What are the side effects of tofacitinib (Xeljanz)?

Side Effects of Tofacitinib

Tofacitinib carries significant risks including serious infections (particularly herpes zoster), increased cardiovascular events, malignancies, blood clots, and hematologic abnormalities, with the 10 mg twice daily dose conferring higher risks than the 5 mg dose. 1, 2

Serious and Life-Threatening Side Effects

Infections

• Serious infections are among the most critical adverse events, including tuberculosis (including disseminated disease), opportunistic infections, and bacterial, fungal, and viral infections 1
• The most common serious infections include cellulitis, urinary tract infection, pneumonia, and herpes zoster 1
• Herpes zoster (shingles) occurs at significantly higher rates with tofacitinib compared to TNF inhibitors and the general RA population, though infections remain clinically manageable 1, 3
• Zoster vaccination (Shingrix) should be considered before initiating therapy, particularly in patients over 70 years or those over 50 at high risk 1, 4

Cardiovascular Events

• Major adverse cardiovascular events (MACE) occur at higher rates with tofacitinib compared to TNF inhibitors in patients over 50 with cardiovascular risk factors (3.4% vs 2.5%) 2
• Pulmonary embolism risk increases five-fold with the 10 mg twice daily dose compared to TNF inhibitor therapy 1
• The European Medicines Agency advises against using the 10 mg dose in patients at increased risk of pulmonary embolus (heart failure, malignancy, recent surgery, inherited coagulation disorders, previous thromboembolism, combined contraceptive therapy or HRT) 1

Malignancies

• Cancer risk is elevated with tofacitinib compared to TNF inhibitors (4.2% vs 2.9%), with noninferiority not demonstrated 2
• Lung and breast cancer are the most common nonhematologic malignancies reported 1
• Lymphoma has been reported, including Epstein Barr virus-associated post-transplant lymphoproliferative disorder in renal transplant patients receiving concurrent immunosuppressive medications 1
• Nonmelanoma skin cancer occurs more frequently with tofacitinib than TNF inhibitors 2

Hematologic Abnormalities

Blood Count Changes

• Lymphopenia (absolute lymphocyte count <500 cells/mm³) occurs in 0.04% of patients after 3 months and correlates with increased incidence of treated and serious infections 1
• Neutropenia can occur, requiring drug discontinuation if ANC <500 cells/mm³ (confirmed by repeat testing) 1
• Anemia (hemoglobin decrease) is significantly more prominent with 10 mg twice daily compared to 5 mg twice daily (RR 1.75,95% CI 1.19-2.58) 5
• Tofacitinib should not be initiated if lymphocyte count is <500 cells/mm³, ANC is <1000 cells/mm³, or hemoglobin is <9 g/dL 1

Laboratory Abnormalities

Lipid Elevations

• Dose-related elevations in serum lipids occur, including triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol 1
• The increase in cholesterol occurs after 1 month of therapy and subsequently remains stable 1

Liver and Renal Effects

• Liver enzyme elevations to more than 3 times the upper limit of normal have been recorded 1
• Serum creatinine increases occur in a dose-related manner 1, 6

Common Non-Serious Side Effects

Gastrointestinal

• Diarrhea, nausea, vomiting, and gastric discomfort (including dyspepsia, gastritis, epigastric discomfort, and abdominal pain) are common 7, 8
• Most gastrointestinal events are mild or moderate in severity, lasting ≤4 weeks 8

Dermatologic

• Acne is a common side effect across all indications 7
• Rash occurs in some patients 7

Other Common Effects

• Headache is frequently reported 7, 8
• Upper respiratory tract infections (common cold, sinus infections) and nasopharyngitis (nasal congestion, sore throat, runny nose) are common 7
• Hypertension (high blood pressure) can develop 7
• Fever may occur, particularly in pediatric patients 7

Dose-Dependent Risk Profile

The 10 mg twice daily dose is associated with higher risk of adverse effects compared to 5 mg twice daily, including increased infection risk, cytopenia, anemia, and cardiovascular events 1, 5, 2. However, at 3-month follow-up, overall adverse drug events, serious adverse events, and discontinuation rates are similar between doses, with anemia being the primary distinguishing factor 5.

Critical Monitoring Requirements

• Permanent discontinuations due to non-serious adverse events occur in <1.0% of RA patients, with gastric discomfort being the most frequent cause of temporary discontinuation (0.3-0.8%) 8
• Most adverse events are mild or moderate in severity, with infections and infestations being the most common category 3
• The safety profile remains consistent during long-term therapy up to 9.5 years in clinical trials 9