann B. Study of possible kinetic in- Limited,41 Centorian Drive, Private Bag 65901, Mairangi
teractions after administration of torasemide and spironolac- Bay, Auckland 10, New Zealand.
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DRUG EVALUATION Drugs 49 (1): 121-142,1995

© Adis International Limited. All rights reserved.

Various sections of the manuscript reviewed by:

4. Drug Interactions . . . . . . . . . 136

© Adis International Limited. All rights reserved. Drugs 49 (1) 1995

© Adis International Limited. All rights reserved. Drugs 49 (1) 1995

torasemide at the subdiuretic dosage of 2.5 mg/day normalised diastolic blood

© Adis International Limited, All rights reserved, Drugs 49 (1) 1995

1.1 Effects on Electrolyte and Water

A linear relationship has been observed between

© Adis International Lirnited. All rights reserved. Drugs 49 (1) 1995

and the logarithm of torasemide dose in healthy 60

transient increases in plasma calcium and magne- Time (h)

© Adis International Lirnited. All rights reserved. Drugs 49 (1) 1995

© Adis International Limited. All rights reserved. Drugs 49 (1) 1995

© Adis International Lirnited. All rights reserved. Drugs 49 (1) 1995

Pharmacokinetic parameters of major metabolites of torasemide (M1, M3 and MS)C

© Adis International Limited. All rights reserved. Drugs 49 (1) 1995

© Adis International Limited. All rights reserved. Drugs 49 (1) 1995

© Adis International Limited, All rights reserved. Drugs 49 (1) 1995

Stauch & Stiehl[72] 34 db, mc, pll, r 4 weeks T5 NAh 94 T= Fb

© Adis International limited. All rights reserved. Drugs 49 (1) 1995

© Adis International Limited. All rights reserved. Drugs 49 (1) 1995

82 a dosage of torasemide 5 mg/day plus spironolac-

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Reference No. of Study Study Dosage Mean decrease in Overall efficacy

Torasemide + aldosterone antagonist

Long term study

© Adis International Limited. All rights reserved. Drugs 49 (1) 1995

© Adis International Lirnited. All rights reserved. Drugs 49 (1) 1995

© Adis International Limited. All rights reserved. Drugs 49 (1) 1995

© Adis International Limited. All rights reserved. Drugs 49 (1) 1995

© Adis International Limited. All rights reserved. Drugs 49 (1) 1995

© Adis International Limited. All rights reserved. Drugs 49 (l) 1995

© Adis International Limited. All rights reserved. Drugs 49 (1) 1995

© Adis International Lirnited. All rights reserved. Drugs 49 (l) 1995

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