Toxic epidermal necrolysis associated with combination therapy of spironolactone and torsemide
Melcy Mary Philip 1*, Kala Kesavan P 1,
Jai Prakash 2
1*Patient safety pharmacovigilance Associate, Govt.
TD Medical College, Vandanam, Alappuzha, Kerala, 688005, India
1HOD, Department of pharmacology, Govt Medical College, Vandanam, Alappuzha,Kerala , India
2Senior Principal
Scientific Officer, Indian Pharmacopoeia Commission, Ghaziabad, U.P.
Web of
Science Researcher ID: NA
ORCID
ID: NA
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Abstract |
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Date Received: 05/08/2020 Date Revised: 20/08/2020 Date Accepted: 24/08/2020 |
Dytor plus tablet is a fixed-dose combination of Torsemide and
Spironolactone used for generalized edema. TEN is a serious, potentially life-threatening dermatological disorder. Here we present a case report of a
47-year-old female who was on Dytor Plus (5/50 mg)therapy once daily for
generalized edema; presented to dermatology outpatient department with a chief
complaints of multiple erosions over oral cavity, swelling of lips with
scaling, redness, and burning sensation in both eyes, multiple well defined
mostly erythematous rashes over the entire body for 2 days .on examination,
her vital signs were stable and lab result indicates she had elevated SGOT(140
IU/L), SGPT (228 IU/L), ALP (162IU/L) and blood urea(47 mg/ml) values. The patient was diagnosed to have developed Dytor plus induced toxic epidermal
necrolysis. Discontinued the medicine and prescribed with Dexamethasone
injection, IgG Injection, Cefotaxime injection, Cloxacilline capsule,
Cetirizine tablet, Hydroxypropyl methylcellulose eye drop, and candid mouth
paint. The patient had a hospital stay of 25 days. The patient improved
symptomatically. Causality was assessed as per the WHO-UMC causality scale
and this case was put in the probable category. This case was uploaded via
vigiflow under the pharmacovigilance programme of India having report Id
2019-30695.
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Keywords Dytor
plus tablet, TEN, toxic epidermal necrolysis, erythematous rash,
Pharmacovigilance
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COPYRIGHT © 2020 JPADR |
Introduction
Toxic epidermal necrolysis (TEN) is a rare, more severe dermatological drug reaction as compared to a stevens-johnson syndrome which is less severe. The main symptoms are severe skin peeling and blistering that progresses quickly, resulting in large raw areas that may ooze or weep (Goodmann et al., 2008). Dytor Plus 5mg Tablet is a combination of two medicines Spironolactone (50mg) + Torsemide (5mg) used to treat edema (fluid overload) and reduce excess fluid levels in the body while maintaining the potassium balance. Dehydration is a very common side effect as well as it lowers down the level of calcium, sodium, and magnesium in the blood. Sometimes it causes dizziness or tiredness
Generally, Oedema associated with nephrotic syndrome was
treated with torsemide 100 mg co-administered with an aldosterone antagonist.
No pharmacokinetic interactions have been reported following coadministration
of torsemide with digoxin, spironolactone, carvedilol, or cimetidine (Joseph et al., 2003). Short-term studies have shown that orally administered torsemide 5 to 20 mg/day decreases the severity of edema and mean bodyweight to a greater extent than
placebo or furosemide 40 mg in patients with chronic CHF. Torsemide 20 mg/day
also achieved a greater reduction in pre-existing edema 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 torsemide 5 to 20 mg/day. Both
torsemide 10 to 200 mg/day as monotherapy, and torsemide 5 to 20 mg/day plus
spironolactone 50 to 200 mg/day, significantly reduced body weight and
peripheral edema after up to 13 weeks of treatment in
patients with nephrotic syndrome.
Torsemide 10 to 20 mg/day coadministered with spironolactone 100 to 200 mg/day
effectively reduced edema, ascites, and body weight in these patients. Torsemide
10 to 20 mg/day plus potassium canrenoate 200 mg/day decreased ascites and
edema in cirrhotic patients to a greater extent than either monotherapy with
potassium canrenoate 400 mg/day for up to 7 days, or furosemide 25 to 50 mg/day
plus potassium canrenoate 200 mg/day for 3 to 4 days. Addition of torsemide 10
to 40 mg/day to pre-existing therapy with spironolactone 50 to 400 mg/day
improved ascites and edema in 73 % and 67 % of patients, respectively, after 6
months of treatment (Dunn
et al., 1995).
