Tofacitinib for Ulcerative Colitis

Tofacitinib is an oral Janus kinase inhibitor used for moderate to severe ulcerative colitis after conventional or biologic treatment has failed. It acts quickly, within days, but carries warnings for serious infection, thrombosis, cardiovascular events and malignancy, so it is generally reserved for patients who have failed at least one biologic.

Classification. Targeted synthetic small molecule; Janus kinase (JAK) inhibitor.

Mechanism. Inhibits JAK1 and JAK3 (and to a lesser extent JAK2), blocking signalling of interleukin 2, 4, 6, 7, 9, 15 and 21 and interferons through the JAK and STAT signalling cascade, and reducing lymphocyte activation and inflammatory cytokine effects.

Pharmacodynamics. Onset within 3 to 8 days in some patients; remission assessed at 8 weeks.

Pharmacokinetics. Oral bioavailability about 74%. Half-life about 3 hours; steady state within 24 to 48 hours. Protein binding about 40%.

Metabolism. About 70% by hepatic CYP3A4 (and minor CYP2C19); about 30% excreted unchanged by the kidneys.

Adult oral doses.

Active moderate to severe ulcerative colitis.

• Induction: 10 mg twice daily for 8 weeks.

• If adequate response is not achieved by week 8, continue 10 mg twice daily for a further 8 weeks (16 weeks total); stop if there is no response by week 16.

• Maintenance: 5 mg twice daily.

• For patients with loss of response on 5 mg twice daily, 10 mg twice daily may be used for the shortest time and at the lowest effective dose, for those without cardiovascular, thrombotic or malignancy risk.

• Use 10 mg twice daily only for the shortest time possible.

Dose adjustments.

• Moderate or severe kidney impairment (CrCl under 60 mL/min): reduce to half the dose (5 mg twice daily for induction; 5 mg once daily for maintenance).

• Moderate liver impairment (Child-Pugh B): reduce to half the dose; avoid in severe impairment (Child-Pugh C).

• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir): halve the dose.

• Strong CYP2C19 and CYP3A4 inhibitors together (fluconazole): halve the dose.

• Lymphocytes under 750 cells/mm3, neutrophils under 1,000 cells/mm3, haemoglobin under 8 g/dL: interrupt treatment.

Children. Not established for ulcerative colitis.

Contraindications.

• Active serious infection, including active tuberculosis.

• Severe liver impairment.

• Pregnancy and breastfeeding.

• Lymphocyte count under 500 cells/mm3, neutrophils under 1,000 cells/mm3 or haemoglobin under 8 g/dL at baseline.

• Hypersensitivity.

Common adverse effects. Headache, nasopharyngitis, upper respiratory infection, raised cholesterol and creatine kinase, acne, herpes zoster, diarrhoea and rash.

Serious adverse effects.

• Serious infections including tuberculosis, invasive fungal infection and herpes zoster; hepatitis B reactivation.

• Venous thromboembolism (deep vein thrombosis, pulmonary embolism), arterial thrombosis and major adverse cardiovascular events, particularly at 10 mg twice daily and in those with risk factors, including age over 65 years and smoking.

• Malignancy, including lymphoma, lung cancer and non-melanoma skin cancer.

• Gastrointestinal perforation.

• Cytopenias (lymphopenia, neutropenia, anaemia), raised liver enzymes and lipid elevation.

Major interactions.

• Strong CYP3A4 inhibitors and combined CYP3A4 and CYP2C19 inhibitors (fluconazole): raise levels; halve the dose.

• Strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John's wort): lower levels; avoid.

• Biologics and potent immunosuppressants (azathioprine, ciclosporin, tacrolimus): avoid combination.

• Live vaccines: avoid.

Special groups.

• Pregnancy: avoid; teratogenic in animals; use effective contraception during treatment and for at least 4 weeks after the last dose.

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

• Children: not established.

• Older adults: over 65 years carries higher infection, malignancy and cardiovascular risk; use only if no alternative.

• Kidney impairment: reduce the dose.

• Liver impairment: reduce in moderate impairment; avoid in severe.

• Regional: limited availability in East Africa; tuberculosis and herpes zoster screening and vaccination (recombinant zoster vaccine) are important.

Formulations. Tablets 5 mg and 10 mg; extended-release tablets 11 mg in some markets; oral solution 1 mg/mL.

Administration.

• Swallow tablets whole, with or without food.

• Avoid grapefruit juice.

• Avoid in patients with cardiovascular risk factors unless no other option.

Baseline.

• Tuberculosis screening, hepatitis B and C, HIV, full blood count (absolute lymphocyte and neutrophil counts, haemoglobin), liver tests, kidney function and fasting lipids.

• Cardiovascular and thrombosis risk assessment; smoking status.

• Pregnancy test and contraception counselling.

• Zoster vaccination and other vaccines before starting.

Monitoring.

• Full blood count at 4 to 8 weeks, then every 3 months.

• Lipids at 8 to 12 weeks after starting, then manage using the patient's cardiovascular risk.

• Liver tests periodically.

• Signs of infection, thrombosis (limb swelling, breathlessness, chest pain) and skin cancer (yearly skin examination).

• Clinical response at 8 weeks; endoscopic response at 16 weeks.

Therapeutic drug monitoring. Not applicable.

Stopping. Stop for serious infection, venous thromboembolism, cytopenias, perforation, malignancy or no response at 16 weeks. Relapse may occur within weeks after stopping.

Referral and escalation. Specialist gastroenterology care throughout. Urgent assessment for chest pain, breathlessness, limb swelling, severe abdominal pain or persistent fever.