What Drug is Most Likely to Cause SJS? An Exploration of High-Risk Medications

October 13, 2025 •

4 min read

Stevens-Johnson Syndrome (SJS), a rare but life-threatening skin disorder, is most commonly triggered by an adverse reaction to a medication. While many different drugs have been implicated, some are far more frequently associated with causing SJS, leading to a focus on certain high-risk culprits during diagnosis and treatment.

Quick Summary

This article explores the medications most frequently associated with causing Stevens-Johnson Syndrome (SJS), a severe adverse drug reaction. Key culprits include allopurinol, certain anticonvulsants like lamotrigine, and sulfonamide antibiotics. Understanding the highest-risk medications and personal risk factors is crucial for prevention and rapid diagnosis.

Key Points

Leading culprits: Medications like allopurinol, specific anticonvulsants (lamotrigine, carbamazepine), and sulfonamide antibiotics are most frequently linked to Stevens-Johnson Syndrome (SJS).
Genetic risk: Certain HLA alleles, particularly HLA-B58:01 for allopurinol and HLA-B15:02 for carbamazepine, increase SJS risk in specific populations, mainly of Asian descent.
Early symptoms: SJS typically begins with flu-like symptoms (fever, malaise) before progressing to a painful rash and blistering of skin and mucous membranes.
Immediate action: The most crucial step upon suspecting SJS is to immediately stop the offending medication under medical supervision and seek emergency care.
High-risk populations: Individuals with HIV, weakened immune systems, certain cancers, or a family history of SJS are at a greater risk.
Prevention strategies: Genetic screening for high-risk patients, vigilant monitoring during the first few weeks of new medications, and avoiding known trigger drugs are key to prevention.

Understanding Stevens-Johnson Syndrome (SJS)

Stevens-Johnson Syndrome (SJS) is a rare but severe and potentially fatal immune-mediated skin and mucous membrane reaction. It lies on a spectrum of disease severity, with Toxic Epidermal Necrolysis (TEN) representing the most severe form. The syndrome is characterized by a prodromal phase of flu-like symptoms, followed by the rapid development of a painful red or purple rash that spreads and blisters. Extensive peeling of the top layer of skin (epidermis) is a hallmark sign, and mucous membranes of the mouth, eyes, and genitals are typically involved. The most common trigger for SJS in adults is medication.

The Most Frequently Implicated Drug Culprits

Determining the single 'most likely' drug to cause SJS is complex, as different studies show varying frequencies based on patient populations and drug usage patterns. However, several drugs and drug classes consistently appear at the top of the list of reported SJS cases.

Allopurinol: A Primary Culprit for Gout Treatment

Allopurinol, a medication widely used to treat gout and kidney stones by reducing uric acid levels, is one of the single most common drugs associated with inducing SJS. The risk is particularly elevated in patients of specific Asian descent (Han-Chinese, Thai, and Korean) who carry the HLA-B*58:01 genetic marker. Additionally, higher doses of allopurinol, especially those exceeding 100 mg per day, have been linked to an increased risk of SJS. The onset of the reaction can occur weeks to months after starting the medication, sometimes complicating the diagnosis.

The Anticonvulsant Class

Several anticonvulsant medications used to treat seizures and certain mental health conditions carry a black box warning from the FDA due to their association with SJS. Lamotrigine is particularly well-known for this risk, with SJS being more likely to occur in the first eight weeks of treatment, particularly if the dose is increased too quickly. Children are also at a higher risk of developing SJS from lamotrigine compared to adults. Other commonly implicated anticonvulsants include:

Carbamazepine
Phenytoin
Phenobarbital

The risk for these drugs is also influenced by genetic factors, such as the HLA-B*15:02 allele, predominantly found in patients of Asian ancestry.

Sulfonamide Antibiotics

Sulfonamide (sulfa) antibiotics are a well-established cause of SJS. The combination antibiotic trimethoprim-sulfamethoxazole (Bactrim) is a frequent trigger, representing a significant percentage of drug-induced SJS cases in many studies. Other antibiotic classes, including penicillins, cephalosporins, and quinolones, have also been implicated, though generally less frequently than sulfa drugs.

