Clinical data
Trade names Xadago
AHFS/ UK Drug Information
  • Fetal malformations in animal studies[1]
Routes of
ATC code none
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability 95%
Protein binding 88–90%
Metabolism Amidases, glucuronidation
Biological half-life 20–30 hrs
Excretion 76% renal, 1.5% faeces
Synonyms EMD-1195686, PNU-15774E;
(2S)-2-[[4-[(3-fluorophenyl)methoxy]phenyl] methylamino]propanamide
CAS Number 133865-89-1 N
202825-46-5 (mesylate)
PubChem (CID) 131682
ChemSpider 116349 YesY
KEGG D10158 N
ECHA InfoCard 100.120.167
Chemical and physical data
Formula C17H19FN2O2
Molar mass 302.34 g/mol
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

Safinamide (INN; brand name Xadago) is a drug indicated for the treatment of Parkinson's disease with monoamine oxidase B inhibiting and other methods of action.[2] It was approved in Europe in February 2015,[3] but is not available in the US as of September 2016. It has also been tested for the use in patients with restless legs syndrome (RLS), but no study results have been published.

Medical uses

Safinamide has been approved by the European Medicines Agency for the treatment of adult patients with idiopathic Parkinson’s disease as add-on therapy to a stable dose of levodopa (L-dopa) alone or in combination with other Parkinson drugs in patients with mid-to-late-stage fluctuating disease.[4]


Safinamide is contraindicated in patients 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.[5]

Adverse effects

Common adverse events in clinical trials (in more than 1% of patients) 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 treated patients.[5][6]

In experiments with rats (but not in those with monkeys), retinopathies have been observed.[1][7]


Expected overdose effects are hypertension (high blood pressure), orthostatic hypotension, hallucinations, psychomotor agitation, nausea, vomiting, and dyskinesia. In studies, a singe patient 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.[5]


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.[5]

Another theoretical interaction is with drugs with affinity to the transporter protein ABCG2 (also known as BCRP), such as pitavastatin, pravastatin, ciprofloxacin, methotrexat, and diclofenac; a study with the latter has shown no clinical relevance.[8] A study testing possible interactions with amidase inhibitors is part of the post-authorisation development plan.[1] There are no relevant interactions related to cytochrome P450 (CYP) liver enzymes, although one inactivation pathway of safinamide seems to be mediated by CYP3A4.[5]


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[6][9] and dopamine reuptake.[10] Additionally, it blocks sodium and calcium channels,[9][11] the relevance of which for its antiparkinson action is however unknown.[5]


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%.[5]

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),[8] the N-dealkylated amine which is then oxidized to a carboxylic acid (NW-1689), and the glucuronide of the latter.[5][12] 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.[5]

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.[5]

Metabolism pathways of safinamide.[8][12] 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, which was acquired by Pharmacia in 1993. In 1995, Pharmacia merged with Upjohn. Safinamide was first published 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.[13][14]

In 2007, a Phase III clinical trial was started, scheduled to run until 2011.[15] 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.[16]

The US Food and Drug Administration (FDA) refused to file Newron's application in 2014 on formal grounds.[17] Newron re-applied in December 2014.[18] In spring 2015, the European Medicines Agency (EMA) approved the drug. Safinamide is the first antiparkinson medication to be approved for ten years.[7]


Potential additional uses might be restless legs syndrome (RLS) and epilepsy.[19] They were being tested in Phase II trials in 2008, but no results are available.

See also


  1. 1 2 3 "Summary of the risk management plan (RMP) for Xadago (safinamide)" (PDF). European Medicines Agency. January 2015.
  2. Fariello, RG (2007). "Safinamide". Neurotherapeutics. 4 (1): 110–116. doi:10.1016/j.nurt.2006.11.011. PMID 17199024.
  3. "EPAR Summary for the Public for Xadago" (PDF). European Medicines Agency. February 2015.
  4. Lawrence, Janna (2015-01-19). "Safinamide recommended for approval as Parkinson's disease therapy". The Pharmaceutical Journal. Royal Pharmaceutical Society. Retrieved 2015-01-19.
  5. 1 2 3 4 5 6 7 8 9 10 Haberfeld, H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  6. 1 2 H. Spreitzer (14 April 2014). "Neue Wirkstoffe – Safinamid". Österreichische Apothekerzeitung (in German) (8/2014): 30.
  7. 1 2 Klement, A (18 July 2016). "Xadago". Österreichische Apothekerzeitung (in German) (15/2016): 10.
  8. 1 2 3 "Summary of Product Characteristics for Xadago" (PDF). European Medicines Agency. 24 February 2015.
  9. 1 2 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.
  10. Merck Serono: Vielversprechende Daten zur kognitiven Wirkung von Safinamid bei Parkinson im Frühstadium. (German) 8 June 2007.
  11. 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.
  12. 1 2 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. doi:10.1002/bdd.1822. PMID 23097240.
  13. 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.
  14. "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 German). Merck KGaA. 4 November 2010.
  15. Study of Safinamide in Early Parkinson's Disease as Add-on to Dopamine Agonist (MOTION)
  16. Merck Returns Rights for Safinamide to Newron, 21 October 2011.
  17. "Information about FDA Refusal to File" (PDF). Newron. 29 July 2014.
  18. "Information about FDA re-application" (PDF). Newron. 29 December 2014.
  19. 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.
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