Case Study
Dytor plus tablet is a fixed-dose combination of
torsemide (which is a loop diuretic) and spironolactone (which is an antagonist
of aldosterone). A 47 years old female patient was suffering from edema and
started a combination therapy of torsemide(5mg) and spironolactone (50 mg) with
a dosage regimen of once a day. There was no history of any concomitant
medication. The patient suffered from a serious adverse event and reported
after a couple of days at the department of dermatology outdoor, with chief
complaints of multiple erosions over oral cavity, swelling of lips with
scaling, redness and burning sensation in both eyes, multiple well defined
mostly erythematous rashes over the entire body. The patient underwent a laboratory test and it was observed that her vital signs were stable and lab
result indicated that she had elevated SGOT(140 IU/L), SGPT(228 IU/L), ALP (162
IU/L) and blood urea (47 mg/ml) values. The patient was diagnosed to have
developed drug-induced toxic epidermal necrolysis. The suspected drug dytor
plus was withdrawn on the same date and the patient was treated medically with
dexamethasone injection, IgG Injection, cefotaxime injection, cloxacillin
capsule, cetirizine tablet, Hydroxypropyl methylcellulose eye drop, and candid
mouth paint. The patient was getting admitted to the hospital resulting in the
adverse event to be considered as a serious adverse drug reaction. The patient had a hospital stay of 25 days.
The patient improved symptomatically. Causality was assessed as per the WHO-UMC
causality scale and this case was put in the probable category as the
de-challenge test resulted in improving the health condition of the patient.
This case was reported to the National coordination center through vigiflow
having a report Id 2019-30695.
Discussion
The
majority of adverse effects associated with spironolactone are dose-dependent.
Higher dose therapy using more than100 mg/day is more likely to cause
hyperkalemia, particularly when there is a cardiac or renal compromise. Other
dose-dependent side effects include menstrual irregularities (metrorrhagia,
amenorrhea, breakthrough bleeding), breast tenderness and enlargement,
orthostatic hypotension, hyperkalemia, and reduced libido (Kim et al., 2012).
A case has been reported for 80 years old man who was
treated with spironolactone for the management of heart failure, his prostate cancer was exaggerated. After 2 weeks
of spironolactone withdrawal, the patient returned to his previous condition.
This indicates that spironolactone is a selective androgen receptor modulator.
Hence, spironolactone should be used in caution with men with prostate cancer,
and should not be used to treat edema (Sundar
et al., 2012).
A drug surveillance program
had been conducted on 13,349 patients treated with spironolactone resulted in
adverse events in 164 patients. Hyperkalemia has mostly occurred in 68 patients
and an increased level of blood urea nitrogen in 161 patients. Other adverse
reactions such as dehydration, hyponatremia, gastrointestinal symptoms,
neurological disturbances, and skin rashes were less common (Greenblatt
et al., 1973).
The most common adverse
reaction in women taking spironolactone was hyperkalemia but it was extremely
uncommon in women age less than 45 years (1.9 % of all hyperkalemia cases).
Increased Google searches and scholarly mentions in the Altmetric database for
spironolactone was also associated with increased reporting of adverse events
in the FAERS database for men and women combined (Wang et al., 2020).
A 28-year-old female patient suffering from Acne for 5 years was prescribed 100 mg spironolactone once daily for
a month. Within 30 min following the consumption of spironolactone, the patient
developed intense pruritus, conjunctivitis, angioedema, skin rash. The patient
recovered from the adverse event in 3 days of medical treatment with 10 mg of
cetirizine hydrochloride and 20 mg of prednisolone (Mehta et al.,
2016).
A study indicated that the rash was a very rare adverse reaction associated with torasemide.
Only around 3 % of the 1,048 medicines analyzed developed rashes (Robert et al., 2019).
Torsemide, a potent loop diuretic of the sulfonylurea
class resulted in a photosensitive lichenoid reaction in an 82 years old male
patient. Adverse generalized and cutaneous reactions to this medication are
uncommon and are usually mild and transient. Because of the potential risk for
cross-reactivity of torsemide with the sulfonamide group of medications,
torsemide should be used cautiously in sulfonamide hypersensitive patients (David et
al., 1997).
Conclusions
We report the first case of
toxic epidermal necrolysis associated with combination therapy of spironolactone and torsemide.
which helps to further demonstrate a possible link between diuretics uses while
treatment of edema. Though it could not be confirmed that the adverse event has
a causal relationship with the drug but still it cannot be ruled out that it
cannot cause such adverse events in the future. Hence the patient should be
taken care of properly with close monitoring to observe the symptoms and
protect from any such adverse drug reaction.
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