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Potentially serious Lamotrigine-related skin rash
Mohammed M. Jan, MBChB, FRCP(C).
ABSTRACT
Lamotrigine (LTG) is a new antiepileptic drug (AED), which has a broad spectrum of antiepileptic properties.1 It works on voltage gated sodium channels, Objective: To report our experience with lamotrigine
thereby stabilizing the neuronal membrane and (LTG)-related skin rash in children with epilepsy.
inhibiting the release of excitatory neurotransmitters Methods: We identified a series of consecutive children
such as glutamate and aspartate.2 Multiple randomized, with epilepsy treated with LTG prospectively over a 5- placebo-control ed and comparative studies demonstrated year period ending 1st October 2005 at King Abdul-Aziz LTG efficacy in partial and generalized pediatric University Hospital and King Faisal Specialist Hospital epilepsy.1,2 Open label trials also documented its and Research Center, Jeddah, Kingdom of Saudi efficacy against infantile spasms, absence and juvenile myoclonic epilepsy.3 Co-administration of valproic acid Results: Of 207 children on LTG, 15 (7.2%) developed
(VPA) and LTG has a synergistic effect with enhanced a skin rash with ages ranging between 3-12 years (mean antiepileptic properties.4 We found this combination 7.5). We used LTG as monotherapy in 3/15 and as add most effective in intractable epilepsy, such as that seen on in 12/15, mostly (10/15) in addition to valproic acid in Lennox-Gastaut syndrome.5 Children may not (VPA). The rash was mild with complete recovery in 7 respond to VPA or LTG as monotherapy or with other children (47%). The remaining 8 (3.9% of the total) AED combinations, however, when used together they had severe rash that necessitated admission to hospital. can result in remarkable seizure control.4,5 Lamotrigine Seven out of these 8 children were also receiving VPA. One child had superimposed secondary bacterial is wel tolerated and most side effects are related to infection and admitted for intravenous antibiotics. the CNS including headache, somnolence, nausea, Two children recovered slowly with extensive post- dizziness, diplopia, ataxia, and insomnia.6 The main inflammatory hyperpigmentation. We diagnosed serious adverse event associated with LTG treatment is a Stevens-Johnson syndrome in 5 children (2.4% of the hypersensitivity reaction primarily presenting as a rash, total). One of these 5 children had progressive symptoms which affects 8-20% of patients.7-10 The occurrence and that evolved to toxic epidermal necrolysis. He required severity of this idiosyncratic, immune-mediated rash prolonged intensive care admission and developed sepsis with disseminated intravascular coagulopathy. are difficult to predict.7,11 If the drug is continued or He deteriorated despite supportive therapy, and died 5 the dose escalated, the rash has a tendency to become weeks after the initiation of LTG therapy. worse.12 Close monitoring of these patients is needed to detect features of Stevens-Johnson syndrome (SJS).13 Conclusions: Lamotrigine is a novel antiepileptic drug
Skin rash is observed in higher proportions of children with a favorable therapeutic profile and good tolerability. on VPA-LTG combination. The risk is higher if LTG However, LTG-related skin rash is a potentially serious was added to a patient already receiving VPA and not adverse event that should be carefully monitored. Although the risk is small, one should weigh this against vice versa. Other risk factors include young age, previous the potential benefits, particularly in children on VPA.
history of hypersensitivity, high LTG starting dose, and rapid titration.10 Fol owing the increased recognition of Neurosciences 2007; Vol. 12 (1): 17-20
serious skin rash, it was recommended that the starting dose should be reduced with gradual dose escalation to From the Department of Pediatrics (Neurology), King Abdul-Aziz University Hospital, Jeddah, Kingdom of Saudi Arabia. In this paper, we report the experience with LTG- Received 12th April 2006. Accepted 15th June 2006. related skin rash in children with epilepsy in view of Address correspondence and reprint request to: Dr. Mohammed M. S. Jan, the updated literature. We hypothesized that based Associate Professor and Consultant of Pediatric Neurology, Department of Pediatrics, King Abdul-Aziz University Hospital, PO Box 80215, on the available pediatric literature, LTG-related skin Jeddah 21589, Kingdom of Saudi Arabia. Tel. +996 (2) 6401000 Ext. rash is potential y serious, particularly when used in 20208. Fax. +996 (2) 6403975. E-mail: mmsjan@yahoo.ca Lamotrigine-related skin rash . Jan Methods. We identified a series of consecutive Results. During the study period, we gave 207
children with epilepsy treated with LTG prospectively children LTG for epilepsy. Most children had tried other over a 5-year period ending the 1st of October, 2005. AEDs with no response. A total of 15 (7.2%) children Patients were identified through referrals to the pediatric developed a skin rash (Table 1). There were 7 males and
neurology services at King Abdul-Aziz University 8 females with ages ranging between 3-12 years (mean Hospital (KAUH) and King Faisal Specialist Hospital 7.5). Four of these children had a previous history and Research center (KFSH&RC), Jeddah, Saudi of hypersensitivity to other AEDs. We used LTG as Arabia. Both are multispecialty adult and pediatric monotherapy in 3/15 and as add on in 12/15, mostly hospitals providing tertiary medical care for most of the (10/15) in addition to VPA therapy. The initial LTG regional population of western Saudi Arabia. Patients dose ranged between 5-25 mg/day (mean 9.5). The rash received LTG as monotherapy or add on for treating developed in the 2nd-4th weak (mean 2.8) after the children with epilepsy. The LTG initial dose was not initiation of LTG. Systemic symptoms were evident in to exceed 25 mg/day or 1.5 mg/kg/day. The dose was 11 (73%) children in the form of malaise, anorexia, fever, doubled every 2 weeks until the minimum effective dose and irritability. The rash was mild with complete recovery was reached (achieving a seizure free outcome) or up to after LTG discontinuation in 7 children (47%). Two of a maximum dose of 10 mg/kg/day (as monotherapy), 5 the 4 children with a previous history of hypersensitivity mg/kg/day (with VPA), or 15 mg/kg/day (with enzyme to other AEDs recovered completely. inducers).15 The risk of drug induced rash was explained Also, 4 out of the 5 children not on concomitant to al parents, who were instructed to stop and seek VPA therapy recovered wel when compared to only medical advice at the first sign of such eruptions. They 3 of the 10 patients on VPA (Table 1). We continued
