Safinamide
safinamide mesylate — Brand name: Xadago
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Parkinson disease — “off” episodes during treatment with levodopa/carbidopa | Adults | Adjunctive to levodopa/carbidopa (with or without other PD drugs) | FDA Approved |
Safinamide is the newest MAO-B inhibitor approved for Parkinson disease and the only one with a dual mechanism: reversible MAO-B inhibition combined with state-dependent sodium and calcium channel blockade that modulates glutamate release. It is approved exclusively as adjunctive therapy to levodopa/carbidopa in patients experiencing off episodes and has not been shown effective as monotherapy. The SETTLE trial and Study 016 demonstrated significant increases in daily on-time without troublesome dyskinesia.
Early PD adjunct to dopamine agonist: The MOTION trial explored safinamide as add-on to dopamine agonists in early PD. The 100 mg dose met the primary endpoint but 50 mg did not. Not FDA-approved for this use. Evidence quality: Moderate
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| PD with off episodes — adjunct to levodopa | 50 mg QD | 50–100 mg QD | 100 mg/day | Same time each day, with or without food; may increase to 100 mg after ≥2 weeks No dietary tyramine restrictions required |
| Moderate hepatic impairment (Child-Pugh B) | 50 mg QD | 50 mg QD | 50 mg/day | Do not exceed 50 mg; discontinue if progression to severe impairment |
| Discontinuation from 100 mg | Taper to 50 mg QD for 1 week, then stop | Reduces withdrawal-emergent hyperpyrexia risk 50 mg can be stopped without taper | ||
Safinamide offers three practical advantages: (1) reversible MAO-B inhibition means enzyme activity recovers within days of stopping; (2) no significant CYP450 interactions, eliminating the dose-capping with ciprofloxacin required for rasagiline; (3) SSRIs are not contraindicated — only monitoring is required (per FDA PI section 7.3), making safinamide the most antidepressant-compatible MAO-B inhibitor for PD patients with comorbid depression.
Pharmacology
Mechanism of Action
Safinamide possesses a dual mechanism distinguishing it from other MAO-B inhibitors. Its primary action is highly selective, reversible inhibition of MAO-B, preventing dopamine catabolism and raising striatal dopamine levels. Complete (>90%) MAO-B inhibition is achieved at doses above 20 mg. At therapeutic concentrations, safinamide additionally blocks voltage-gated sodium channels and N-type calcium channels in a state-dependent manner, reducing pathological glutamate release from hyperactive corticostriatal neurons. This anti-glutamatergic property is mechanistically relevant because excessive glutamate in the basal ganglia contributes to motor fluctuations and levodopa-induced dyskinesia. Safinamide also demonstrates sigma-1 receptor activity and weak dopamine/serotonin reuptake inhibition, though these secondary actions’ clinical significance is uncertain.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapid; Tmax 2–3 h (fasting); bioavailability 95%; negligible first-pass. Food delays Tmax but does not affect AUC or Cmax | Can be given with or without food. Linear PK over 50–300 mg. Near-complete oral absorption |
| Distribution | Vss ~165 L; protein binding 88–89% (unbound 11–12%); extensive extravascular distribution | Large volume of distribution indicates substantial tissue uptake including CNS |
| Metabolism | Primarily amidases (non-CYP) → safinamide acid (NW-1153, inactive); minor CYP3A4. No meaningful CYP inhibition or induction | Non-CYP metabolism eliminates CYP-mediated drug interactions. May inhibit intestinal BCRP at 100 mg |
| Elimination | 76% renal (as inactive metabolites); t½ 20–26 h; clearance 4.6 L/h; steady state 5–6 days | Long half-life supports once-daily dosing. No renal adjustment. Moderate hepatic impairment increases AUC ~80% |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dyskinesia | 21% (50 mg) / 18% (100 mg) vs 9% placebo | Most common AE; reduce levodopa if bothersome. Dyskinesia caused 1% discontinuation (both doses) vs 0% placebo |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Hypertension | 7% (50 mg) / 5% (100 mg) vs 4% placebo | Monitor BP; no tyramine restriction at approved doses but avoid foods >150 mg tyramine |
