Section 03 · Monograph

Safinamide

Reviewed Nov 2026FDA label

XadagoMAO-B inhibitor

Indications

Adjunctive treatment to levodopa/carbidopa in patients with Parkinson's disease experiencing 'off' episodesFDA-labeled

Highly selective, reversible inhibitor of monoamine oxidase type B (MAO-B), reducing central dopamine catabolism and increasing dopaminergic tone
More than 1000-fold selectivity for MAO-B over MAO-A at recommended doses
Achieves greater than 90% MAO-B inhibition at doses above 20 mg/day; selectivity for MAO-B decreases in a dose-dependent manner above the recommended dose range
Also blocks voltage-gated sodium channels and modulates stimulated glutamate release, distinguishing it mechanistically from older, non-selective MAO inhibitors

Initiate at 50 mg orally once daily at a consistent time, without regard to meals
After 2 weeks, may increase to 100 mg once daily based on individual need and tolerability
Doses above 100 mg/day provide no additional benefit and increase adverse reaction risk
If discontinuing from 100 mg/day, taper by reducing to 50 mg for one week before stopping to avoid withdrawal-emergent hyperpyrexia/confusion
If a dose is missed, take the next dose at the usual time the following day — do not double up

Moderate hepatic impairment (Child-Pugh B): maximum dose 50 mg once daily
Severe hepatic impairment (Child-Pugh C): contraindicated; discontinue if patient progresses from moderate to severe impairment

Concurrent use of other MAOIs or potent monoamine oxidase inhibitors (including linezolid)
Concurrent opioid drugs, including meperidine and its derivatives, methadone, propoxyphene, and tramadol — serious, sometimes fatal reactions reported
Concurrent SNRIs, tricyclic/tetracyclic/triazolopyridine antidepressants, cyclobenzaprine, methylphenidate, amphetamines, or St. John's wort
Concurrent dextromethorphan
History of hypersensitivity to safinamide (angioedema, dyspnea, rash)
Severe hepatic impairment (Child-Pugh Class C)

Absolute contraindication with other MAOIs (risk of hypertensive crisis); allow a 14-day washout in either direction when switching
Contraindicated with opioids (meperidine, methadone, propoxyphene, tramadol) — risk of serious CNS toxicity/serotonin syndrome-like reactions
Contraindicated with dextromethorphan — reports of psychosis/bizarre behavior when combined with MAOIs
Contraindicated with SNRIs, tricyclic/tetracyclic/triazolopyridine antidepressants, cyclobenzaprine, and St. John's wort due to serotonin syndrome risk
SSRIs are not contraindicated but require monitoring for serotonin syndrome; use the lowest effective SSRI dose
Contraindicated with methylphenidate and amphetamines; use caution with sympathomimetic decongestants and cold remedies (monitor for hypertension)
Isoniazid has MAO-inhibiting activity — monitor for hypertension and tyramine-type reactions
Although dietary tyramine restriction is not routinely required at recommended doses, very high-tyramine foods (>150 mg, e.g., aged cheese, cured/fermented/smoked/pickled foods) could still precipitate a hypertensive reaction, especially above 100 mg/day
Dopamine antagonists (antipsychotics, metoclopramide) may reduce safinamide effectiveness and worsen parkinsonian symptoms

Dyskinesia — most common adverse reaction; 21% (50 mg) and 18% (100 mg) vs. 9% placebo; can cause or worsen pre-existing dyskinesia and was the leading cause of adverse-event discontinuation
Falls (6% vs. 4% placebo)
Nausea (6% vs. 4% placebo)
Insomnia (4% vs. 2% placebo)
Orthostatic hypotension, anxiety, cough, and dyspepsia (each ~2% vs. 1% placebo)
New-onset or worsening hypertension (7% at 50 mg, 5% at 100 mg, vs. 4% placebo)
Asymptomatic ALT/AST elevations to the upper limit of normal (7% and 6% respectively at 100 mg vs. 3% placebo)
Hypersensitivity reactions: tongue/gingival swelling, dyspnea, rash
Somnolence and sudden sleep onset without warning during activities, including driving

Blood pressure at baseline and periodically, especially with sympathomimetics or isoniazid co-therapy
Signs/symptoms of serotonin syndrome if used with SSRIs
Daytime somnolence or sudden sleep episodes; counsel on driving/hazardous activity precautions
Dyskinesia severity — consider levodopa dose reduction if it worsens
New or worsening hallucinations, psychotic behavior, or impulse control/compulsive behaviors (gambling, hypersexuality, spending, binge eating) via direct questioning
Liver function in patients with moderate hepatic impairment; discontinue if progression to severe impairment
Periodic ophthalmologic/retinal evaluation in patients with retinal disease risk factors (retinal degeneration seen in animal studies)
Gradual tapering on discontinuation to avoid withdrawal-emergent hyperpyrexia and confusion

No adequate data on use in pregnant women; animal reproduction studies showed dose-related fetal urogenital, visceral, and skeletal malformations at clinically relevant exposures (as low as ~2–5 times the maximum recommended human dose)
Embryofetal death and cardiac/skeletal malformations observed in rabbits when safinamide was combined with levodopa/carbidopa at less than the maximum recommended human dose exposure
Use in pregnancy only if potential benefit justifies potential fetal risk
No data on presence of safinamide in human milk; animal data showed skin discoloration in nursing rat pups
Weigh the developmental and health benefits of breastfeeding against the mother's clinical need for safinamide and any potential adverse infant effects