Safinamid: Effects in Parkinson's Disease

Safinamid (trade name Xadago) is a selective and reversible inhibitor of monoamine oxidase B (MAO B) with additional modulation of glutamate release. Licensed in Europe since 2015, it is used as add-on therapy in patients with Parkinson's disease who suffer from levodopa fluctuations such as wearing off or on-off phenomena. It thus supplements the spectrum of Parkinson's medications with a substance having a dual mechanism of action.

Compared to classical MAO B inhibitors such as selegiline and rasagiline, safinamid has an additional non-dopaminergic effect through modulation of voltage-dependent sodium channels and reduction of glutamate release. This component can theoretically positively influence motor complications such as dyskinesia and non-motor symptoms such as sleep disorders or pain. Clinically, safinamid is a reasonable option for patients who are insufficiently treated with selegiline or rasagiline or who have tolerability issues.

Mechanism of Action

Safinamid selectively and reversibly inhibits monoamine oxidase B (MAO B) in the central nervous system. MAO B breaks down dopamine in the synaptic cleft. Inhibition of this enzyme increases dopamine availability and prolongs the effect of levodopa, which reduces wearing off phenomena. In contrast to selegiline and rasagiline (irreversible MAO B inhibitors), the binding of safinamid to MAO B is reversible, which theoretically offers a more favorable side effect profile.

Additionally, safinamid blocks voltage-dependent sodium channels and thereby reduces the release of glutamate. This non-dopaminergic effect could contribute to reducing levodopa-induced dyskinesia. Studies show a significant prolongation of the ON phase without an increase in dyskinesia, which distinguishes safinamid from some other add-on therapies.

Pharmacokinetically, safinamid shows good oral bioavailability (approximately 95 percent), the half-life is 20 to 26 hours, which allows once-daily dosing. Metabolism occurs predominantly hepatically via multiple pathways without major CYP3A4 involvement, which reduces the risk of classical drug interactions.

Indications

• Parkinson's disease in adult patients with advanced disease as add-on to levodopa-based therapy, especially in cases of wearing off or on-off phenomena
• Add-on therapy with combined Parkinson's treatment with dopamine agonists and levodopa
• Off-label in early stages or as monotherapy is not recommended due to limited data

Safinamid is not approved for first-line therapy of Parkinson's disease. In very young patients or in less advanced disease, dopamine agonists or levodopa monotherapy are established. Self-medication is not an option.

Dosage and Administration

Adults: Start with 50 mg once daily orally. After two weeks, increase to 100 mg once daily if clinically indicated and well tolerated.

Time of administration: Once daily, approximately at the same time each day, with or without food. Swallow tablet whole with water.

Duration of therapy: Long-term, as long as efficacy and tolerability are maintained. Re-evaluation after three and six months is advisable.

Renal impairment: No dose adjustment at eGFR above 30 ml per minute. In severe renal impairment (eGFR below 30), use caution and individual assessment. Hepatic impairment: With moderate impairment, maximum dose 50 mg daily. Not recommended in severe hepatic impairment.

Levodopa adjustment: In patients on safinamid, a reduction of levodopa dose may be warranted if dyskinesia occurs or marked ON phase with hyperkinesias is reported. Adjustment is made by the treating neurologist.

Side Effects

Common: Dyskinesia, insomnia, orthostatic hypotension, nausea, headache, falls.

Occasional: Worsening of hallucinations or delusions, confusion, elevation of liver transaminases, loss of appetite, constipation.

Rare but relevant: Impulse control disorders with pathological gambling, hypersexual behavior, excessive shopping or eating. These phenomena are characteristic of dopaminergic therapies and should be actively inquired about at every visit.

Eye side effects: In isolated cases, worsening of pre-existing retinopathy has been observed. Safinamid is contraindicated in patients with albinism, family history of hereditary retinitis pigmentosa, uveitis, or retinopathy.

Serotonin syndrome: Theoretically increased risk with concomitant use of serotonergic substances, clinically rare.

Drug Interactions

• Other MAO inhibitors (selegiline, rasagiline, tranylcypromine, moclobemide, linezolid): Combination with safinamid is contraindicated due to additive MAO inhibition.
• SSRI and SNRI (fluoxetine, paroxetine, sertraline, venlafaxine, duloxetine): Theoretically increased risk of serotonin syndrome. Cautious combination with low SSRI doses, clinical monitoring.
• Tricyclic antidepressants: Increased risk of serotonin syndrome or hypertensive reaction, combination is critical.
• Tramadol, pethidine, methadone: Theoretical risk of serotonin syndrome, individual assessment.
• Sympathomimetics (pseudoephedrine, phenylephrine, cocaine): Hypertensive reactions possible, avoid combination.
• Levodopa and dopamine agonists: Intended combination as add-on therapy. Levodopa dose can be adjusted.
• BCRP substrates (rosuvastatin, imatinib, methotrexate): Safinamid inhibits BCRP, levels can increase. Caution and monitoring with high-dose methotrexate.

Special Precautions

Pregnancy: Data limited. Use is not recommended except in cases of imperative indication and after individual counseling. Women of childbearing age should use reliable contraception. Breast-feeding: Use during breast-feeding not recommended due to unclear data.

Children and adolescents: Not approved.

Eye examinations: Safinamid is contraindicated in patients with albinism, history of retinitis pigmentosa, uveitis, or other retinal diseases. Dermatological and ophthalmological history before start of therapy.

Before start of therapy: History of psychiatric conditions, impulse control disorders in the past, retinal diseases, liver diseases. Check concomitant medications, especially antidepressants and pain-relief drugs.

Patient education: Patients and relatives should be informed about impulse control disorders and their symptoms, because these often develop gradually and are not spontaneously reported by the patient.

Lifestyle in Parkinson's disease: Physiotherapy, speech therapy, occupational therapy, regular neurological check-ups, if necessary deep brain stimulation in advanced stages as complementary options. Fall prevention and adaptation of the home environment.

Driving ability: Restricted in case of insomnia, confusion, or orthostasis. Sudden sleep onset is a rare but relevant side effect of dopaminergic therapies. Patients should carefully monitor their reaction capacity.

You might also be interested in

• Levodopa, standard therapy for Parkinson's disease
• Rasagiline, another MAO B inhibitor with a slightly different profile
• Entacapone, COMT inhibitor as add-on in wearing off
• Pramipexole, dopamine agonist as add-on or first-line
• Donepezil, cholinesterase inhibitor in Parkinson's dementia

Frequently Asked Questions

Sources

• EMA, Xadago (Safinamid) EPAR
• Gelbe Liste, Safinamid active substance profile
• BfArM, Federal Institute for Drugs and Medical Devices
• AWMF, Guidelines for Parkinson's Disease
• German Society for Neurology