lamotrigine is a new , anti - epileptic drug used in the treatment of partial and generalized seizures and maintenance treatment of bipolar i disorder .
common adverse effects of lamotrigine include headache , nausea , vomiting , tremors , anxiety and insomnia .
the major adverse drug reaction leading to lamotrigine discontinuation is skin rash , observed in 3 - 10% of users .
lamotrigine related rashes are mostly simple maculopapular exanthems , observed within first eight weeks of treatment and resolve promptly on withdrawal of the drug .
however , in a small percentage of patients , lamotrigine can cause serious adverse cutaneous reactions like stevens - johnson syndrome and toxic epidermal necrolysis .
we report two cases of toxic epidermal necrolysis resulting from lamotrigine therapy and discuss the risk factors associated with the development of serious reactions , with emphasis on the importance of adhering to the recommended dosage guidelines .
a 47-year - old female presented with fever , oral erosions and blisters all over the body for ten days .
patient was a known epileptic , on valproic acid 300 mg / day since four months .
two weeks prior to onset of symptoms she had been initiated on lamotrigine 50 mg twice daily by her physician .
examination revealed multiple , flat target - like lesions , diffuse erythema , flaccid blisters and erosions over face , trunk and extremities including palms and soles [ figure 1 ] . body surface involvement was around 60% .
the diagnosis of lamotrigine induced toxic epidermal necrolysis was established using the naranjo adverse drug reaction probability scale . patient was admitted to intensive care unit , and lamotrigine and valproic acid were discontinued .
after a tumultuous course in the hospital extending up to 45 days , patient made an eventual recovery but was left with pigmentary changes , nail dystrophy , bilateral ectropion and corneal scarring .
erythematous papules , bullae , erosions and separation of necrotic epidermis a 26 year old female was under treatment with valproic acid 750 mg / day , propranolol 10 mg / day , clomipramine 10 mg / day , and risperidone 2 mg / day for bipolar mood disorder and obsessive compulsive disorder since two years .
four weeks prior to presentation , she had been initiated on lamotrigine at 25 mg / day , which was rapidly increased to 50 mg bd over 2 weeks and 100 mg bd over another 2 weeks , at which time she developed skin rash and oral erosions .
examination revealed a rash typical of toxic epidermal necrolysis with erythematous macules , papules , flaccid blisters , targetoid lesions , and erosions over face , trunk and palms involving around 30% of body surface area [ figure 2 ] .
genital and oral erosions with hemorrhagic crusting over lips and severe conjunctival congestion were observed .
a causality assessment of this adverse event revealed a probable association between lamotrigine and toxic epidermal necrolysis based on the naranjo probability scale .
prednisolone was tapered gradually , and the patient made an uneventful recovery and was discharged .
multiple targetoid lesions , bullae , and erosions on the face and hemorrhagic crusting on the lips antiepileptic drugs are frequently associated with idiosyncratic adverse skin reactions , which are a leading cause of withdrawal of the drug . among the traditional antiepileptic drugs , aromatic compounds like phenytoin , carbamazepine and phenobarbitone
of the nine newer antiepileptics introduced in the past decade , lamotrigine has been most associated with rash , in up to 3 - 10% of users in clinical trials .
most of the rashes with lamotrigine are benign and resolve promptly on discontinuation of treatment .
the incidence of rash due to lamotrigine , associated with hospitalization in clinical trials was three of 1000 in adults ( 0.3% ) and one of 100 in children ( 1% ) .
co - administration of valproic acid with lamotrigine significantly increases the risk for development of serious adverse cutaneous reactions .
the elimination half life of lamotrigine when used as monotherapy is 25 - 30 hours and it is more than doubled to 60 hours when combined with valproic acid . it has also been suggested that a high starting dose and a rapid dose escalation may increase the occurrence of skin rashes with lamotrigine .
the risk of allergic reactions is decreased when treatment is started at a low dose and the doses are increased gradually following the recommended dosage guidelines , possibly because slow titration may allow desensitization to occur .
both of our patients were on valproic acid when lamotrigine was initiated as an add - on therapy .
high starting doses were employed and dose was also rapidly increased in both the cases .
history of a rash attributed to another antiepileptic drug results in a five times greater increase in the rate of an antiepileptic drug rash .
hirsch et al . have concluded that a rash with another antiepileptic drug is the greatest risk factor for developing a rash with lamotrigine . in the first patient
the phenomenon of cross reactivity may be a general feature of patients predisposed to drug rashes .
also a patient with a prior medication related rash would be more vigilant and likely to notice a drug related rash from a new medication .
females have a higher risk for antiepileptic skin reactions compared to males ; probably due to hormonal factors .
a causality assessment using naranjo probability scale was performed in both the patients that revealed a probable association between lamotrigine and toxic epidermal necrolysis in both of the cases .
our second patient was on several medications ( valproic acid , propranolol , clomipramine , risperidone ) since two years .
these drugs have a very low potential for causing serious drug reactions like toxic epidermal necrolysis .
the rates of skin rash with valproic acid are very low as compared to lamotrigine .
thus it is unlikely that they were responsible for causing toxic epidermal necrolysis in the second patient .
the international prescribing guidelines regarding use lamotrigine as an adjunctive treatment with valproic acid , recommend that lamotrigine should be initiated at a dose of 12.5 mg once daily for first two weeks , followed by 25 mg once daily for next two weeks , and increased thereafter by 25 mg every other week until a maintenance dose of 100 - 200 mg daily .
it must be pointed out , however , that serious reactions can occur with recommended dosing and titration schedules , and without concurrent valproic acid .
increased vigilance is thus required when initiating lamotrigine in a patient and treatment should be discontinued if any rash appears . when lamotrigine is prescribed as an adjunctive treatment with valproic acid
a 47-year - old female presented with fever , oral erosions and blisters all over the body for ten days .
