Stevens-Johnson syndrome lamotrigine

Drug overdose Of 16 796 toxic exposures to antiepileptic drugs (phenytoin, valproic acid, and carbamazepine) in the USA in 2006, 12 resulted in death, as reported by the US Toxic Surveillance System [67 ]. Some specific problems determined by overdose of some old and new antiepileptic drugs have been briefly reviewed. For example, topiramate can cause a significant metabolic acidosis, lamotrigine Stevens-Johnson syndrome, oxcarbazepine hyponatremia, and levetiracetam psychosis. Possible adoption of guidelines for critical care management of overdose are discussed. 

A concern with the administration of lamotrigine is that it has the potential to induce the Stevens-Johnson syndrome (exfoliative dermatitis). The incidence of a serious rash in clinical trials appears to be about 0.08% with monotherapy and 0.13% with combination therapy. The rash usually resolves when lamotrigine is stopped, but all patients starting lamotrigine should be cautioned to be vigilant for the development of a rash, especially during the first 6 months of treatment. 

Serious rashes requiring hospitalization and discontinuation of treatment have been reported in association with lamotrigine use. The incidence of these rashes, which include Stevens-Johnson syndrome, is approximately 1 % in pediatric patients (younger than 16 years of age) and 0.3% in adults. 

A maculopapular rash develops in 5%-10% of patients taking lamotrigine, usually in the first 8 weeks of treatment. Serious rashes requiring hospitalization and discontinuation of treatment may occur. The incidence of these rashes, which have included Stevens-Johnson syndrome, is approximately 0.08% (0.8 per 1,000). Stevens-Johnson syndrome is potentially fatal. Patients must be advised of this risk and of the necessity to call the office at once if they develop a rash. Development of a rash with concomitant systemic symptoms is a particularly ominous sign, and the patient should be evaluated immediately. 

Side effects. The most common side effects are headache, nausea and vomiting, diplopia, dizziness, ataxia and tremor. There are also reports that lamotrigine can cause such psychiatric side effects as aggression, agitation, confusion, hallucinations and psychosis, some of these effects possibly being associated with a reduction in the glutamatergic system. Rashes are a frequent side effect, occurring in up to 5% of patients. Usually rashes are mild but occasionally can be severe and amount to a Stevens-Johnson syndrome. The severe rash occurs more commonly in children. 

Published and unpublished cases of Stevens-Johnson syndrome (n = 43) and toxic epidermal necrolysis (n = 14) associated with lamotrigine have been reviewed (44). The patients with Stevens-Johnson syndrome were younger than those with toxic epidermal necrolysis (21 versus 31 years) the median time to onset for both reactions was 17 days the median dosage at onset (50 mg for Stevens-Johnson syndrome, 87.5 mg for toxic epidermal necrolysis) did not differ significantly. Valproate comedication was present in 74% and 64% of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis respectively. In three patients, toxic epidermal necrolysis occurred in the context of the anticonvulsant hypersensitivity syndrome. 

Stevens-Johnson syndrome, and 3 as suggestive of Stevens-Johnson syndrome two deaths were reported. Rashes associated with one or more symptoms of hypersensitivity reactions occurred in 19 children. Of 29 patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or hypersensitivity reactions, for whom precise details were available, 83% were taking lamotrigine with concomitant valproate and 85% were taking lamotrigine dosages higher than recommended. 

A 33-year-old woman, who had taken valproate for 3 years, developed Stevens-Johnson syndrome soon after starting to take lamotrigine 150 mg/day (46). Lamotrigine was withdrawn and prednisolone given the signs and symptoms progressively resolved over 10 days. 

Although serious skin rashes have been reported with traditional anticonvulsants, the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis with these drugs appears to be lower than with lamotrigine. Data from the Saskatchewan Health Plan suggest that the risk of serious rashes is in the order of 0.9 1000 (1.4 1000 in children) for phenytoin, 0.6 1000 (1.4 1000 in children) for carbamaze-pine, and 0 1000 for valproate, but Stevens-Johnson syndrome constituted only a small minority of these cases (47). 

Co-administration of valproate is one of the most important risk factors for skin reactions to lamotrigine valproate co-medication was present in 74 and 64% of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis respectively (44). 

Yalcin B, Karaduman A. Stevens-Johnson syndrome associated with concomitant use of lamotrigine and valproic acid. J Am Acad Dermatol 2000 43(5 Pt 2) 898-9. 

Stevens-Johnson syndrome (2007) Shen YC +, Int Clin Psychopharmacol 22(4), 247 (with lamotrigine)... 

The following drugs have been most often associated with erythema multiforme and Stevens-Johnson syndrome allopurinol, lamotrigine phenytoin, barbiturates, carbamazepine, estrogens/progestins, gold, NSAIDs, penicillamine, sulfonamides, tetracycline, and tolbutamide. 

Lamotrigine is a potent inhibitor of dihydrofolate reductase. Folate concentrations are decreased when this drug is administered. If folate replacement is not implemented, rash and anemia may be experienced when lamotrigine is at its therapeutic concentration. Lamotrigine has also been associated with development of severe rash (Stevens-Johnson syndrome) in approximately 1% of patients receiving lamotrigine. These side effects are not drug concentration related. 

Lamotrigine Blocks Na+ channels and glutamate receptors Absence and partial seizures Sedation, ataxia, diplopia, j Stevens-Johnson syndrome j... 

TOXICITY Common adverse effects when lamotrigine is added to another antiseizure drug are dizziness, ataxia, blurred or double vision, nausea, vomiting, and rash. A few cases of Stevens-Johnson syndrome and disseminated intravascular coagulation have been reported. The incidence of serious rash in children (-0.8%) is higher than in adults (0.3%). 

Lamotrigine 22-36 h 200-500 mg Lethargy, dizziness, ataxia, stupor, nystagmus, hypertonia, seizures QRS prolongation nausea and vomiting hypokalemia hypersensitivity fever, rash (Stevens-Johnson syndrome) hepatitis, renal failure. 

Skin Stevens—Johnson syndrome has been reported in a patient taking a combination of clobazam, lamotrigine, and valproic acid [6 ]. 

Skin Stevens-Johnson syndrome [159 ] and anticonvulsant hypersensitivity syndrome [160" ] have been described in patients taking lamotrigine. 

Haematologic A case of quetiapine- and valproate-associated neutropenia and thrombocytopenia has been described after previous lamotrigine-induced Stevens-Johnson syndrome [226 ]. Two cases of neutropenia have been reported with the concomitant use of quetiapine and sodium valproate in elderly patients [227 ]. Another case of neutropenia in a 21-year-old male who was also on mirtazapine resolved following switch to ziprasidone is reported [228 ]. 

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