Safinamide

---

title: "Safinamide" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public tags: ["antidyskinetic-agents", "calcium-channel-blockers", "dopamine-reuptake-inhibitors", "3-fluorophenyl-compounds", "drugs-developed-by-merck", "monoamine-oxidase-inhibitors", "propionamides", "sigma-receptor-modulators", "sodium-channel-blockers", "serotonin-reuptake-inhibitors"] description: "Reversible monoamine oxidase B inhibitor" topic_path: "general/antidyskinetic-agents" source: "https://en.wikipedia.org/wiki/Safinamide" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Reversible monoamine oxidase B inhibitor ::

::data[format=table title="Infobox drug"]

Field	Value
Verifiedfields	changed
Watchedfields	changed
verifiedrevid	464386010
image	Safinamide.svg
image_class	skin-invert-image
width	250
tradename	Xadago, others
Drugs.com
pregnancy_AU
pregnancy_category	Fetal malformations in animal studies
routes_of_administration	By mouth
ATC_prefix	N04
ATC_suffix	BD03
legal_AU	S4
legal_AU_comment
legal_CA	Rx-only
legal_CA_comment
legal_UK	POM
legal_UK_comment
legal_US	Rx-only
legal_US_comment
legal_EU	Rx-only
legal_EU_comment
bioavailability	95%
protein_bound	88–90%
metabolism	Amidases, glucuronidation
elimination_half-life	20–30 hrs
excretion	76% Kidney, 1.5% faeces
index2_label	mesylate
CAS_number_Ref
CAS_number	133865-89-1
CAS_number2	202825-46-5
PubChem	131682
DrugBank_Ref
DrugBank	DB06654
IUPHAR_ligand	8291
ChEBI	134718
ChemSpiderID_Ref
ChemSpiderID	116349
UNII_Ref
UNII	90ENL74SIG
ChEMBL_Ref
ChEMBL	396778
ChEMBL2	48582
KEGG	D10158
KEGG_Ref
KEGG2	D10191
KEGG2_Ref
synonyms	EMD-1195686, PNU-15774E;
(2S)-2-[[4-[(3-fluorophenyl)methoxy]phenyl] methylamino]propanamide
IUPAC_name	N2-{4-[(3-fluorobenzyl)oxy]benzyl}-L-alaninamide
C	17
SMILES	O=C(N)C@@HC
StdInChI_Ref
StdInChI	1S/C17H19FN2O2/c1-12(17(19)21)20-10-13-5-7-16(8-6-13)22-11-14-3-2-4-15(18)9-14/h2-9,12,20H,10-11H2,1H3,(H2,19,21)/t12-/m0/s1
StdInChIKey_Ref
StdInChIKey	NEMGRZFTLSKBAP-LBPRGKRZSA-N
::

| Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 464386010 | image = Safinamide.svg | image_class = skin-invert-image | width = 250 | alt =

| tradename = Xadago, others | Drugs.com = | pregnancy_AU = | pregnancy_category = Fetal malformations in animal studies | routes_of_administration = By mouth | ATC_prefix = N04 | ATC_suffix = BD03 | ATC_supplemental =

| legal_AU = S4 | legal_AU_comment = | legal_CA = Rx-only | legal_CA_comment = | legal_UK = POM | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = | legal_EU = Rx-only | legal_EU_comment = | legal_status =

| bioavailability = 95% | protein_bound = 88–90% | metabolism = Amidases, glucuronidation | metabolites = | onset = | elimination_half-life = 20–30 hrs | duration_of_action= | excretion = 76% Kidney, 1.5% faeces

| index2_label = mesylate | CAS_number_Ref = | CAS_number = 133865-89-1 | CAS_number2 = 202825-46-5 | PubChem = 131682 | DrugBank_Ref = | DrugBank = DB06654 | IUPHAR_ligand = 8291 | ChEBI = 134718 | ChemSpiderID_Ref = | ChemSpiderID = 116349 | UNII_Ref = | UNII = 90ENL74SIG | ChEMBL_Ref = | ChEMBL = 396778 | ChEMBL2 = 48582 | KEGG = D10158 | KEGG_Ref = | KEGG2 = D10191 | KEGG2_Ref = | synonyms = EMD-1195686, PNU-15774E; (2S)-2-[[4-[(3-fluorophenyl)methoxy]phenyl] methylamino]propanamide

| IUPAC_name = N2-{4-[(3-fluorobenzyl)oxy]benzyl}-L-alaninamide | C=17 | H=19 | F=1 | N=2 | O=2 | SMILES = O=C(N)C@@HC | StdInChI_Ref = | StdInChI = 1S/C17H19FN2O2/c1-12(17(19)21)20-10-13-5-7-16(8-6-13)22-11-14-3-2-4-15(18)9-14/h2-9,12,20H,10-11H2,1H3,(H2,19,21)/t12-/m0/s1 | StdInChIKey_Ref = | StdInChIKey = NEMGRZFTLSKBAP-LBPRGKRZSA-N

Safinamide, sold under the brand name Xadago among others, is a medication used as treatment for Parkinson's disease with "off" episodes; it has multiple modes of action, including the inhibition of monoamine oxidase B.