patient was a known epileptic , on valproic acid 300 mg / day since four months .
two weeks prior to onset of symptoms she had been initiated on lamotrigine 50 mg twice daily by her physician .
examination revealed multiple , flat target - like lesions , diffuse erythema , flaccid blisters and erosions over face , trunk and extremities including palms and soles [ figure 1 ] . body surface involvement was around 60% .
the diagnosis of lamotrigine induced toxic epidermal necrolysis was established using the naranjo adverse drug reaction probability scale . patient was admitted to intensive care unit , and lamotrigine and valproic acid were discontinued .
after a tumultuous course in the hospital extending up to 45 days , patient made an eventual recovery but was left with pigmentary changes , nail dystrophy , bilateral ectropion and corneal scarring .
a 26 year old female was under treatment with valproic acid 750 mg / day , propranolol 10 mg / day , clomipramine 10 mg / day , and risperidone 2 mg / day for bipolar mood disorder and obsessive compulsive disorder since two years .
four weeks prior to presentation , she had been initiated on lamotrigine at 25 mg / day , which was rapidly increased to 50 mg bd over 2 weeks and 100 mg bd over another 2 weeks , at which time she developed skin rash and oral erosions .
examination revealed a rash typical of toxic epidermal necrolysis with erythematous macules , papules , flaccid blisters , targetoid lesions , and erosions over face , trunk and palms involving around 30% of body surface area [ figure 2 ] .
genital and oral erosions with hemorrhagic crusting over lips and severe conjunctival congestion were observed .
a causality assessment of this adverse event revealed a probable association between lamotrigine and toxic epidermal necrolysis based on the naranjo probability scale .
prednisolone was tapered gradually , and the patient made an uneventful recovery and was discharged .
multiple targetoid lesions , bullae , and erosions on the face and hemorrhagic crusting on the lips
antiepileptic drugs are frequently associated with idiosyncratic adverse skin reactions , which are a leading cause of withdrawal of the drug . among the traditional antiepileptic drugs , aromatic compounds like phenytoin , carbamazepine and phenobarbitone
of the nine newer antiepileptics introduced in the past decade , lamotrigine has been most associated with rash , in up to 3 - 10% of users in clinical trials .
most of the rashes with lamotrigine are benign and resolve promptly on discontinuation of treatment .
the incidence of rash due to lamotrigine , associated with hospitalization in clinical trials was three of 1000 in adults ( 0.3% ) and one of 100 in children ( 1% ) .
co - administration of valproic acid with lamotrigine significantly increases the risk for development of serious adverse cutaneous reactions .
the elimination half life of lamotrigine when used as monotherapy is 25 - 30 hours and it is more than doubled to 60 hours when combined with valproic acid . it has also been suggested that a high starting dose and a rapid dose escalation may increase the occurrence of skin rashes with lamotrigine .
the risk of allergic reactions is decreased when treatment is started at a low dose and the doses are increased gradually following the recommended dosage guidelines , possibly because slow titration may allow desensitization to occur .
both of our patients were on valproic acid when lamotrigine was initiated as an add - on therapy .
high starting doses were employed and dose was also rapidly increased in both the cases .
history of a rash attributed to another antiepileptic drug results in a five times greater increase in the rate of an antiepileptic drug rash .
hirsch et al . have concluded that a rash with another antiepileptic drug is the greatest risk factor for developing a rash with lamotrigine . in the first patient
the phenomenon of cross reactivity may be a general feature of patients predisposed to drug rashes . also a patient with a prior medication related rash
would be more vigilant and likely to notice a drug related rash from a new medication .
females have a higher risk for antiepileptic skin reactions compared to males ; probably due to hormonal factors .
a causality assessment using naranjo probability scale was performed in both the patients that revealed a probable association between lamotrigine and toxic epidermal necrolysis in both of the cases .
our second patient was on several medications ( valproic acid , propranolol , clomipramine , risperidone ) since two years .
these drugs have a very low potential for causing serious drug reactions like toxic epidermal necrolysis .
the rates of skin rash with valproic acid are very low as compared to lamotrigine .
thus it is unlikely that they were responsible for causing toxic epidermal necrolysis in the second patient .
the international prescribing guidelines regarding use lamotrigine as an adjunctive treatment with valproic acid , recommend that lamotrigine should be initiated at a dose of 12.5 mg once daily for first two weeks , followed by 25 mg once daily for next two weeks , and increased thereafter by 25 mg every other week until a maintenance dose of 100 - 200 mg daily .
it must be pointed out , however , that serious reactions can occur with recommended dosing and titration schedules , and without concurrent valproic acid .
increased vigilance is thus required when initiating lamotrigine in a patient and treatment should be discontinued if any rash appears . when lamotrigine is prescribed as an adjunctive treatment with valproic acid
 anti - epileptic drugs can be associated with a wide spectrum of cutaneous adverse reactions ranging from simple maculopapular rashes to more severe and life threatening reactions like stevens - johnson syndrome and toxic epidermal necrolysis . 
 these rashes are well documented with older antiepileptic drugs like phenytoin , phenobarbitone and carbamazapine . 
 lamotrigine is a newer , unrelated antiepileptic drug that causes skin rashes in 3 - 10% of new users . 
 higher starting dose or rapid escalation , concurrent treatment with valproic acid , and a previous history of a rash with other antiepileptic drugs are well recognized risk factors for lamotrigine related serious rashes . 
 we report two patients with toxic epidermal necrolysis , resulting from concomitant use of lamotrigine and valproic acid . 
 it is emphasized that clinicians adhere to the recommended dosage guidelines and adopt a slow dose titration when initiating treatment with lamotrigine . 
Introduction
Case Reports
Case 1
Case 2
Discussion