were warned that the rash could become more severe if LTG in one case (patient 10) as the rash disappeared they do not stop the drug immediately. Fol ow up by spontaneously after dose reduction. The remaining one pediatric neurologist was performed to document 8 (3.9% of the total) had severe rash that necessitated the occurrence of skin rash. The period of fol ow-up admission to hospital for symptomatic therapy. Seven visits were standardized at 2, 4, and 6 weeks after LTG out of these 8 children were also receiving VPA. These introduction. To be included, diffuse erythematous rash children had targetoid lesions with diffuse erythematous should have been recognized 1-4 weeks fol owing LTG maculopapular eruptions. One child (patient 14) had therapy and documented by the treating physician. superimposed secondary bacterial infection and we Patient and disease related data were col ected at the time admitted him for intravenous antibiotic therapy. Two of initial presentation with skin rash. Clinical course and other admitted children recovered slowly with extensive outcome data were also col ected on fol ow-up visit or post-inflammatory cutaneous pigmentary change on fol ow-up. This slowly recovered over a period of few Table 1 - Clinical details of 15 children with Lamotrigine-related skin rash.
Systemic
Other AED
Duration of
symptoms
symptoms
PHB - Phenobarbitone, VPA - Valproic Acid, TPM - Topiramate, CBZ - Carbamazepine, SJS - Stevens-Johnson syndrome, TENS - toxic epidermal necrolysis Lamotrigine-related skin rash . Jan months. We diagnosed SJS in 5 (2.4% of the total) regimen, immediately before and during LTG therapy. children with additional erosions of the conjunctiva, They did not start LTG within 2 weeks of a rash, viral oral, and genital mucosa. One of these 5 children (patient il ness, or vaccination. They also asked their patients 4) had progressive symptoms that evolved to toxic to avoid new medications, new foods, detergents, and epidermal necrolysis (TEN), confirmed by skin biopsy. fabric softeners in the first 3 months of treatment. He required prolonged ICU admission and developed Fol owing these recommendations, skin rash occurred sepsis with disseminated intravascular coagulopathy. He in 5% of their patients.9 Milder maculopapular skin deteriorated despite supportive therapy and died 5 weeks rash beginning within 2 weeks of therapy may disappear spontaneously in some patients, despite the continuation of therapy.13 This is similar to one of our patients where Discussion. The patients described herein the rash disappeared spontaneously after dose reduction.
confirm that LTG-related skin rash is potential y The rash was mild with complete recovery after LTG serious, as approximately 4% of the children required discontinuation in 7 of our 15 children. Recently, some hospitalization, 2.4% had SJS, and one child died authors reported successful rechal enge with LTG after with TEN. In general, children are at increased risk the initial drug-induced rash.7 It is possible that the rash for developing LTG-related skin rash when compared in some of these children was not related to LTG, which to adults.10 Increased liver cytochrome P450 catalyzed explains the successful rechal enge. Reintroducing LTG metabolism could result in increased formation of the in children with history of rash that developed within reactive metabolite and a higher incident of rash.10 In the first 4 weeks of therapy should be taken with extreme addition, children frequently receive higher mg/kg doses caution. Such a child may be sensitized to LTG, which resulting in increased LTG reactive metabolites. We had results in a stronger and severer reaction if LTG is a lower overal incidence of skin rash (7.2%) as compared reintroduced. Of possible relevance is a rare LTG-related to the rate in other studies (8-20%), most likely because lupus case diagnosed in an adult female patient.19 Her of our dosing and slow increment. Other authors used symptoms and lupus serology gradual y normalized after an even lower initial dose (5 mg/day) and much slower drug withdrawal.19 titration by 5 mg every 2 weeks.7,9 The incidence of To conclude, LTG is a novel antiepileptic drug LTG-related skin rash in these studies was 5-6%. Most of with a favorable therapeutic profile. The drug has good our children with severe rash (8/15) were also receiving tolerability; however, skin rash is a potential y serious VPA (7/8), which is similar to other literature reports.16 adverse event that the parents should careful y monitor Valproic acid interferes with the metabolism of LTG by and promptly report to the treating physician. Although inhibiting hepatic glucuronides, leading to increased the risk is smal , we should weigh this against the LTG blood levels.12,16 Therefore, LTG dose should not potential benefits, particularly in children on VPA.
Steven and Johnson described SJS in 1922. The Acknowledgment. I grateful y acknowledge the Pediatric
syndrome includes systemic symptoms (fever) and a Consultants at King Abdul-Aziz University Hospital who participated with their referred patients. I particularly would like to thank Prof. Ali variety of skin and mucous membrane lesions including Shaabat for his support, advice, and guidance. erythematous papules, targetoid lesions, bul ae, and erosions.17 It is a hypersensitivity reaction to infections References
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