Other Notable Medications

While allopurinol, anticonvulsants, and sulfonamides are the most common causes, other medications are known to trigger SJS in rarer instances, including:

Nevirapine: An antiretroviral drug used in HIV treatment, which carries a heightened risk in HIV-positive patients.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Pain relievers like ibuprofen, naproxen, and piroxicam, particularly the oxicam type, have been reported as causes.
Acetaminophen (Paracetamol): Can cause SJS in rare cases, though the risk is considered low.

Factors That Increase SJS Risk

An individual's risk for drug-induced SJS is influenced by several factors beyond simply taking a high-risk medication.

Genetic Predisposition: Specific HLA alleles, such as HLA-B58:01 and HLA-B15:02, significantly increase risk for allopurinol and carbamazepine-induced SJS, respectively, especially in people of Asian descent.
HIV Infection: People with HIV have a significantly higher risk of developing SJS compared to the general population.
Compromised Immune System: Conditions that weaken the immune system, including cancer, organ transplantation, and autoimmune diseases, increase susceptibility.
Personal or Family History: A history of SJS or a family history of the condition increases the likelihood of recurrence or developing it.
Drug-Related Factors: As seen with lamotrigine, the speed of dose escalation is a risk factor. Drug interactions can also increase risk, such as combining lamotrigine with valproate.

A Comparison of High-Risk SJS Medications


Feature	Allopurinol (Anti-gout)	Lamotrigine (Anticonvulsant)	Sulfonamides (Antibiotics)
Associated Condition	Gout, kidney stones	Epilepsy, bipolar disorder	Bacterial infections
Primary Risk Factors	HLA-B*58:01 allele (especially in Asian populations), high dosage (>100mg)	Rapid dose escalation, concurrent valproate use, pediatric patients	HIV infection, specific genetic predispositions
Typical Onset Time	Weeks to months after starting the drug, often within the first 44 days	Within the first 2 to 8 weeks, especially with rapid titration	Generally within 4 to 28 days of administration
Mechanism	Delayed type IV hypersensitivity reaction, T-cell mediated response against epidermal cells	Immunological reaction mediated by T-cells and HLA phenotypes	T-cell mediated delayed hypersensitivity
Genetic Marker	Strongly associated with HLA-B*58:01 allele	Associated with HLA-B*15:02 allele, especially in Asian patients	Various genetic factors, but less a specific HLA marker compared to allopurinol

Preventing Drug-Induced SJS

Preventing SJS involves a combination of healthcare provider awareness and patient vigilance. For at-risk individuals, genetic screening for specific HLA markers can be considered before starting allopurinol (in certain Asian populations) or carbamazepine. Patients should also be educated on the early warning signs of SJS, such as flu-like symptoms, fever, and a spreading rash. The most critical step upon suspicion is to immediately stop the suspected drug.

Conclusion: Vigilance is Crucial for SJS Prevention

While no single drug can be definitively named as the most likely to cause SJS universally, allopurinol, lamotrigine, and sulfonamide antibiotics are consistently reported as major culprits across many studies. The risk profile is not solely dependent on the medication but also on patient-specific factors, particularly genetics and underlying health conditions. By understanding these risk factors and practicing careful medication management, both patients and clinicians can significantly reduce the risk of this devastating condition. Promptly discontinuing the causative drug is the single most important intervention in managing SJS and improving outcomes. For authoritative information on SJS, the Mayo Clinic is an excellent resource.

Frequently Asked Questions

The earliest signs of SJS are often non-specific and mimic the flu, including fever, body aches, fatigue, and a sore throat or mouth. These symptoms precede the painful red or purplish skin rash that blisters and spreads.

No, SJS is a very rare reaction to allopurinol. However, allopurinol is one of the single most common drug causes, especially at higher doses and in individuals with specific genetic markers like HLA-B*58:01.

Yes, although less common than with prescription drugs, some over-the-counter medications like certain NSAIDs (ibuprofen, naproxen) and acetaminophen have been reported to cause SJS.

Drug-induced SJS typically begins within the first few weeks to two months of starting a new medication, though it can occur up to several weeks after stopping the drug.

Prevention strategies include genetic screening for certain HLA alleles in at-risk populations before starting medications like allopurinol or carbamazepine. For drugs like lamotrigine, slow dose titration is recommended to minimize risk.

Yes, aside from medication, risk factors include having an HIV infection, a weakened immune system, certain cancers, or a personal or family history of SJS.

If you suspect SJS due to a new medication, seek emergency medical care immediately. You should stop taking the suspected drug under a doctor's supervision, as prompt discontinuation is critical for treatment.