Fingolimod

Fingolimod is an oral sphingosine 1-phosphate receptor modulator used for relapsing-remitting multiple sclerosis, with higher efficacy than first-line oral drugs. It causes first-dose bradycardia and heart block, macular oedema and serious infections, and severe rebound disease can follow stopping.

Mechanism. Phosphorylated to fingolimod phosphate, which causes lymphocytes to be retained in lymph nodes and reduces their entry to the central nervous system.

Pharmacokinetics. Bioavailability about 93% and half-life 6 to 9 days. It is metabolised by sphingosine kinase and cytochrome P450 4F2. Effects on lymphocytes last about 2 months after stopping.

Specialist use. Relapsing-remitting multiple sclerosis in adults and in children and adolescents, usually after first-line therapy or with highly active disease.

• Oral fingolimod: 0.5 mg once daily in adults and in children 10 years and over weighing over 40 kg. For children 10 years and over weighing 40 kg or less, 0.25 mg once daily.

• First-dose monitoring: check an ECG and blood pressure before the first dose, and observe for at least 6 hours with hourly pulse and blood pressure and an ECG at the end. Extend observation if the heart rate is lowest at 6 hours, if new heart block appears, or if the QTc exceeds 500 ms.

• Repeat first-dose monitoring after missing a dose for 1 day or more in the first 2 weeks, 7 days or more in weeks 3 to 4, or more than 2 weeks after the first month.

Kidney, liver, weight and age.

• Kidney: no adjustment.

• Liver: mild to moderate impairment, no change but closer monitoring. Severe impairment (Child-Pugh C), contraindicated.

• Older adults: use caution over age 65.

Contraindications. Myocardial infarction, unstable angina, stroke, transient ischaemic attack or decompensated heart failure in the last 6 months, class III or IV heart failure, second degree Mobitz II or third degree block or sick sinus syndrome without a pacemaker, QTc over 500 ms, treatment with class Ia or III antiarrhythmics, immunodeficiency, severe active infection, active cancer, severe hepatic impairment, pregnancy and women of childbearing potential not using effective contraception, and hypersensitivity.

Serious adverse effects. Bradycardia and atrioventricular block, macular oedema, serious infections (cryptococcal meningitis, herpes viral infections, progressive multifocal leukoencephalopathy), lymphopenia, liver enzyme elevation, hypertension, skin cancers including basal cell carcinoma, severe disease rebound after stopping, and posterior reversible encephalopathy syndrome.

Common adverse effects. Headache, influenza-like illness, diarrhoea, back pain, cough and raised liver enzymes.

Interactions. Beta blockers, diltiazem, verapamil, ivabradine and digoxin add bradycardia. Class Ia and III antiarrhythmics and other QT-prolonging drugs are contraindicated or avoided. Ketoconazole raises levels, and carbamazepine lowers them. Live vaccines are avoided during treatment and for 2 months after.

Common prescribing errors. Skipping first-dose monitoring. Starting without ophthalmic and varicella checks. Not repeating monitoring after a gap. Stopping without a plan.

Special groups.

• Pregnancy: contraindicated. Use effective contraception during treatment and for 2 months after stopping.

• Breastfeeding: avoid.

• Regional: screen for hepatitis B, hepatitis C, HIV and tuberculosis before starting, and be alert to cryptococcal infection.

Formulations. Capsules 0.25 and 0.5 mg. Oral solution in some markets. Take once daily at the same time, with or without food.

Monitoring.

• Baseline: ECG, blood pressure, full blood count with lymphocytes, liver function, varicella antibody (vaccinate if negative and wait 1 month), pregnancy test, ophthalmic examination, and skin check.

• Ongoing: liver function at 1, 3, 6, 9 and 12 months and then periodically. Ophthalmic examination at 3 to 4 months, and earlier with visual symptoms. Full blood count periodically, interrupting for lymphocytes under 0.2 x 10^9/L. Annual skin examination and blood pressure checks.

Stopping. Rebound relapses can be severe within 4 to 24 weeks, so plan the next therapy with the specialist before stopping.

Referral and escalation. Manage under a multiple sclerosis specialist. Refer urgently for visual change, serious infection, new neurological deficit or symptomatic bradycardia.