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A Case of Stevens - Johnson Syndrome Suspectedly Caused by Concurrent Use of Lamotrigine and Valproate
Jane Gau, Ping-Yu Lee, Zon-Min Lee

Abstract
The purpose of this paper is to report the case of a 29-year-old woman with epilepsy, and to discuss how lamotrigine causes the complicated treatment process and induces Stevens-Johnson Syndrome (SJS). This 29-year-old female patient has a history of epilepsy, and she had been treated with valproate SR 500mg bid at one hospital for 12 years. She started to receive medication of acetaminophen, valproate, and clarinase at our hospital since Sept. 2007. Adjustment of antiepileptic drugs was made on Nov. 7. Instead of titrating up lamotrigine slowly and decreasing dosage of valproate gradually, the patient was administered lamotrigine 100 mg bid. Unfortunately, erythematous confluent macules and desquamation over her face and limbs were noted, and the patient complained about her abdominal pain, mucosa damage and stomatitis starting on Dec. 20.
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She was admitted with all currently u s e d d r u g s s u s p e n d e d . Va l p r o a t e (500mg bid) was administered to control epilepsy the following day, and methylprednisolone, cyproheptadine, levocetirizine, mometasone cream, vena (amp) were given for relief of SJS. Based on the observation, acetaminophen, lamotrigine, and clarinase may all have the possibility to cause SJS. However, only lamotrigine-induced SJS was cited in the past studies. So lamotrigine is suspected to have caused this adverse drug reaction (ADR). Yet, concurrent use of lamotrigine and valproate may result in increased elimination half-life of lamotrigine, may also lead to lamotrigine toxicity and an increased risk of lifethreatening rashes. Therefore, this ADR may be caused by the combination use of lamotrigine and valproate, as well as lamotrigine alone. Key words: Stevens-Johnson Syndrome, lamotrigine, valproate

A Case of Stevens - Johnson Syndrome Suspectedly Caused by Concurrent Use of Lamotrigine and Valproate

Introduction
S te v e n s - J o h n s o n S y n d r o m e ( S J S ) and toxic epidermal necrolysis (TEN) are rare but life-threatening severe cutaneous adverse reactions.1 The exact pathogenesis of TEN and SJS is still unknown. 2 These two syndromes are severe, multisystem diseases caused mainly by reaction to drugs. The clinical features include: changes on the skin and mucosa as well as lesions in the internal organs. 3 Carbamazepine and trimethoprim-sulfamethoxazole are the common causes of SJS4,5, other drugs like minoxidil, allopurinol might have the same adverse effect as well.1,6 TEN has the highest mortality (30-35%); SJS and transitional forms correspond to the same syndrome, but with less extensive skin detachment and a lower mortality (5-15%).
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most cases.9 The combination of lamotrigine and valproate is often used in the treatment of epilepsies. It is supposed that the combination of these two drugs has a synergistic pharmacodynamic interaction. Another advantage of this combination is that valproate- in contrast to enzyme-inducing antiepileptic drugs, e.g. carbamazepine, phenobarbital, and phenytoin- does not decrease the lamotrigine concentration, but markedly increases its concentrations.10

Case report
This 29-year-old female patient has a history of epilepsy, and she had taken valproate SR 500mg bid at one hospital for 12 years. She then started to receive medication of acetaminophen, valproate, and clarinase at our hospital since Sep. 2007. Adjustment of anti-epileptic drugs was made on Nov. 7. Instead of titrating up lamotrigine slowly and decreasing dosage of valproate gradually, the patient was administered lamotrigine 100 mg bid. Unfortunately, erythematous confluent macules and desquamation over her face and limbs were noted, and the patient complained of her abdominal pain, mucosa damage and stomatitis starting on Dec.20. Therefore, she was admitted to our emergency room for help