| Fall | 4–6% vs 4% placebo | Multifactorial in PD; assess gait and home safety |
| Nausea | 3–6% vs 4% placebo | Dopaminergic effect; usually self-limiting |
| Insomnia | 1–4% vs 2% placebo | More common at 100 mg; consider earlier dosing |
| ALT elevation (>ULN) | 5–7% vs 3% placebo | No ALT ≥3× ULN in trials; typically mild |
| AST elevation (>ULN) | 6–7% vs 3% placebo | AST ≥3× ULN similar to placebo |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Serotonin syndrome | Rare (with serotonergic drugs) | Hours to days | Stop serotonergic agents; supportive care. SSRIs require monitoring only; SNRIs/TCAs are contraindicated |
| Hypertensive crisis | Rare at recommended doses | After very high tyramine (>150 mg) | Emergent BP reduction; ED evaluation |
| Hallucinations / psychosis | Uncommon | Variable | Dose reduction or discontinuation; avoid in major psychotic disorders |
| Sleep attacks | Uncommon | Variable | Discontinue safinamide; counsel against driving |
| Impulse control disorders | Uncommon (class effect) | Weeks to months | Dose reduction or discontinuation |
| Retinal pathology | Preclinical finding only | N/A | Monitor ophthalmology in at-risk patients (retinal disease, albinism, retinitis pigmentosa) |
| Withdrawal hyperpyrexia | Very rare | Days after abrupt stop | Taper 100 mg to 50 mg for 1 week before stopping |
Despite the high dyskinesia incidence (18–21%), safinamide’s pivotal trials measured “on-time without troublesome dyskinesia” as the primary endpoint, and safinamide significantly increased this measure. The glutamate-modulating mechanism may attenuate dyskinesia severity. When dyskinesia occurs, reducing the levodopa dose typically resolves it.
Drug Interactions
Safinamide has a simpler interaction profile than selegiline or rasagiline because it does not undergo CYP-mediated metabolism to a clinically significant degree. It retains MAOI class contraindications but with one key distinction: SSRIs are not contraindicated — only monitoring is required.
Monitoring
- Blood PressureEvery visit
RoutineHypertension in 5–7% vs 4% placebo. Monitor for new-onset or worsening hypertension, especially with sympathomimetics. - Hepatic FunctionBaseline; periodically
RoutineALT/AST shifts above ULN in 5–7% (vs 3% placebo). Contraindicated in severe impairment; cap at 50 mg in moderate. - Motor StatusEvery visit
RoutineAssess on/off time and dyskinesia. Dyskinesia is the most common AE; may require levodopa dose reduction. - Mental StatusEvery visit
RoutineScreen for hallucinations, psychotic behavior, and impulse control disorders. - OphthalmologyPeriodically in at-risk patients
Trigger-basedRetinal degeneration seen in rat studies. Monitor patients with retinal disease, albinism, retinitis pigmentosa, or active retinopathy. - SomnolenceEvery visit
Trigger-basedAsk about daytime sleepiness and sudden sleep. Discontinue if episodes occur.
Contraindications & Cautions
Absolute Contraindications
- MAOIs / linezolid — hypertensive crisis
- Opioids (meperidine, tramadol, methadone, propoxyphene) — serotonin syndrome
- SNRIs, TCAs, tetracyclics, triazolopyridines — serotonin syndrome
- Cyclobenzaprine, methylphenidate, amphetamines, St. John’s Wort
- Dextromethorphan — psychosis/abnormal behavior
- Hypersensitivity to safinamide — angioedema reported
- Severe hepatic impairment (Child-Pugh C)
Relative Contraindications
- Major psychotic disorder — risk of exacerbation
- Retinal disease, albinism, retinitis pigmentosa — preclinical retinal toxicity
Use with Caution
- SSRIs — monitor for serotonin syndrome (NOT contraindicated)
- Moderate hepatic impairment — max 50 mg/day
- Sympathomimetics / BCRP substrates — monitor BP and drug levels
Safinamide is a selective MAO-B inhibitor at recommended doses. Concomitant use with SNRIs, TCAs, opioids, or stimulants can cause life-threatening serotonin syndrome. Very high tyramine intake (>150 mg) may cause severe hypertension. Retinal degeneration was observed in animal studies; ophthalmologic monitoring is recommended in patients with pre-existing retinal conditions.
