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Safinamide
Quick Facts
- Generic Name
- Safinamide
- Brand Names
- Xadago
- Drug Class
- MAO-B inhibitor
- FDA Approved
- 2017
How It Works
Safinamide is a selective, reversible inhibitor of monoamine oxidase type B (MAO-B) with a unique dual mechanism of action: in addition to MAO-B inhibition, it blocks voltage-dependent sodium channels and modulates glutamate release at higher doses. This combination of dopaminergic and non-dopaminergic mechanisms distinguishes it from older MAO-B inhibitors (selegiline, rasagiline) and may provide additional benefit for both motor and non-motor symptoms of Parkinson's disease.
What to Expect as a Patient
Safinamide is added to levodopa when wearing-off motor fluctuations develop. Most people start to notice smoother, longer-lasting on-periods within the first few weeks. Your doctor will start at 50mg once daily and may increase to 100mg after 2 weeks — the higher dose activates the additional glutamate-modulating mechanism. Common side effects include increased involuntary movements (dyskinesia, usually manageable with levodopa dose adjustment), trouble sleeping, and occasional nausea. An eye exam is recommended at baseline and periodically during treatment, as preclinical studies showed retinal changes at very high doses. As with all MAO-B inhibitors, avoid certain pain medications (meperidine, tramadol) and discuss antidepressants with your doctor.
Typical Dosing
Start 50mg once daily; may increase to 100mg once daily after 2 weeks. The 100mg dose activates the sodium channel/glutamate mechanism. Used only as adjunct to levodopa.
Dosing is individualized by the prescribing physician. The information above is for general reference only.
Common Side Effects
- Dyskinesia
- Falls
- Nausea
- Insomnia
Serious Side Effects
Seek medical attention immediately if you experience any of the following:
- Serotonin syndrome
- Impulse control disorders
- Retinal degeneration (seen in preclinical studies — ophthalmic monitoring recommended)
Contraindications
- Concurrent opioids (meperidine, tramadol)
- Concurrent MAO inhibitors
- Severe hepatic impairment
- Concurrent dextromethorphan
Food Interactions
May be taken with or without food.
Drug Interactions
The following interactions have been documented with Safinamide. Always inform your healthcare provider about all medications you are taking.
Two MAO-B inhibitors should never be combined due to excessive MAO inhibition.
Clinical effects: Risk of hypertensive crisis, serotonin syndrome.
Management: Never combine. Adequate washout period required between agents.
Two MAO-B inhibitors must never be combined due to risk of excessive monoamine oxidase inhibition.
Clinical effects: Hypertensive crisis, serotonin syndrome if combined with serotonergic agents, potentially fatal.
Management: Never combine. Allow at least 14 days washout when switching between MAO-B inhibitors.
Safinamide has weak serotonergic activity. Pimavanserin is a 5-HT2A inverse agonist. Theoretical risk of altered serotonergic signaling.
Clinical effects: Potential for altered serotonin balance. Clinical significance uncertain but monitor for mood changes.
Management: Monitor for changes in mood, behavior, or psychotic symptoms. Combination may actually be complementary (MAO-B inhibition plus antipsychotic without dopamine blockade).
How Safinamide Compares to Alternatives
Safinamide is the newest of three MAO-B inhibitors for PD. Its key differentiator is the dual mechanism: MAO-B inhibition plus sodium channel blockade/glutamate modulation at the 100mg dose. This non-dopaminergic component may explain observed benefits for pain and motor fluctuations beyond what MAO-B inhibition alone provides. Compared to rasagiline and selegiline: safinamide is approved ONLY as adjunct to levodopa (not monotherapy); it is reversible (returns to baseline after stopping, whereas rasagiline/selegiline are irreversible); and it may offer additional benefit for non-motor symptoms. Clinical trials showed safinamide increases daily on-time by approximately 1.4 hours vs. approximately 0.8-1.0 hours for rasagiline as add-on therapy.
When Is Safinamide Used by Disease Stage?
Not appropriate for early PD as monotherapy — safinamide is FDA-approved only as adjunct to levodopa. Mid-stage PD (Stage 2.5-3): Primary role — added when wearing-off motor fluctuations develop. The dual mechanism at 100mg may provide broader benefit than older MAO-B inhibitors. Advanced PD (Stages 4-5): Continued as part of multi-drug regimens. The glutamate modulation component may be particularly relevant for pain management in advanced disease.
Additional Notes
The newest MAO-B inhibitor (FDA approved 2017). Used only as adjunct to levodopa in mid-to-late stage PD — unlike rasagiline and selegiline, it is NOT approved as monotherapy. The SETTLE trial demonstrated that safinamide 100mg/day increased daily on-time by 1.42 hours compared to 0.57 hours with placebo, while reducing off-time by 1.03 hours. The dual mechanism at the 100mg dose may provide benefit for pain and other non-motor symptoms through glutamate modulation.
Clinical Perspective
Safinamide represents an interesting evolution in MAO-B inhibitor design. Where rasagiline and selegiline are straightforward MAO-B inhibitors, safinamide adds a second, non-dopaminergic mechanism that theoretically addresses some of the limitations of purely dopaminergic therapy. The clinical trial data supports modestly greater on-time improvement than older MAO-B inhibitors, though no head-to-head trials exist. The restriction to adjunctive use (no monotherapy approval) and higher cost limit its role. Nevertheless, for patients with mid-stage PD experiencing both motor fluctuations and pain, safinamide's dual mechanism offers a theoretically appealing option.
This perspective is based on published clinical evidence and guidelines. Individual treatment decisions should always be made with your neurologist.
Sources
- [1]Borgohain R, Szasz J, Stanzione P, et al. Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson disease. Mov Disord. 2014;29(10):1273-1280
- [2]Schapira AH, Fox SH, Hauser RA, et al. Assessment of safety and efficacy of safinamide as a levodopa adjunct in patients with Parkinson disease and motor fluctuations (SETTLE): a randomized, double-blind, placebo-controlled trial. JAMA Neurol. 2017;74(2):216-224
- [3]Cattaneo C, Sardina M, Bonizzoni E. Safinamide as add-on therapy to levodopa in mid- to late-stage Parkinson disease fluctuating patients: post hoc analyses of studies 016 and SETTLE. J Parkinsons Dis. 2016;6(1):165-173
- [4]Tanner CM, Ostrem JL. Parkinson disease. N Engl J Med. 2024;391(5):442-452
- [5]Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA. 2014;311(16):1670-1683
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