Pharmacogenomic in Neurology II:SJS/TEN caused by Carbamazepine,

Phenobarbital and Phenytoin

Lect. Nin Prapongsena, M.Ph.

Huachiew Chalermpraiet University

Outline

• Introduction SJS/TEN

– Clinical presentation

– Management

• Pharmacogenomic related to cutaneous ADR in CBZ, Phenytoin, Phenobarbital usage.

• Introduction of HLA type

• Which HLA type related to cutaneous ADR in CBZ, Phenytoin, Phenobarbital usage???

Drugs induced SJS/TEN

Antibiotics Sulphonamides, Vancomycin,Penicillins, Cephalosporins, Quinolones

Anticonvulsants CBZ, Phenytoin, Phenobarbital,Valporate, Lamotrigine

NSAIDs Piroxicam, Aspirin, Diclofenac

ARV NVP, ABC, Protease inhibitors

Anti-TB Isoniazid, Ethambutol

Anti-Gout Allopurinol

Translational Research 2012 Volume 159 Number 5

SJS vs TEN

Harr and French Orphanet Journal of Rare Diseases 2010, 5:39

SJS vs TEN

SJS SJS/TEN TEN

Occurred within 4 -28 days

SJS vs TEN (systemic sign)

Severity SJS/TEN Assessment

SJS/TEN Management (Supportive Care)

SJS/TEN Management (Supportive Care)

SJS/TEN Management (Drugs Therapy)

• Systemic steroids: “Pulse” High dose of dexamethasone

• Thalidomide: Anti-TNFα (No Benefit)

• Cyclosporine: 3-5 mg/kg oral/IV for 8-24 d or re-epithelialisation then taper off 2wk

• Cyclophosphamide: Should be benefit (small trials)

SJS/TEN Management (Continue)

• IVIG: High dose of IVIG (0.25-0.75 g/kg for 3-4 d)

Pharmacogenomic and Cutaneous ADR

http://www.youtube.com/watch?v=VPvCekgPwRI

Polymorphism of HLA type on MHC I Related to Cutaneous ADR (SJS/TEN)

What’s polymorphism of HLA type that Related to SJS/TEN in Anticonvulsant

• HLA-A*3101• HLA-B*1502

HLA-A*3101

HLA-B*1502

HLA-B*1502

HLA-B*1502 Cross-reacted to Phenobarbital and Phenytoin (Case Report)

Case I (China)Feb 2005:•Female 61 y (Complex partial seizure 2-4 times/month)• On CBZ 200 mg 1*3: (10th day: Erythematous rashes, Maculopapular rashes and leucocyte increased)• Then off CBZ (1 week: rashes were clear)• On ValproateFeb 2010:• Tonic-clonic seizure: On Valproate 500 mg 1*2

+ OXC 900 mg OD (2wk later: skin rxn)• Off OXC (5d: rashes were clear)• Lab testing HLA-B*1502 (+)Nov 2010:Valproate 500 mg 1*2 + Levetiracetam 1000 mg OD (no symp)

Case II (China)March 2004:• Female 20 y (Complex partial seizure q 2-3 month)• EEG (+)• On Phenytoin 100 mg 1*1• 10d later: infected eyes, sore throat, erythematous rash (+), high fever (39.1), oral ulcer, maculopapule rashes >30% & leucocytosis• Off Phenytoin but On steroid and antihistamine:(Rash cleared)• Switched to Phenobarbital 90 mg OD• 2wk later rashes were recurrence• Switched to CBZ 100mg 1*3 and 300 mg 1*2, respectively• 2wk later rashes were recurrence• Now on topiramate 75 mg 1*2 (seizure free)• Lab testing: HLA-B*1502 (+)

Conclusion

• HLA-A*3101 Related to SJS/TEN of CBZ (In Europe)

• HLA-B*1502 Related to SJS/TEN of CBZ (In Thailand)Note: HLA-B*1502 cross-reacted to phenobarbital, phenytoin (case report)

Pharmacist’s role

• Interpreted Laboratory data of pharmacogenomicthat related to SJS/TEN

• Suggested doctor to avoid CBZ, Phenytoin and Phenobarbital If patients are HLA-B*1502 (+)

• Suggested doctor to switch medication to Topiramate/ Valproate/ Levetiracetam