What medications can cause Stevens-Johnson Syndrome (SJS)?

Medications That Cause Stevens-Johnson Syndrome

The most common medications causing SJS are allopurinol, carbamazepine, lamotrigine, phenytoin, phenobarbital, sulfonamide antibiotics (especially sulfamethoxazole), sulfasalazine, nevirapine, and oxicam NSAIDs, with these drugs requiring immediate discontinuation at the first sign of rash. 1

High-Risk Medications by Category

Anticonvulsants (Highest Risk in First 2 Months)

• Carbamazepine - crude relative risk 90 during first 2 months of treatment 2; strongest signal with IC025/ROR025=5.25/43.88 3
• Phenytoin - crude relative risk 53 during first 2 months 2; second strongest signal with IC025/ROR025=5.60/57.65 3
• Phenobarbital - crude relative risk 45 during first 2 months 2
• Lamotrigine - listed among most common causes 1; most commonly associated antiepileptic with SJS 4
• Valproic acid - crude relative risk 25 during first 2 months 2

Antibiotics

• Sulfonamide antibiotics - particularly trimethoprim-sulfamethoxazole with crude relative risk 172 2; most common drug class causing SJS 5
• Sulfasalazine - listed among most common causes 1
• Aminopenicillins - multivariate relative risk 6.7 2
• Quinolones - multivariate relative risk 10 2
• Cephalosporins - multivariate relative risk 14 2

Other High-Risk Medications

• Allopurinol - crude relative risk 52 during first 2 months 2; strongest overall signal with IC025/ROR025=5.86/69.84 3; particularly at doses above 100 mg per day 6
• Oxicam NSAIDs - crude relative risk 72 during first 2 months 2
• Nevirapine - listed among most common causes 1
• Corticosteroids - crude relative risk 54 during first 2 months 2

Medications in Children

In pediatric populations, anticonvulsants and antibiotics are the primary implicated medications 1. Paracetamol and ibuprofen have unclear associations and are likely confounders, though ibuprofen has been associated with higher complication risk in children 1. New anticancer medications must also be considered as potential causes 1.

Critical Timing Considerations

For drugs used chronically (anticonvulsants, allopurinol, NSAIDs), the increased risk is confined largely to the first two months of treatment 2. The typical latent period between drug initiation and SJS onset is 5-28 days, unless there is previous exposure to the same drug, which may shorten the latency 1.

Genetic Risk Factors

HLA-B*1502 Allele

• Carbamazepine should not be used in HLA-B*1502 positive patients unless benefits clearly outweigh risks 7
• Strong association in patients of Chinese ancestry and other Southeast Asian populations 7, 4
• Prevalence: >15% in Hong Kong, Thailand, Malaysia, parts of Philippines; ~10% in Taiwan; ~4% in North China; 2-4% in South Asians; <1% in Japan, Korea, and non-Asian populations 7
• Testing for HLA-B*1502 should be performed prior to initiating carbamazepine in patients with ancestry in at-risk populations 7
• Limited evidence suggests HLA-B*1502 may also increase risk with phenytoin in Chinese ancestry patients 7, 8

HLA-A*3101 Allele

• Moderate association with hypersensitivity reactions including SJS from carbamazepine 7
• Present in >15% of Japanese, Native American, Southern Indian, and some Arabic populations; up to 10% in Han Chinese, Korean, European, Latin American populations 7

Other HLA Associations

• Japanese patients with HLA-B31:01 and Koreans with HLA-B44:03 at increased risk with lamotrigine and carbamazepine 4

Clinical Management Implications

All medications (including over-the-counter preparations) taken by the patient over 2 months prior to symptom onset must be documented 1. Any suspected medication should be withdrawn immediately as this decreases mortality risk 1. The drug should be permanently avoided, documented in medical records, and reported to pharmacovigilance authorities 1.

Important Caveats

• No reliable laboratory test exists to determine the offending drug; diagnosis relies on patient history and empirical drug risk 5
• Provocation tests are contraindicated due to risk of life-threatening reactions 5
• When causative drug cannot be identified, consider infectious etiologies such as Mycoplasma pneumoniae (particularly in children where up to 50% of cases are infection-related) 1
• Over 90% of carbamazepine-induced SJS/TEN occurs within the first few months of treatment 7