It was approved in the European Union in February 2015,

Medical uses

Safinamide is used to treat idiopathic Parkinson's disease as add-on for people taking a stable dose of levodopa (L-dopa) alone or in combination with other Parkinson drugs, to help with "off" episodes when levodopa stops working.

Contraindications

Safinamide is contraindicated in people with severe liver impairment, with albinism, retinitis pigmentosa, severe diabetic neuropathy, uveitis and other disorders of the retina. Combination with other monoamine oxidase (MAO) inhibitors and pethidine is also contraindicated.

It is not safe for women to take during pregnancy. It is excreted in breast milk and the effects on infants are unknown.

Adverse effects

Common adverse events in clinical trials (in more than 1% of people) included nausea, dizziness, tiredness, sleeplessness, orthostatic hypotension (low blood pressure), and headache. There was no significant difference in the occurrence of these effects between safinamide and placebo.

Overdose

Expected overdose effects are hypertension (high blood pressure), orthostatic hypotension, hallucinations, psychomotor agitation, nausea, vomiting, and dyskinesia. In studies, a single person was suspected to have overdosed for a month; symptoms were confusion, drowsiness and mydriasis (dilation of the pupils) and subsided completely after the drug was discontinued. No specific antidote is available.

Interactions

As a MAO inhibitor, safinamide can theoretically cause hypertensive crises, serotonin syndrome and other severe side effects when combined with other MAO inhibitors or with drugs that are known to interact with MAO inhibitors, such as pethidine, dextromethorphan, selective serotonin reuptake inhibitors (SSRIs), serotonin–noradrenaline reuptake inhibitors (SNRIs), tricyclic and tetracyclic antidepressants. An interaction with tyramine, a substance found in various foods, could be expected by the same reasoning but has been excluded in studies.

Another theoretical interaction is with drugs with affinity to the transporter protein ABCG2 (also known as BCRP), such as pitavastatin, pravastatin, ciprofloxacin, methotrexate, and diclofenac; a study with the latter has shown no clinical relevance. A study testing possible interactions with amidase inhibitors is part of the post-authorisation development plan. There are no relevant interactions related to cytochrome P450 (CYP) liver enzymes, although one inactivation pathway of safinamide seems to be mediated by CYP3A4.

Pharmacology

Mechanisms of action

Like the older antiparkinson drugs selegiline and rasagiline, safinamide is a selective monoamine oxidase B inhibitor, reducing degradation of dopamine; in contrast to the other two, its action is reversible. Safinamide also inhibits glutamate release and dopamine and serotonin reuptake. It binds to the sigma receptors as well, with IC50 values for binding inhibition of 19 nM for σ1 and 1,590 nM for σ2. Additionally, it blocks sodium and calcium channels, the relevance of which for its antiparkinson action is however unknown.

Pharmacokinetics

Safinamide is absorbed quickly and nearly completely from the gut and reaches highest blood plasma concentrations after 1.8 to 2.8 hours. There is no relevant first-pass metabolism; total bioavailability is 95%. The substance is bound to plasma proteins to 88–90%.

The metabolism is not well understood. The principal step is mediated by amidases which have not been identified, and produces safinamide acid (NW-1153). Other relevant metabolites are O-debenzylated safinamide (NW-1199), the N-dealkylated amine which is then oxidized to a carboxylic acid (NW-1689), and the glucuronide of the latter. In tests with liver microsomes, dealkylation seemed to be mediated by CYP3A4, but other CYP enzymes appear to be involved as well. Safinamide acid binds to the organic anion transporter 3 (OAT3), but this has probably no clinical relevance. Safinamide itself transiently binds to ABCG2. No other transporter affinities have been found in preliminary studies.

Safinamide is eliminated, mainly (90%) in form of its metabolites, via the kidney, with an elimination half-life of 20 to 30 hours. Only 1.5% are found in the stool.

