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Trade namesXadago, Onstryv, others
Other namesEMD-1195686, PNU-15774E;
(2S)-2-[[4-[(3-fluorophenyl)methoxy]phenyl] methylamino]propanamide
  • N2-{4-[(3-fluorobenzyl)oxy]benzyl}-L-alaninamide
Clinical data
Drug classMonoamine oxidase inhibitor[1]
Main usesParkinson's disease[2]
Side effectsTrouble sleeping, difficulty controlling movements, sleepiness, dizziness, headache, cataracts, low blood pressure with standing[1]
InteractionsMAO inhibitors[2]
  • Fetal malformations in animal studies[3]
Routes of
By mouth
Typical dose50 to 100 mg OD[4]
External links
License data
Legal status
Protein binding88–90%
MetabolismAmidases, glucuronidation
Elimination half-life20–30 hrs
Excretion76% Kidney, 1.5% faeces
Chemical and physical data
Molar mass302.349 g·mol−1
3D model (JSmol)
  • O=C(N)[C@@H](NCc2ccc(OCc1cccc(F)c1)cc2)C
  • InChI=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 checkY

Safinamide, sold under the brand name Xadago among others, is a medication used as an add-on treatment for Parkinson's disease with off episodes.[2] Specifically it is used together with levodopa-carbidopa.[2] It is taken by mouth.[2]

Common side effects include trouble sleeping, difficulty controlling movements, sleepiness, dizziness, headache, cataracts, and low blood pressure with standing.[1] Other side effects may include high blood pressure, serotonin syndrome, sudden onset of sleep, an urge to gamble, and hallucinations.[2] is an inhibitor of monoamine oxidase B and therefore increases levels of dopamine.[1]

Safinamide was approved for medical use in Europe in 2015,[1] the United States in 2017,[2] and Canada in 2019.[5] In the United Kingdom a month of medication costs the NHS about £70 as of 2021.[4] In the United States this amount costs about 1,000 USD.[6]

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.[7][8][9]


The typical dose is 50 to 100 mg per day.[4]


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.[7]

It is pregnancy category C in the US; it is not safe for women to take during pregnancy.[8] It is excreted in breast milk and the effects on infants are unknown.[7]

Side effects

Common side events (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.[10][11]

In experiments with rats (but not in those with monkeys), retinopathies have been observed.[3][12]


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.[10]


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.[10]

Safinamide should not be given with opioids; some fatal reactions have occurred.[8]

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.[13] A study testing possible interactions with amidase inhibitors is part of the post-authorisation development plan.[3] There are no relevant interactions related to cytochrome P450 (CYP) liver enzymes, although one inactivation pathway of safinamide seems to be mediated by CYP3A4.[10]


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[11][14] and dopamine and serotonin reuptake.[15] 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.[16] Additionally, it blocks sodium and calcium channels,[14][17] the relevance of which for its antiparkinson action is however unknown.[10]


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%.[10]

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),[13] the N-dealkylated amine which is then oxidized to a carboxylic acid (NW-1689), and the glucuronide of the latter.[10][18] 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.[10]

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.[10]

Metabolism pathways of safinamide.[13][18] Enzymes: CYP = cytochrome P450, MAO-A = monoamine oxidase A, ALDH = aldehyde dehydrogenases, UGT = UDP-glucuronosyltransferases. Gluc = acyl glucuronide.


The compound was originally discovered at Farmitalia-Carlo Erba,[19] which was acquired by Pharmacia in 1993. In 1995, Pharmacia merged with Upjohn. Safinamide was first disclosed in 1998.[20] 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.[21]

In 2007, a Phase III clinical trial was started, scheduled to run until 2011.[22] 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.[23]

The US Food and Drug Administration (FDA) refused to file Newron's application in 2014 on formal grounds.[24] Newron re-applied in December 2014.[25] In spring 2015, the European Medicines Agency (EMA) approved the drug. Safinamide is the first antiparkinson medication to be approved for ten years.[12] Safinamide was approved by US FDA in March 2017 for people with Parkinsons taking levodopa/carbidopa during "off" episodes.[26][27]


