TofacitinibRx

Trade Names: Xeljanz

Drug Class: Janus-associated kinase (JAK) inhibitor, targeted synthetic DMARD

Preparations: 5 mg tablet

Dose: 5 mg twice a day; reduce to 5 mg daily in moderate or severe renal impairment, moderate hepatic impairment, or interacting drugs that inhibit its metabolism

Indications: Moderate to severe active RA in adults

Mechanism of Action: Inhibit JAKs 1, 2 and 3 thus decreasing activation of the signal transducer and activator of transcription (STAT) pathway affecting lymphocyte differentiation and inflammation.

Contraindications: Hypersensitivity, untreated tuberculosis or other opportunistic infections, sepsis, active infections, chronic localized or recurrent infections, severe hepatic impairment, other strong immunosuppressants

Precautions: Increased risk of serious infections including TB and fungal. Exclude latent or active TB with a skin test or TB blood test (interferon-gamma release assays or IGRA). Caution in debilitated or high risk of infection or GI perforation. Exclude hepatitis B or C infection. Avoid live virus vaccines and BCG. Do not use with biologics or strong immunosuppressants (e.g., azathioprine, cyclosporine, tacrolimus, cyclophosphamide). Do not initiate therapy in patients with lymphocyte count <500 /mm3, neutrophil count <1000 cells/mm3, or hemoglobin <9 g/dL.

Monitoring: Monitor clinically for infection. CBC with diff and platelet count, LFTs and creatinine at baseline, after 4-8 weeks and every 3 months thereafter; check lipids at 4-8 weeks and periodically. Discontinue if lymphocyte count <500/mm3 or neutrophil count <500 cells/mm3. Interrupt therapy if neutrophil count 500-1000 /mm3 until ANC count >1000. Interrupt therapy if hemoglobin decreases more than 2 g/dL or is <8 g/dL. After therapy started, additional TB testing may be indicated for individuals likely to have exposure to TB.

Pregnancy Risk: C

Adverse Effects
Common: Diarrhea, upper respiratory infections, increased LDL cholesterol
Less common: Neutropenia, anemia, lymphopenia, increased creatinine, elevated liver enzymes, allergy, infection (bacterial and viral (zoster) but also opportunistic infections such as tuberculosis, cryptococcosis and fungal).
Rare: Lymphoma, cancer, GI perforation

Drug Interactions: Do not use with biologics or strong immunosuppressants (e.g., azthioprine, cyclosporine, tacrolimus, cyclophosphamide).
Increased tofacitinib levels: CYP4503A inhibitors (strong inhibitors include clarithromycin, telithromycin, ketoconazole, itraconazole, nefazodone and many HIV drugs; moderate inhibitors include aprepitant, diltiazem, verapamil, erythromycin, fluconazole, posaconazole, voriconazole, grapefruit juice)
Decreased tofacitinib concentrations: Potent CYP4503A inducers (e.g., rifampin) should be avoided.

Patient Instructions: Avoid live virus vaccines. Avoid pregnancy. Notify physician for fever or infection.

Comments: In RA patients on background methotrexate, tofacitinib and adalimumab resulted in approximately equal responses. Patients start to respond quickly, usually within 4–6 weeks but maximum response may take 4-6 months. Combined therapy with MTX is more effective than either drug alone. Long term safety data are limited.

Clinical Pharmacology: Half-life is 3 hours, hepatic metabolism by CYP4503A4 and renal excretion

Cost: $$$$$

BIBLIOGRAPHY

van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 2012;367:508-19. PMID: 22873531.