Safinamide

Safinamide is a reversible monoamine oxidase B inhibitor with additional glutamate-modulating activity, used only as an add-on to levodopa in mid to late Parkinson disease with motor fluctuations. It offers once daily dosing and, unlike older monoamine oxidase B inhibitors, enzyme inhibition is reversible.

Mechanism. Reversibly inhibits monoamine oxidase B, which slows dopamine breakdown. It also blocks voltage-gated sodium channels and reduces excessive glutamate release.

Pharmacokinetics. Bioavailability about 95% and protein binding about 90%. Half-life is 20 to 26 hours. It is metabolised mainly by amidases, not by cytochrome P450, and metabolites are excreted in urine.

Alternative use. Adjunct to levodopa (with or without other Parkinson drugs) for OFF time in mid to late disease. It is not used alone.

• Oral safinamide: 50 mg once daily. After 2 weeks, increase to 100 mg once daily if clinically needed. Maximum 100 mg daily. No titration beyond this is needed.

• If dyskinesia increases at the start, reduce the levodopa dose.

Kidney, liver, weight and age.

• Kidney: no adjustment.

• Liver: mild to moderate impairment, maximum 50 mg daily. Severe impairment, contraindicated.

• Older adults: no adjustment; monitor falls, hypotension and hallucinations.

Contraindications. Severe hepatic impairment, concurrent monoamine oxidase inhibitors, pethidine, tramadol and methadone, and in some labels albinism, retinal degeneration, uveitis or inherited retinopathy. Contraindicated in pregnancy in some labels.

Serious adverse effects. Worsened dyskinesia, serotonin syndrome with serotonergic drugs, hypertensive reactions with sympathomimetics, hallucinations and psychosis, impulse control disorders, sudden sleep onset and falls.

Common adverse effects. Dyskinesia, insomnia, nausea, falls, orthostatic hypotension and cataract.

Interactions. Allow at least 7 days between stopping safinamide and starting a monoamine oxidase inhibitor or pethidine, and at least 5 weeks after stopping fluoxetine before starting safinamide. Use caution with antidepressants, dextromethorphan and sympathomimetics. Safinamide can raise levels of drugs transported by the breast cancer resistance protein, such as rosuvastatin.

Common prescribing errors. Using it without levodopa. Co-prescribing opioids such as tramadol. Not reducing levodopa when dyskinesia rises.

Special groups.

• Pregnancy: avoid; use effective contraception in women of childbearing potential.

• Breastfeeding: avoid.

• Regional: costly and seldom available; over-the-counter decongestants and cough products may interact.

Formulations. Tablets 50 and 100 mg. Take once daily, with or without food.

Monitoring.

• Motor diary, dyskinesia, lying and standing blood pressure, mood, impulse control and sleepiness.

• Liver function at baseline in those with liver risk, and eye symptoms during treatment.

Stopping. Stop gradually where possible, as the benefit fades over days.

Referral and escalation. Refer for troublesome dyskinesia, psychosis, impulse control disorders or serotonin syndrome features.