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TEN is the most severe and potentially life-threatening cutaneous reaction associated with lamotrigine. The risk of developing TEN during lamotrigine therapy is low and previously reported cases most involved epileptic patients. H o w e v e r, t h e r i s k o f T E N w i t h combination of lamotrigine and valproate is greater than with monotherapy. Skin rash is the most frequent side effect leading to lamotrigine discontinuation in
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situation became stable without any complaints. Her GOT and GPT returned to normal range.

as the situation deteriorated on Dec. 24, with all currently used drugs suspended. She denied having taken any herbal or OTC drugs. Under the suspicion of SJS, she was transferred to our ICU for further observation and treatment. Valproate (500mg bid) was for control of epilepsy the following day, and methylprednisolone (40mg q6h), cyproheptadine (4mg tid), levocetirizine (5mg qd), mometasone cream (qd), vena (30mg/amp) were given for relief of SJS. Pantoprazole (40mg qd) was administered for relief of abdominal pain, especially for prophylaxis of stress ulcer or methylprednisolone-related ulcer. On day 4 of admission, the patient's oral mucosa damage improved, and lip fissure healed. Then pantoprazole was switched to famotidine (20mg bid) while symptom subsided. Methylprednisolone was tapered from 40mg q6h to 40mg q12h. The next day, cutaneous lesion improved, and methylprednisolone was gradually tapered. On day 8, methylprednisolone was discontinued as skin rashes and mucosal lesion had been improving significantly and clinical condition was more stable. Domperidone (10mg tid) was administered to relieve her abdominal fullness and decreased bowel sound. She was discharged from our hospital on the next day as clinical
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Discussion
In this case, valproate has been used for many years and SJS never occurred. The drug level was monitored on Dec. 28, 2007, which was found within the normal range. Valproate (500mg bid) was administered again for control of epilepsy after she was transferred to ICU. So this drug is less likely to have caused this ADR.11 Based on the observation, acetaminophen, lamotrigine, and clarinase stand the greatest possibility of having caused SJS. However, only lamotrigine-induced skin lesions were cited in the past studies.8,12 So lamotrigine is highly suspected . Concurrent use of lamotrigine and valproate may result in increased elimination half-life of lamotrigine leading to lamotrigine toxicity, such as fatigue, drowsiness, and ataxia, and an increased risk of life-threatening rashes. 8,13,14 In this case, instead of titrating up lamotrigine slowly and decreasing dosage of valproate gradually, lamotrigine was started at 100 mg bid on Nov. 7. Therefore, drug interaction might occur as well. Conversion to lamotrigine

A Case of Stevens - Johnson Syndrome Suspectedly Caused by Concurrent Use of Lamotrigine and Valproate

monotherapy from valproate in patients with epilepsy is complicated.

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preventing a patient from being harmed are essential for a clinical practitioner.

Yet the

study conducted by Sale Mark, etc. 15 may be accepted as guidelines, that is Dose conversion was conducted in four steps: (a)escalate lamotrigine to 200 mg/ day according to package insert for addon to valproate; (b) once at 200 mg/day lamotrigine, gradually decrease valproate to 500 mg/day by no greater than 500 mg/week dose decrements and hold stable for 1 week; (c)decrease valproate to 250 mg/day and increase lamotrigine to 300 mg/day, holding stable for 1 week; and (d)discontinue valproate, and make weekly adjustment of lamotrigine based on clinical response.

