Introduction
Xadago (safinamide) is a novel antiparkinsonian agent approved as an adjunct therapy to levodopa/carbidopa in patients with Parkinson's disease experiencing "off" episodes. Developed by Zambon and Newron Pharmaceuticals, it received FDA approval in 2017 and represents an important addition to the treatment arsenal for Parkinson's disease management.
Mechanism of Action
Safinamide exhibits a dual mechanism of action:
- Reversible MAO-B inhibition: Highly selective and reversible inhibition of monoamine oxidase-B (MAO-B), increasing dopamine availability in the striatum
- Sodium channel blockade: Modulates glutamate release through state-dependent sodium channel blockade, providing potential neuroprotective effects and reducing motor complications
This unique combination addresses both dopaminergic and glutamatergic pathways implicated in Parkinson's disease pathophysiology.
Indications
- Adjunctive treatment to levodopa/carbidopa in patients with Parkinson's disease experiencing "off" episodes
- Not indicated as monotherapy for Parkinson's disease
- Off-label uses: Currently under investigation for other neurological conditions but not FDA-approved for these indications
Dosage and Administration
Initial dose: 50 mg orally once daily Maintenance dose: May increase to 100 mg once daily based on clinical response and tolerability Administration: Take with or without food at the same time each day Special populations:- Renal impairment: No dosage adjustment needed for mild to moderate impairment; use caution in severe impairment
- Hepatic impairment: Contraindicated in severe hepatic impairment
- Elderly: No dosage adjustment required
- Pediatric: Safety and effectiveness not established
Pharmacokinetics
Absorption: Rapidly absorbed with Tmax of 2-3 hours; bioavailability approximately 95% Distribution: Volume of distribution ~165 L; protein binding 8-10% Metabolism: Primarily hydrolyzed by amidases; minor metabolism via CYP3A4 (approximately 5%) Elimination: Half-life 20-26 hours; primarily renal excretion (76%, mostly as unchanged drug)Contraindications
- Concomitant use with other MAO inhibitors
- Concomitant use with sympathomimetic amines, amphetamines, or cold medications containing decongestants
- Severe hepatic impairment
- History of hypersensitivity to safinamide or any component of the formulation
Warnings and Precautions
Hypertension: May cause elevated blood pressure; monitor regularly Serotonin syndrome: Risk when used with other serotonergic drugs Dyskinesia: May exacerbate or precipitate levodopa-induced dyskinesias Falling asleep during activities of daily living: Patients should be cautioned about driving or operating machinery Retinal pathology: Periodic ophthalmologic monitoring recommended Impulse control disorders: May occur; monitor for new or worsening compulsive behaviors Withdrawal-emergent hyperpyrexia and confusion: Similar to other MAO inhibitorsDrug Interactions
Contraindicated combinations:- Other MAO inhibitors (including linezolid and intravenous methylene blue)
- Sympathomimetic amines (pseudoephedrine, phenylephrine)
- Amphetamines
- Dextromethorphan
- Serotonergic drugs (SSRIs, SNRIs, tricyclic antidepressants, tramadol)
- CYP3A4 inhibitors/inducers (moderate potential for interaction)
- Other dopaminergic medications
Adverse Effects
Common (≥5%):- Dyskinesia
- Nausea
- Insomnia
- Falls
- Hypertension
- Hypertensive crisis
- Serotonin syndrome
- Hallucinations and psychotic behavior
- Impulse control disorders
- Retinal pathology
- Withdrawal symptoms
Monitoring Parameters
- Blood pressure: Baseline and regularly during treatment
- Motor function: Parkinson's disease symptoms and dyskinesias
- Mental status: Hallucinations, confusion, impulse control disorders
- Ophthalmologic exams: Periodic retinal examination
- Liver function: Baseline and periodically in patients with hepatic impairment
- Renal function: In patients with renal impairment
Patient Education
- Take medication at the same time each day, with or without food
- Do not exceed prescribed dosage
- Report any symptoms of hypertension (headache, palpitations), serotonin syndrome (agitation, confusion, fever), or impulse control disorders (gambling, shopping, eating urges)
- Avoid foods high in tyramine (aged cheeses, cured meats, fermented foods) although risk is lower than with non-selective MAO inhibitors
- Inform all healthcare providers about Xadago use before starting any new medications
- Be cautious when driving or operating machinery due to potential drowsiness
- Do not stop medication abruptly without medical supervision
- Keep regular appointments for blood pressure monitoring and follow-up
References
1. FDA Prescribing Information: Xadago (safinamide) tablets. 2017 2. Schapira AHV, et al. Assessment of Safety and Efficacy of Safinamide as a Levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial. JAMA Neurol. 2017;74(2):216-224 3. Cattaneo C, et al. Safinamide in Parkinson's disease: Focus on pharmacological and clinical profile. Expert Rev Neurother. 2016;16(6):669-678 4. Borgohain R, et al. Randomized trial of safinamide add-on to levodopa in Parkinson's disease with motor fluctuations. Mov Disord. 2014;29(2):229-237 5. Müller T. Safinamide: The Evidence of Its Therapeutic Impact in Parkinson's Disease. Drug Des Devel Ther. 2021;15:2949-2957