What are the side effects and safety considerations of tofacitinib?

Tofacitinib Side Effects and Safety Considerations

Tofacitinib carries four FDA black box warnings covering serious infections (including tuberculosis and opportunistic infections), increased mortality, thrombosis, and malignancies including lymphoma, which mandate careful patient selection and monitoring. 1, 2

FDA Black Box Warnings

The FDA has issued four critical black box warnings for tofacitinib 1, 2:

• Serious infections: Including tuberculosis, invasive fungal infections, bacterial, viral, and other opportunistic pathogens 1
• Mortality: Increased death rates observed in high-risk populations 1, 2
• Thrombosis: Elevated risk of venous thromboembolism, particularly pulmonary embolism 1, 2
• Malignancies: Including lymphoma and increased rates of EBV-mediated post-transplant lymphoproliferative disorder 1

Cardiovascular and Thrombotic Risks

In patients over 50 years with cardiovascular risk factors, tofacitinib increases major adverse cardiovascular events (MACE) and cancer compared to TNF inhibitors. 2

• Pulmonary embolism risk increases five-fold at the 10 mg twice daily dose compared to TNF inhibitor therapy 2
• The European Medicines Agency restricts use in patients ≥65 years, current or long-term smokers, those with cardiovascular disease history, or increased cancer risk—only when no suitable alternatives exist 2
• Patients receiving tofacitinib should be on at least prophylactic-dose anticoagulation during treatment, particularly for severe conditions 1, 3

Infection Risks

Herpes zoster infection occurs at substantially higher rates with tofacitinib than with TNF inhibitors or in the general RA population. 2, 4, 5

• In ulcerative colitis maintenance trials, herpes zoster incidence rates were 2.1 per 100 patient-years for 5 mg twice daily and 6.6 per 100 patient-years for 10 mg twice daily, compared to 1.0 for placebo 4
• Serious infections occur at a rate of 2.0 per 100 patient-years in UC patients 4
• Opportunistic infections occur at 1.3 per 100 patient-years 4
• Tuberculosis reactivation is a documented risk requiring mandatory screening before initiation 1, 3, 6

Malignancy Risks

Tofacitinib produced lymphomas in monkeys at exposure levels approximately 6 times the recommended human dose. 7

• In 24-month rat studies, tofacitinib caused benign Leydig cell tumors, hibernomas (malignancy of brown adipose tissue), and benign thymomas at high doses 7
• Malignancy excluding non-melanoma skin cancer occurs at 0.7 per 100 patient-years 4
• Non-melanoma skin cancer occurs at 0.7 per 100 patient-years 4

Common Adverse Events

Infections and infestations are the most common adverse events, with most being mild to moderate in severity. 5

• Nasopharyngitis and upper respiratory tract infections are the most frequently reported 8
• In COVID-19 trials, patients receiving tofacitinib experienced more serious adverse events (RR: 1.18; 95% CI: 0.64,2.15) 1
• Drug hypersensitivity reactions including angioedema and urticaria have been reported 7
• Acne has been observed in post-marketing surveillance 7

Laboratory Abnormalities and Monitoring Requirements

Tofacitinib causes dose-dependent lipid elevations and requires regular hematologic monitoring. 3

• Do not initiate if lymphocyte count <500 cells/mm³, absolute neutrophil count <1000 cells/mm³, hemoglobin <9 g/dL, or platelets <150 × 10⁹/L 3
• Do not start if baseline liver enzymes exceed 1.5 × upper limit of normal 3
• Repeat CBC with differential at 4-8 weeks, then every 3 months 3
• Recheck liver enzymes at 4 weeks, then every 3 months 3
• Lipid profile should be measured at 4-12 weeks after initiation, then annually 3

Reproductive and Developmental Toxicity

Tofacitinib was teratogenic in animal studies, causing external malformations, soft tissue defects, and skeletal abnormalities. 7

• In rats, teratogenic effects occurred at exposure levels approximately 73-146 times the maximum recommended human dose 7
• In rabbits, teratogenicity was observed at 6.3-13 times the maximum recommended dose 7
• Pregnancy testing is required in all patients of childbearing potential before initiation 2, 3
• Use only if potential benefit justifies potential risk to the fetus 2, 7

Gastrointestinal Complications

• Gastrointestinal perforations occur at 0.2 per 100 patient-years 4
• This risk is particularly relevant in ulcerative colitis patients where baseline perforation risk may be elevated 4

Contraindications and High-Risk Populations

Absolute contraindications include active serious infections, active tuberculosis, and patients with history of or current thrombosis. 1, 3

• Patients with personal or first-degree family history of blood clotting disorders were excluded from clinical trials 1
• Those with immunosuppression, active cancer, or certain cytopenias should not receive tofacitinib 1
• Avoid in patients ≥65 years unless no suitable alternative exists, due to significantly higher serious infection rates 2, 9

Drug Interactions Increasing Adverse Event Risk

Tofacitinib should not be combined with potent immunosuppressants or biologic DMARDs due to added immunosuppression risk. 3, 7

• Do not combine with azathioprine, tacrolimus, cyclosporine, or biologic DMARDs 3, 7
• Do not use with tocilizumab or other IL-6 inhibitors 1, 3
• Live vaccines are contraindicated once tofacitinib is started 3

Critical Clinical Pitfalls to Avoid

• Do not assume absence of symptoms rules out latent tuberculosis—formal IGRA or tuberculin testing is mandatory for all patients 3
• Do not use the 10 mg twice daily dose for rheumatoid arthritis due to documented increased thromboembolic events 2, 9
• Ensure zoster vaccination (Shingrix) is completed before initiation, as herpes zoster incidence more than doubles compared to biologic DMARDs 3
• Do not start tofacitinib during any active serious infection until fully resolved 3, 6