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Clinical
Pharmacology
"Adverse Drug
Event of the month"
| Month
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September
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| Year
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2003 |
Probable Gatifloxacin induced erythema
multiforme
A 47 year old female patient presented to the dermatology outpatient
department (OPD) of our institute with an erythematous rash of 10 days
duration. She gave a history of fever for 15 days for which she was
treated with Gatifloxacin 400 mg twice a day for 2 days by the her general
practitioner (In the present paper, Day 1 is taken as the day of start
of gatifloxacin). Subsequently, her general practitioner reduced the
dose of Gatifloxacin to 200 mg once daily on day 3 and asked her to
stop treatment. He also advised her to take Paracetamol ( 1 tablet of
500mg) as and when she got fever. The patient took 2 tablets of Paracetamol
on Day 1 only, and did not subsequently take it. She gave a history
of hypertension since 1993 for which she was taking a combination of
atenolol (50mg) and lisinopril (5mg). On Day 7, she developed red, pruritic,
raised lesions on the back along with headache. For this, she was treated
with Tab Dexamethasone (0.5mg) QID for 3 days by the same general practitioner.
The rash progressed despite symptomatic treatment with central discoloration.
She presented to our institute on Day 16 with multiple non pruritic
red raised lesions on the face, trunk and extremities. On examination,
the patient had well defined edematous erythematous plaques measuring
about 1cm - 2cm in diameter distributed over the malar region, forehead,
neck, upper back, chest and upper extremities. There were few erythematous
papules and targetoid lesions symmetrically distributed over the distal
aspects of both extremities including the palms and soles. Deep dermal
tenderness was positive. Based on these findings the rash was diagnosed
as erythema multiforme and the patient was hospitalized. Treatment was
initiated with Tab. Prednisolone (40 mg) once a day, Injection tetanus
toxoid, 0.5 cc intramuscularly, Tab. Chlorpheniramine maleate (4 mg)
thrice a day, calamine lotion for local application, and oral KMnO4
gargles. The anti-hypertensive medications were continued. Biochemical
investigations showed Glucose ®: 119.0, urea nitrogen: 20.0mg %, creatinine:
2.0mg% and Na+/K+: 134/3.6. Patient's rash subsided slowly and she made
an uneventful recovery. She was discharged on Day 19.
Erythema multiforme is an immune mediated disorder due to various aetiological
factors like infections, drugs, radiation therapy and underlying malignancy.
The disease presents clinically with polymorphic lesions like erythematous
macules, papules, plaque, vesicles and bullae. The 'target' or 'iris'
lesion is typical and is characterized by dusky red centre, sometimes
topped with a vesicle or crust, surrounded by a pale edematous zone
and peripheral bright red rings giving a bulls eye appearance. The lesions
are predilected to distal extremities with involvement of palms and
soles. One or more mucous membranes may be involved. In the above case,
we attributed a cause effect relationship of erythema multiforme to
Gatifloxacin in view of the temporal relationship with the drugs (onset
4 days after stopping Gatifloxacin), and the exceeding of the therapeutic
dose due to irrational use of the drug (Odom R.B. et al, 2000). Using
the Naranjao's Adverse drug reactions (ADR) probability scale we made
a causality assessment which categorized this reaction as probable (a
score of 5 was obtained). The Naranjo's algorithm categories adverse
reactions as definite (score > 9), probable (score between 5-8), possible
(1-4) and doubtful (< 1). (Naranjo C.A.et al, 1981). The adverse event
was not attributed to either paracetamol or the anti-hypertensive medications
since the patient had taken them in the past without any adverse events.
Fluoroquinolones as a class have been available for the last two decades
and have been found to be generally well tolerated and safe. Adverse
events due to fluoroquinolones are either inherent to the class or influenced
by structural modifications. The commonest adverse events are gastrointestinal
(GI) and central nervous system (CNS) reactions; nephrotoxicity and
tendonitis are infrequent, but agents differ greatly in phototoxic potential.
Because of possible effects on articular cartilage, they are not currently
recommended for children or pregnant women (Lipsky B.A.et al, 1999)
Gatifloxacin is a new 8-methoxyfluoroquinolone antimicrobial and has
an extended spectrum of antimicrobial activity. It was approved for
use in the United states in 1999 and was introduced in India in October
2001. Gatifloxacin is available in both oral and injectable forms and
is administered once daily. The drug is not indicated for use in undiagnosed
fevers and is used specifically for the treatment of urinary tract infections,
gonorrhoea, and community acquired pneumonias. The commonly seen adverse
events with the drug are nausea, diarrhea, headache and dizziness. It
has not been shown to produce phototoxic effects at therapeutic doses
(Perry C.M. et. al, 1999)
A number of fluoroquinolone analogues have been withdrawn from the market
or their development discontinued because of serious adverse reactions.
They are as follows: Flerofloxacin (1990; Phototoxicity), Temafloxacin
(1992; hypoglycemia, hepatic and renal dysfunction, haemolytic anaemia
and anaphylaxis), Grepafloxacin (1999, Prolongation of QTc interval),
trovafloxacin (1999; serious liver toxicity), Sparfloxacin (2001; from
US market; Phototoxicity). Recently, the labeling of moxifloxacin, gatifloxacin
and levofloxacin has been modified to add a warning about potential
prolongation of the QTc interval and disturbances of blood glucose (only
for Gatifloxacin) (Leone R. et.al., 2003) Physicians should be aware
of the potential of fluoroquinolones to produce skin reactions including
erythema multiforme. In addition, drugs such as gatifloxacin should
be used judiciously, i.e, only when indicated and when the benefits
outweigh risks.
The relation of adverse events to the structure is given in the figure
below: (To view the figure click on the following link)
Quinolone & fluroroquinolone structure: adverse event relationship
[3]
Structure
of Gatifloxacin
Adverse event reported by:
Department of Dermatology,
Seth GS Medical college,
KEM Hospital, Parel,
Mumbai- 400012,
India
Manscript prepared by:
MS Aroskar, NJ Gogtay, SP Waingankar & NA Kshirsagar
Department of Clinical pharmacology
DCGI Centre for ADR Monitoring
WHO Special Centre
Seth GS Medical College & KEM Hospital Parel,
Mumbai- 400012,
India
&
VV Janawade & US Khopkar
Department of Dermatology
Seth GS Medical College & KEM Hospital Parel,
Mumbai- 400012,
India
References:
1. Lipsky B.A.& Baker C.A. (1999). Fluoroquinolone toxicity profile:
A review focusing on newer agents. Clinical Infectious Diseases, 28:
352-364.
2. Perry C.M., Balfour J.A. & Lamb H.M. (1999). Gatifloxacin.Drugs,
58: 683-696.
3. Naranjo C.A., Busto U., Seller E.M., Sandor P., Ruiz
I., Roberts E.A., Janecek E., Domecq C. & Greenblatt D.J. (1981). A
method for estimating the probability of adverse drug reaction. Clinical
Pharmacology & Therapeutics, 30: 239-245.
4.Odom R.B., James W.D. & Berger T.G. (2000). Erythema Multiforme. In:
Andrew's Diseases of skin, 9th edition, Ellen B. G. (ed.), USA, pp.
147-151
5. Leone R., Venegoni M., Motola D., Moretti U., Piazzetta V., Cocci
A., Mozzo F., Velo G., Burzilleri L., Montanaro N. & Conforti A. (2003).
Adverse drug reactions related to the use of fluoroquinolone antimicrobial.
Drug Safety, 26: 109-120
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