Potential additional uses might be restless legs syndrome (RLS) and epilepsy.[28] 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.[29]

See also

  • Evenamide, structurally-related antipsychotic in-development
  • Lacosamide, used for partial-onset seizures and diabetic neuropathic pain
  • Ralfinamide, very similar structure (different fluorine position)


  1. 1.0 1.1 1.2 1.3 1.4 "Xadago". Archived from the original on 6 March 2021. Retrieved 10 October 2021.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "Safinamide Monograph for Professionals". Archived from the original on 5 October 2021. Retrieved 10 October 2021.
  3. 3.0 3.1 3.2 "Summary of the risk management plan (RMP) for Xadago (safinamide)" (PDF). European Medicines Agency. January 2015. Archived (PDF) from the original on 2017-03-29. Retrieved 2021-08-04.
  4. 4.0 4.1 4.2 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 447. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
  5. Government of Canada, Health Canada (2012-04-25). "Drug Product Database Online Query". Archived from the original on 2021-08-29. Retrieved 2019-07-21.
  6. "Xadago Prices, Coupons & Patient Assistance Programs". Archived from the original on 17 January 2021. Retrieved 10 October 2021.
  7. 7.0 7.1 7.2 "Xadago - Summary of Product Characteristics". UK Electronic Medicines Compendium. 1 February 2017. Archived from the original on 9 February 2019. Retrieved 2 April 2017.
  8. 8.0 8.1 8.2 "Safinimide label" (PDF). FDA. March 2017. Archived (PDF) from the original on 3 April 2017. Retrieved 2 April 2017. See FDA index page for NDA 207145 Archived 2017-06-29 at the Wayback Machine for updates.
  9. Perez-Lloret, S; Rascol, O (2016). "The safety and efficacy of safinamide mesylate for the treatment of Parkinson's disease". Expert Review of Neurotherapeutics. 16 (3): 245–58. doi:10.1586/14737175.2016.1150783. PMID 26849427. S2CID 37787896.
  10. 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 Haberfeld, H, ed. (2015). Austria-Codex (in Deutsch). Vienna: Österreichischer Apothekerverlag.
  11. 11.0 11.1 H. Spreitzer (14 April 2014). "Neue Wirkstoffe – Safinamid". Österreichische Apothekerzeitung (in Deutsch) (8/2014): 30.
  12. 12.0 12.1 Klement, A (18 July 2016). "Xadago". Österreichische Apothekerzeitung (in Deutsch) (15/2016): 10.
  13. 13.0 13.1 13.2 "Summary of Product Characteristics for Xadago" (PDF). European Medicines Agency. 24 February 2015. Archived (PDF) from the original on 17 March 2018. Retrieved 4 August 2021.
  14. 14.0 14.1 Caccia, C; Maj, R; Calabresi, M; Maestroni, S; Faravelli, L; Curatolo, L; Salvati, P; Fariello, RG (2006). "Safinamide: From molecular targets to a new anti-Parkinson drug". Neurology. 67 (7 Suppl 2): S18–23. doi:10.1212/wnl.67.7_suppl_2.s18. PMID 17030736. S2CID 26420481.
  15. Fabbri M, Rosa MM, Abreu D, Ferreira JJ (2015). "Clinical pharmacology review of safinamide for the treatment of Parkinson's disease". Neurodegener Dis Manag. 5 (6): 481–96. doi:10.2217/nmt.15.46. PMID 26587996.
  16. Salvati P, Maj R, Caccia C, Cervini MA, Fornaretto MG, Lamberti E, Pevarello P, Skeen GA, White HS, Wolf HH, Faravelli L, Mazzanti M, Mancinelli E, Varasi M, Fariello RG (1999). "Biochemical and electrophysiological studies on the mechanism of action of PNU-151774E, a novel antiepileptic compound". J. Pharmacol. Exp. Ther. 288 (3): 1151–9. PMID 10027853.
