Does Clozapine Cause Stevens-Johnson Syndrome?
Yes, clozapine can cause Stevens-Johnson syndrome, and the FDA drug label explicitly contraindicates clozapine in patients with a history of serious hypersensitivity to clozapine, including Stevens-Johnson syndrome. 1
FDA-Mandated Contraindication
The official FDA labeling for clozapine (Clozaril) lists Stevens-Johnson syndrome as a contraindication, stating that clozapine tablets are contraindicated in patients with a history of serious hypersensitivity to clozapine, specifically including erythema multiforme or Stevens-Johnson syndrome. 1 This represents the highest level of regulatory warning against rechallenge in patients who have experienced this reaction.
Clinical Evidence of Association
A documented case report confirms that clozapine can induce Stevens-Johnson syndrome even after prolonged, previously well-tolerated treatment. 2 The reported case involved a 54-year-old male with chronic schizophrenia who developed acute-onset SJS after 2 years of stable clozapine 200 mg/day treatment, presenting with mouth edema, multiple oral and ocular ulcers, mucosal swelling, and widespread erythematous rashes. 2
The proposed mechanism involves clozapine's immunomodulatory effects, with accumulated lymphocytes and macrophages in the epidermis and elevated TNF-α causing immune reactions and apoptosis that manifest as SJS. 2
Risk Context Among Medications
While clozapine is not among the highest-risk medications for SJS/TEN (which include allopurinol, carbamazepine, lamotrigine, phenytoin, phenobarbital, sulfonamide antibiotics, sulfasalazine, nevirapine, and oxicam NSAIDs), 3 it remains a documented cause that warrants clinical vigilance. The most commonly implicated drugs in SJS/TEN are sulfonamides, NSAIDs, antimalarials, anticonvulsants, and allopurinol. 4
Clinical Management Implications
If a patient on clozapine develops any rash or mucocutaneous symptoms, immediately discontinue the medication. 3 All suspected medications must be withdrawn immediately to decrease mortality risk, as delayed discontinuation significantly worsens outcomes. 3
Key warning signs to monitor:
- Macular exanthema focusing on face, neck, and central trunk 4
- Rapid confluence of lesions with positive Nikolsky's sign 4
- Prominent involvement of mucosal, conjunctival, and anogenital membranes 4
- Fever, oral ulcers, and ocular symptoms 2
Documentation requirements:
- Permanently document the reaction in all medical records 3
- Report to pharmacovigilance authorities (Yellow Card Scheme in UK, MedWatch in US) 5, 3
- Recommend MedicAlert bracelet listing clozapine allergy 5
Important Caveats
Never rechallenge with clozapine after confirmed SJS. 1 Unlike lamotrigine, where careful rechallenge protocols exist for mild rashes, 6 the FDA explicitly contraindicates clozapine rechallenge after SJS. 1
The latency period between drug initiation and SJS onset typically ranges from 5-28 days, 5 though this case demonstrates that SJS can occur even after years of stable treatment. 2 This underscores the need for ongoing vigilance throughout the entire treatment course, not just during initial titration.
When evaluating any patient on clozapine with new skin findings, obtain a complete drug history from multiple sources (patient, family, pharmacy records) covering the 2 months prior to symptom onset. 3 Consider infectious etiologies like Mycoplasma pneumoniae if no clear drug culprit is identified, particularly in pediatric populations where up to 50% of SJS cases are infection-related. 3