Tofacitinib

Tofacitinib is an oral Janus kinase inhibitor with preferential activity against JAK1 and JAK3, used in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis and polyarticular juvenile idiopathic arthritis. It is a targeted synthetic disease-modifying drug used after conventional therapy, and is restricted in patients with cardiovascular, thrombotic or malignancy risk.

Class. Janus kinase inhibitor, targeted synthetic disease-modifying anti-rheumatic drug.

Mechanism. It inhibits JAK1 and JAK3 (and to a lesser extent JAK2), blocking signalling of interleukins 2, 4, 7, 9, 15 and 21, interferons and others through the signal transducer and activator of transcription route, reducing lymphocyte activation and inflammatory cytokine output.

Pharmacokinetics. Bioavailability about 74 percent, peak at 0.5 to 1 hour, half-life about 3 hours (immediate release). Metabolised mainly by CYP3A4 (70 percent) and CYP2C19, with about 30 percent renal excretion unchanged.

Rheumatoid arthritis and psoriatic arthritis (after inadequate response to conventional drugs).

• 5 mg orally twice daily, or 11 mg modified release once daily.

• Loading dose: none.

• Maximum dose: 10 mg daily in rheumatological use.

Ankylosing spondylitis. 5 mg twice daily.

Ulcerative colitis.

• Induction: 10 mg twice daily for at least 8 weeks, extended to 16 weeks if no response.

• Maintenance: 5 mg twice daily; 10 mg twice daily only for patients with loss of response or high risk, at the lowest effective dose.

• Maximum dose: 20 mg daily.

Polyarticular juvenile idiopathic arthritis (2 years and over, specialist). Weight-banded oral solution twice daily.

Dose adjustments.

• Moderate to severe renal impairment (creatinine clearance under 30 mL/min): 5 mg once daily.

• Moderate hepatic impairment (Child-Pugh B): 5 mg once daily; severe hepatic impairment (Child-Pugh C): avoid.

• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin) or combined moderate CYP3A4 and strong CYP2C19 inhibitors (fluconazole): halve the dose (for example 5 mg once daily).

• Interrupt for lymphocytes under 0.5 x 10^9/L, neutrophils under 1.0 x 10^9/L, haemoglobin under 8 g/dL or a fall of over 2 g/dL.

Contraindications. Active serious infection including tuberculosis, severe hepatic impairment, pregnancy, and hypersensitivity. Avoid in patients with past venous thromboembolism or high thrombotic risk.

Boxed-warning-level risks. Serious infections, increased all-cause and cardiovascular mortality, malignancy (lymphoma, lung cancer), major adverse cardiovascular events (in patients aged 50 years and over with a cardiovascular risk factor), and thrombosis (deep vein thrombosis, pulmonary embolism and arterial thrombosis). Regulatory restrictions in many regions limit use in patients aged 65 years and over, current or past long-term smokers, and those with cardiovascular or malignancy risk, unless no suitable alternative exists.

Adverse effects. Common: upper respiratory infection, headache, diarrhoea, nasopharyngitis, hypertension, raised cholesterol, raised transaminases. Serious: herpes zoster (common), tuberculosis and opportunistic infection, gastrointestinal perforation, venous thromboembolism, lymphopenia, neutropenia, anaemia, raised creatine kinase, interstitial lung disease.

Major interactions. Strong CYP3A4 inhibitors and inducers (rifampicin lowers exposure by about 85 percent; avoid), fluconazole, potent immunosuppressants such as azathioprine and ciclosporin (avoid), other biologics (avoid), live vaccines (avoid).

Common prescribing errors. Using in an older smoker with cardiovascular risk when alternatives exist; not reducing the dose with fluconazole or renal or hepatic impairment; omitting lipid, blood count and tuberculosis checks.

Special groups.

• Pregnancy: contraindicated; contraception during treatment and for at least 4 weeks after the last dose.

• Breastfeeding: avoid during treatment and for at least 18 hours after the last dose.

• Children: weight-banded dosing for polyarticular juvenile idiopathic arthritis only.

• Older adults: avoid where possible from 65 years; use the lowest effective dose.

• Kidney impairment: 5 mg once daily with creatinine clearance under 30 mL/min.

• Liver impairment: 5 mg once daily in moderate impairment; avoid in severe.

• Region: tuberculosis, hepatitis B and C and HIV are common in East Africa; screen before starting and consider recombinant zoster vaccination. Rifampicin used for tuberculosis treatment greatly reduces exposure.

Formulations. 5 mg and 10 mg immediate release tablets, 11 mg and 22 mg modified release tablets, and oral solution. Take with or without food; swallow modified release tablets whole.

Baseline. Tuberculosis screen, hepatitis B and C and HIV serology, full blood count with lymphocyte and neutrophil counts, ALT, AST, creatinine, lipid profile, creatine kinase, cardiovascular risk review, and vaccination update (recombinant zoster vaccine).

Monitoring. Full blood count and liver enzymes at 4 to 8 weeks then every 3 months; lipids 4 to 8 weeks after starting then every 6 to 12 months; creatinine every 3 to 6 months; skin and lung cancer vigilance; infection and thrombosis symptoms at each visit.

Stop or hold thresholds. Lymphocytes under 0.5 x 10^9/L (stop), neutrophils under 1.0 x 10^9/L (hold), haemoglobin under 8 g/dL (hold), ALT over 3 times the upper limit of normal with suspected drug injury (hold and investigate), serious infection, venous thromboembolism, or gastrointestinal perforation.

Referral and escalation. Specialist initiated. Refer for suspected thromboembolism, cardiovascular events, or persistent cytopenia.