Patient Counselling
Purpose of Therapy
Safinamide is added to levodopa/carbidopa to reduce “off” time — periods when PD symptoms return because medications have worn off. It works by preventing dopamine breakdown and calming overactive brain signals.
How to Take
Take one tablet once daily at the same time each day, with or without food. No special diet is required. If stopping the 100 mg dose, reduce to 50 mg for one week first.
Sources
- Xadago (safinamide) tablets — FDA-approved prescribing information. March 2017. accessdata.fda.govPrimary source for all dosing, adverse event incidence (Table 1), PK parameters, contraindications, and taper guidance.
- European Medicines Agency. Xadago EPAR — product information. ema.europa.euEU label providing additional safety data and the EU indication for mid- to late-stage PD with motor fluctuations.
- Borgohain R, Szasz J, Stanzione P, et al. Randomized trial of safinamide add-on to levodopa in Parkinson’s disease with motor fluctuations. Mov Disord. 2014;29(2):229–237. doi:10.1002/mds.25751Study 016 (Study 1 in FDA label): 24-week pivotal trial demonstrating safinamide 50/100 mg increased on-time without troublesome dyskinesia.
- Schapira AHV, Fox SH, Hauser RA, et al. Assessment of safety and efficacy of safinamide as a levodopa adjunct (SETTLE). JAMA Neurol. 2017;74(2):216–224. doi:10.1001/jamaneurol.2016.4467SETTLE trial (Study 2): confirmatory 24-week trial with 100 mg showing significant on-time improvement and off-time reduction.
- Borgohain R, Szasz J, Stanzione P, et al. Two-year study of safinamide as add-on to levodopa in mid to late Parkinson’s disease. Mov Disord. 2014;29(10):1273–1280. doi:10.1002/mds.25961Study 018: 18-month extension confirming sustained efficacy and safety over 2 years.
- Pringsheim T, Day GS, Smith DB, et al. Practice guideline: treatment of motor symptoms of Parkinson disease. Neurology. 2024;103(6):e209739. doi:10.1212/WNL.0000000000209739AAN guideline update addressing MAO-B inhibitors as adjunctive therapy for motor fluctuations.
- Fox SH, Katzenschlager R, Lim SY, et al. MDS evidence-based medicine review. Mov Disord. 2018;33(8):1248–1266. doi:10.1002/mds.27372MDS review classifying safinamide as efficacious for reducing off-time as adjunct to levodopa.
- Caccia C, Maj R, Calabresi M, et al. Safinamide: from molecular targets to a new anti-Parkinson drug. Neurology. 2006;67(7 Suppl 2):S18–S23. doi:10.1212/WNL.67.7_suppl_2.S18Preclinical review of dual mechanism: reversible MAO-B inhibition and glutamate modulation via sodium/calcium channel blockade.
- Gardoni F, Di Luca M. Safinamide: safety and efficacy. Expert Opin Drug Saf. 2018;17(6):647–656. doi:10.1080/14740338.2018.1472766Safety review covering retinal toxicology, hepatic transaminase data, and the SSRI interaction distinction.
- Blair HA, Dhillon S. Safinamide: a review in Parkinson’s disease. CNS Drugs. 2017;31(2):169–176. doi:10.1007/s40263-017-0408-1Comprehensive review covering 95% bioavailability, 20–26 h half-life, amidase-based metabolism, and positioning among MAO-B inhibitors.
- Marvanova M. Safinamide: a new therapeutic option. Am J Health Syst Pharm. 2018;75(1):e57–e68. doi:10.2146/ajhp170168Formulary review with detailed MAO-B inhibitor comparison for dosing, contraindications, and CYP interaction profiles.