  17. Pevarello, P; Bonsignori, A; Caccia, C; Amici, R; Salvati, P; Fariello, RG; McArthur, RA; Varasi, M (1999). "Sodium channel activity and sigma binding of 2-aminopropanamide anticonvulsants". Bioorganic & Medicinal Chemistry Letters. 9 (17): 2521–2524. doi:10.1016/s0960-894x(99)00415-1. PMID 10498200.
  18. 18.0 18.1 Krösser, Sonja; Marquet, Anne; Gallemann, Dieter; Wolna, Peter; Fauchoux, Nicolas; Hermann, Robert; Johne, Andreas (2012). "Effects of ketoconazole treatment on the pharmacokinetics of safinamide and its plasma metabolites in healthy adult subjects". Biopharmaceutics & Drug Disposition. 33 (9): 550–9. doi:10.1002/bdd.1822. PMID 23097240. S2CID 12986951.
  19. Pevarello, P; Varasi, M (2018). "Discovery and Development of Safinamide, a New Drug for the Treatment of Parkinson's Disease". Successful Drug Discovery (Eds J. Fischer, C. Klein and W. E. Childers). 3: 383–415. doi:10.1002/9783527808694.ch14. ISBN 9783527808694.
  20. Pevarello, P; Bonsignori, A; Dostert, P; Heidempergher, F; Pinciroli, V; Colombo, M; McArthur, RA; Varasi, M (1998). "Synthesis and Anticonvulsant Activity of a New Class of 2-[(Arylalkyl)amino]alkanamide Derivatives". Journal of Medicinal Chemistry. 41 (4): 579–590. doi:10.1021/jm970599m. PMID 9484507.
  21. "Wichtigste Ergebnisse der Langzeitstudie mit Safinamid als Begleittherapie zu Levodopa bei Parkinson im fortgeschrittenen Stadium" [Major results from the long-term study of safinamide as add-on to levodopa for late-stage Parkinson] (in Deutsch). Merck KGaA. 4 November 2010. Archived from the original on 11 June 2011.
  22. "Study of Safinamide in Early Parkinson's Disease as Add-on to Dopamine Agonist (MOTION)". Archived from the original on 2020-09-29. Retrieved 2021-08-04.
  23. Merck Returns Rights for Safinamide to Newron Archived 2015-12-08 at the Wayback Machine, 21 October 2011.
  24. "Information about FDA Refusal to File". Newron. 29 July 2014. Archived from the original on 4 March 2016. Retrieved 4 August 2021.
  25. "Information about FDA re-application" (PDF). Newron. 29 December 2014. Archived from the original (PDF) on 4 March 2016. Retrieved 4 August 2021.
  26. "Press Announcements - FDA approves drug to treat Parkinson's disease". FDA. March 21, 2017. Archived from the original on April 23, 2019. Retrieved August 4, 2021.
  27. "After an odyssey of setbacks, FDA finally green-lights Newron's Parkinson's drug Xadago". Archived from the original on 2017-03-22. Retrieved 2017-03-21.
  28. Chazot, PL (2007). "Drug evaluation: Safinamide for the treatment of Parkinson's disease, epilepsy and restless legs syndrome". Current Opinion in Investigational Drugs. 8 (7): 570–579. PMID 17659477.
  29. Qureshi, Abdul Rehman; Rana, Abdul Qayyum; Malik, Suleiman H.; Rizvi, Syed Fayyaz H.; Akhter, Shakib; Vannabouathong, Christopher; Sarfraz, Zainab; Rana, Ruqqiyah (2018). "Comprehensive Examination of Therapies for Pain in Parkinson's Disease: A Systematic Review and Meta-Analysis". Neuroepidemiology. 51 (3–4): 190–206. doi:10.1159/000492221. ISSN 1423-0208. PMID 30153669.

External links

External sites:
  • "Safinamide mesylate". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 2020-10-19. Retrieved 2021-08-04.