Xeljanz - Drug Monograph

Introduction

Xeljanz (tofacitinib) is an oral Janus kinase (JAK) inhibitor developed by Pfizer for the treatment of autoimmune conditions. First approved by the FDA in 2012, it represents a novel class of small molecule immunomodulators that target intracellular signaling pathways rather than extracellular targets like many biologic therapies.

Mechanism of Action

Tofacitinib inhibits Janus kinase enzymes (JAK1, JAK2, JAK3, and to a lesser extent TYK2), which are critical for cytokine signaling in immune cells. By blocking the JAK-STAT pathway, Xeljanz prevents the phosphorylation and activation of STAT proteins, thereby modulating the immune response. Specifically, it interferes with signaling for multiple cytokines including interleukins (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21) and interferons, which are involved in inflammation and immune activation in autoimmune diseases.

Indications

FDA-approved indications include:

• Moderate to severe rheumatoid arthritis (as monotherapy or in combination with methotrexate)
• Psoriatic arthritis
• Ulcerative colitis
• Ankylosing spondylitis (extended-release formulation)

Off-label uses (with varying evidence) include:

• Crohn's disease
• Alopecia areata
• Juvenile idiopathic arthritis

Dosage and Administration

• Immediate-release: 5 mg twice daily
• Extended-release: 11 mg once daily

• Induction: 10 mg twice daily for at least 8 weeks
• Maintenance: 5 mg twice daily or 11 mg once daily

• Renal impairment: Reduce dose for moderate to severe impairment
• Hepatic impairment: Reduce dose for moderate impairment; not recommended for severe impairment
• Elderly: No specific dose adjustment required
• Pediatrics: Safety and effectiveness not established

Pharmacokinetics

• Absorption: Rapid absorption with peak plasma concentrations in 0.5-1 hour
• Distribution: Volume of distribution ~87 L; 40% bound to plasma proteins
• Metabolism: Primarily hepatic via CYP3A4 and CYP2C19
• Elimination: Half-life ~3 hours; 70% excreted in urine, 30% in feces
• Bioavailability: 74%

Contraindications

• Hypersensitivity to tofacitinib or any component
• Active serious infections (including tuberculosis, bacterial, viral, fungal)
• Severe hepatic impairment
• Concomitant use with potent immunosuppressants

Warnings and Precautions

• Serious infections leading to hospitalization or death
• Increased risk of all-cause mortality, major adverse cardiovascular events, and malignancy (observed in rheumatoid arthritis patients 50+ with cardiovascular risk factors)
• Thrombosis (including pulmonary embolism, deep venous thrombosis)

• Lymphoma and other malignancies
• Gastrointestinal perforations
• Laboratory abnormalities (neutropenia, lymphopenia, anemia, liver enzyme elevations)
• Vaccinations: Avoid live vaccines during therapy
• HBV/HCV reactivation monitoring required

Drug Interactions

• Potent CYP3A4 inhibitors (ketoconazole, clarithromycin): Increase tofacitinib exposure
• Potent CYP3A4 inducers (rifampin, carbamazepine): Decrease tofacitinib exposure
• Immunosuppressants: Increased risk of infections
• NSAIDs: Potential increased GI toxicity

Adverse Effects

• Upper respiratory tract infections
• Headache
• Diarrhea
• Nasopharyngitis
• Hypertension
• Increased cholesterol levels

• Serious infections (pneumonia, cellulitis, herpes zoster)
• Venous thromboembolism
• Malignancies (lymphoma, lung cancer)
• Gastrointestinal perforations
• Hematologic toxicity (neutropenia, anemia)

Monitoring Parameters

• CBC with differential
• Liver function tests
• Lipid profile
• Tuberculosis screening
• Viral hepatitis screening
• Pregnancy test if applicable

• Infection signs/symptoms at every visit
• CBC, LFTs, lipids at 4-8 weeks then every 3 months
• Blood pressure monitoring
• Clinical response assessment
• Thrombosis risk assessment

Patient Education

• Take exactly as prescribed; do not crush or chew extended-release tablets
• Report signs of infection immediately (fever, cough, sores)
• Seek immediate medical attention for shortness of breath, chest pain, or leg swelling
• Avoid live vaccines during treatment
• Use effective contraception during treatment
• Regular laboratory monitoring is essential
• Report any new or worsening symptoms promptly
• Maintain all follow-up appointments

References

1. US Food and Drug Administration. (2021). Xeljanz prescribing information. 2. Winthrop KL, et al. (2021). N Engl J Med; 385(7):566-575. 3. Ytterberg SR, et al. (2022). N Engl J Med; 386(4):316-326. 4. Sandborn WJ, et al. (2017). N Engl J Med; 377(5):496-497. 5. van Vollenhoven RF, et al. (2019). Lancet; 394(10214):2108-2117. 6. American College of Rheumatology. (2021). Arthritis Care Res; 73(7):924-939. 7. European Medicines Agency. (2022). Xeljanz product information. 8. Cohen SB, et al. (2020). Arthritis Rheumatol; 72(9):1455-1466.