References:
1. Kaniwa N, Saito Y, Aihara M, et al: Allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis. Pharmacogenomics 2008; 9(11): 1617-22. 2. Teo L, Tay YK, Liu TT, et al: Stevens-Johnson syndrome and toxic epidermal necrolysis: efficacy of intravenous immunoglobulin and a review of treatment options. Singapore Medical Journal 2009; 50(1): 29-33. 3. Chlystowska M, Pietruszka CA, Szafranski T, et al: Stevens-Johnson syndrome in the literature and authors' own studies. Medycyna Wieku Rozwojowego 2008; 12(3): 799-803. 4. Lin LC, Lai PC, Yang SF, et al: Oxcarbazepine-induced Stevens-Johnson syndrome: a case report. Kaohsiung Journal of Medical Sciences 2009; 25(2): 82-6. 5. Wanat KA, Anadkat MJ, Klekotka PA: Seasonal variation of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with trimethoprim-sulfamethoxazole. Journal of the American Academy of Dermatology 2009; 60(4): 589-94. 6. Karaoui LR, Chahine CC: Fatal toxic epidermal necrolysis associated with minoxidil. Pharmacotherapy 2009; 29(4): 460-7.. 7. Pierre DG, Jean CR: Treatment of severe drug reactions: Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis and Hypersensitivity syndrome. Dermatology Online Journal 2002; 8(1): 5 8. Chuan CC, Shiah IS, Hsin AC, et al: Toxic epidermal necrolysis with combination lamotrigine and valproate in bipolar disorder. Progress in Neuro-Psychopharmacology &Biological Psychiatry 2006; 30(1): 147-50.

Conclusion
Occurrences of drug interactions seem to be frequent and inevitable during daily practice. In this case, instead of titrating up lamotrigine slowly and decreasing d o s a g e o f v a l p r o a t e g r a d u a l l y, lamotrigine was started at 100 mg bid on Nov. 7. Therefore, this ADR may be caused by combination use of lamotrigine and valproate, or by lamotrigine alone. Side effects with lamotrigine add-on therapy are more likely associated with starting doses and titration procedure rather than comedication with valproate. Consequently, titrating drug levels and

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acetaminophen, valproate, clarinase 11 7 valproatelamotrigine, lamotrigine 100mg bid 12 20 (erythematous confluent macules) valproate (500 mg bid) methylprednisolone, cyproheptadine, levocetirizine, mometasone cream vena (amp) SJS acetaminophen, lamotrigine clarinase (ADR) lamotrigine SJS lamotrigine ADR, valproate lamotrigine lamotrigine , lamotrigine , ADR lamotirginevalproate lamotirgine lamotrigine valproate Jane Gau, Ping-Yu Lee, Zon-Min Lee Department of Pharmacy, Chang Gung Memorial Hospital- Kaohsiung Medical Center, Taiwan

9. Gelisse P, Crespel A: Reintroduction of treatment with lamotrigine in combination with valproate after an initial allergic skin reaction. Neurologique 2006; 162(11): 1122-4. 10. Mihaela IM, Theodor WM, Bernhard R: Does lamotrigine influence valproate concentrations? Therapeutic Drug Monitoring 2002; 24(5): 631-6. 11. Michael E: Winter Basic Clinical Pharmacokinetics. (2nd edition) 1988: 349. 12. Steinhoff BJ: How to replace lamotrigine with valproate. Epilepsia 2006; 47(11): 1943-4. 13. Cuadrado A, Valdizan EM, Armijo JA: Synergistic interaction between valproate and lamotrigine against seizures induced by 4-aminopyridine and pentylenetetrazole in mice. European Journal of Pharmacology 2002; 453(1): 43-52. 14. Song ZB, Liao WP, Zhao QH, et al: Lamotrigine pharmacokinetics in Chinese adults and the influence of valproate. 25th International Epilepsy Congress (poster discussion): drug therapy 2003; 44(8): 152. 15. Sale M, Vuong A, Hoyler S, et al: Conversion to lamotrigine monotherapy from valproate in patients with epilepsy. Neuropharmacology (poster session) 2003; 44(9): 98-9. 16. Sale ME, Natarajan S, Biton V, et al: A dosing algorithm for converting from valproate monotherapy to lamotrigine monotherapy in patients with epilepsy. Epilepsy&Behavior 2005; 6(1): 63-70.

29 lamotrigine (SJS)29 valproate SR 500mg bid12 20079

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