::figure[src="https://upload.wikimedia.org/wikipedia/commons/4/4a/Safinamide_metabolism.svg" caption="Metabolism pathways of safinamide. Enzymes: CYP = [[cytochrome P450]], MAO-A = [[monoamine oxidase A]], ALDH = [[aldehyde dehydrogenase]]s, UGT = [[UDP-glucuronosyltransferase]]s. Gluc = acyl [[glucuronide]]."] ::

History

The compound was originally discovered at Farmitalia-Carlo Erba, which was acquired by Pharmacia in 1993. In 1995, Pharmacia merged with Upjohn. Safinamide was first disclosed in 1998. In the course of a major restructuring in the same year, all rights for safinamide were transferred to the newly formed company Newron Pharmaceuticals, which developed the drug until it was sold to Merck KGaA in 2006.

In 2007, a Phase III clinical trial was started, scheduled to run until 2011. In October 2011 Merck, now Merck-Serono, announced that they would give all rights to develop the compound back to Newron because they wanted to prioritise other projects and had corrected their estimates for safinamide's market potential downwards.

The US Food and Drug Administration (FDA) refused to file Newron's application in 2014 on formal grounds. Newron re-applied in December 2014. In spring 2015, following a commercial agreement between Newron and the Italian pharmaceutical company Zambon, the European Medicines Agency (EMA) approved the drug. In the following years, the drug has been launched in several European countries. Safinamide is the first antiparkinson medication to be approved for ten years. Safinamide was approved by US FDA in March 2017 for people with Parkinsons taking levodopa/carbidopa during "off" episodes.

Research

Potential additional uses might be restless legs syndrome (RLS) and epilepsy. Safinamide was being tested in Phase II trials in 2008, but no results are available. When used as an adjunct to parkinsonian medication, safinamide was found to be efficacious in reducing pain in PD.

In experiments with rats (but not in those with monkeys), retinopathies have been observed.

References

References

1. (January 2015). "Summary of the risk management plan (RMP) for Xadago (safinamide)". [[European Medicines Agency]].
2. (24 September 2025). "Safinamide Medicianz (Medsurge Pharma Pty Ltd)".
3. (23 October 2014). "Summary Basis of Decision (SBD) for Onstryv".
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5. (1 February 2017). "Xadago - Summary of Product Characteristics". UK Electronic Medicines Compendium.
6. (March 2017). "Safinimide label". FDA.
7. (2016). "The safety and efficacy of safinamide mesylate for the treatment of Parkinson's disease". Expert Review of Neurotherapeutics.
8. (25 April 2012). "Onstryv Product information".
9. (14 April 2014). "Neue Wirkstoffe – Safinamid". Österreichische Apothekerzeitung.
10. (October 2006). "Safinamide: from molecular targets to a new anti-Parkinson drug". Neurology.
11. (December 2015). "Clinical pharmacology review of safinamide for the treatment of Parkinson's disease". Neurodegenerative Disease Management.
12. (March 1999). "Biochemical and electrophysiological studies on the mechanism of action of PNU-151774E, a novel antiepileptic compound". The Journal of Pharmacology and Experimental Therapeutics.
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16. (December 2012). "Effects of ketoconazole treatment on the pharmacokinetics of safinamide and its plasma metabolites in healthy adult subjects". Biopharmaceutics & Drug Disposition.
17. (2018). "Successful Drug Discovery".
18. (February 1998). "Synthesis and anticonvulsant activity of a new class of 2-[(arylalky)amino]alkanamide derivatives". Journal of Medicinal Chemistry.
19. (4 November 2010). "Wichtigste Ergebnisse der Langzeitstudie mit Safinamid als Begleittherapie zu Levodopa bei Parkinson im fortgeschrittenen Stadium". Merck KGaA.
20. "Study of Safinamide in Early Parkinson's Disease as Add-on to Dopamine Agonist (MOTION)". PDtrials.org.
21. (21 October 2011). "Merck Returns Rights for Safinamide to Newron". Merck Group.
22. (29 July 2014). "Information about FDA Refusal to File". Newron.
23. (29 December 2014). "Information about FDA re-application". Newron.
24. (18 December 2014). "Xadago EPAR Public assessment report". European Medicines Agency.
25. (29 February 2016). "Parkinson, Zambon annuncia l'arrivo in Italia di safinamide". Aboutpharma.
26. (18 July 2016). "Xadago". Österreichische Apothekerzeitung.
27. (21 March 2017). "FDA approves drug to treat Parkinson's disease". Food and Drug Administration.
28. (21 March 2017). "After an odyssey of setbacks, FDA finally green-lights Newron's Parkinson's drug Xadago".
29. (July 2007). "Safinamide for the treatment of Parkinson's disease, epilepsy and restless legs syndrome". Current Opinion in Investigational Drugs.
30. (2018). "Comprehensive Examination of Therapies for Pain in Parkinson's Disease: A Systematic Review and Meta-Analysis". Neuroepidemiology.

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