Upadacitinib

Upadacitinib is an oral selective Janus kinase 1 inhibitor given once daily as an extended release tablet, used in rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, giant cell arteritis, atopic dermatitis, ulcerative colitis and Crohn disease. It shares the class warnings of serious infection, thrombosis, major cardiovascular events, malignancy and mortality.

Class. Selective Janus kinase 1 inhibitor, targeted synthetic disease-modifying anti-rheumatic drug.

Mechanism. It inhibits JAK1 more than JAK2, JAK3 and TYK2, blocking signalling of interleukin 6, interferon gamma and other cytokines through signal transducer and activator of transcription proteins.

Pharmacokinetics. Extended release gives a peak at 2 to 4 hours and a half-life of about 8 to 14 hours. Metabolised mainly by CYP3A4, with minor CYP2D6. About 24 percent is excreted unchanged in urine. Food has little effect.

Rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis (after inadequate response to conventional or biological drugs).

• 15 mg orally once daily.

• Loading dose: none.

• Maximum dose: 15 mg daily in these indications.

Giant cell arteritis. 15 mg once daily with a glucocorticoid taper over 26 weeks.

Atopic dermatitis (adult, and adolescent from 12 years and 30 kg). 15 mg once daily; adults may increase to 30 mg once daily for inadequate response. Maximum dose 30 mg daily.

Ulcerative colitis.

• Induction: 45 mg once daily for 8 weeks (extend to 16 weeks if there is no response).

• Maintenance: 15 mg once daily; 30 mg once daily for severe or extensive disease or inadequate response.

• Maximum dose: 45 mg daily during induction only.

Crohn disease.

• Induction: 45 mg once daily for 12 weeks.

• Maintenance: 15 mg once daily; 30 mg once daily for severe disease. Maximum 30 mg daily in maintenance.

Dose adjustments.

• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin): in bowel disease use 30 mg once daily for induction and 15 mg once daily for maintenance; in atopic dermatitis use 15 mg once daily.

• Strong CYP3A4 inducers (rifampicin): avoid.

• Renal impairment: no change for eGFR 30 mL/min or more; eGFR 15 to 29 mL/min, use 15 mg daily (30 mg for bowel disease induction, 15 mg maintenance); under 15 mL/min, avoid.

• Hepatic impairment: no change in mild to moderate impairment (Child-Pugh A and B for the 15 mg dose); avoid in severe impairment (Child-Pugh C).

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 (including lymphoma and lung cancer), major adverse cardiovascular events, and thrombosis. Regulatory restrictions in many regions limit use in patients aged 65 years and over, long-term smokers, and those with cardiovascular or malignancy risk, unless no suitable alternative exists.

Adverse effects. Common: upper respiratory infection, nausea, raised creatine kinase, cough, acne, herpes zoster and simplex, raised cholesterol, neutropenia, raised transaminases, headache. Serious: opportunistic infection and tuberculosis reactivation, venous thromboembolism, gastrointestinal perforation, lymphopenia, anaemia, hepatotoxicity, rhabdomyolysis (rare).

Major interactions. Strong CYP3A4 inhibitors (halve exposure by reducing dose) and inducers (avoid), potent immunosuppressants such as ciclosporin and azathioprine (avoid), other biologics and JAK inhibitors (avoid), live vaccines (avoid), grapefruit.

Common prescribing errors. Giving 45 mg beyond induction; not adjusting for strong CYP3A4 inhibitors; using in an older smoker with cardiovascular risk when alternatives exist; omitting blood count and lipid checks.

Special groups.

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

• Breastfeeding: avoid during treatment and for 6 days after the last dose.

• Children: from 12 years and 30 kg in atopic dermatitis at 15 mg once daily; other uses in children are not established.

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

• Kidney impairment: as stated under dose adjustments.

• Liver impairment: avoid in severe impairment.

• 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 lowers exposure markedly.

Formulations. 15 mg, 30 mg and 45 mg extended release tablets, swallowed whole with or without food, at the same time each day. Do not split, crush or chew.

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; no live vaccines).

Monitoring. Full blood count and liver enzymes at 4 to 12 weeks then every 3 months; lipids 12 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.