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Safinamide Mesylate

Class: Monoamine Oxidase B Inhibitors
Chemical Name: (2S)-2-[[4-[(3-fluorophenyl)methoxy]phenyl]methylamino]propanamide;methanesulfonic acid
Molecular Formula: C18H23FN2O5S
CAS Number: 133865-89-1
Brands: Xadago

Medically reviewed on May 7, 2018

Introduction

See also: Gocovri

Selective reversible MAO-B inhibitor.1 2 5 6 8 14

Uses for Safinamide Mesylate

Parkinsonian Syndrome

Used as an adjunct to levodopa-carbidopa for the symptomatic treatment of parkinsonian syndrome (e.g., parkinsonism, Parkinson disease [paralysis agitans]) in patients who experience “off” episodes (i.e., time when drug effect wears off and parkinsonian manifestations return).1 2 3

Shown to be effective only in combination with levodopa-carbidopa; efficacy of safinamide monotherapy not established.1 2 3

Safinamide Mesylate Dosage and Administration

Administration

Oral Administration

Administer orally once daily at the same time each day without regard to meals.1

If a dose is missed, omit dose and administer next dose at the regularly scheduled time the following day.1

Dosage

Available as safinamide mesylate; dosage expressed in terms of safinamide.1

Adults

Parkinsonian Syndrome
Adjunctive Therapy with Levodopa-Carbidopa
Oral

Initially, 50 mg once daily.1

After 2 weeks, may increase dosage to 100 mg once daily based on individual response and tolerability.1

Dosages >100 mg daily not shown to provide additional benefit and may increase risk of hypertensive reactions.1 If dyskinesia occurs, may reduce dosage of concomitant levodopa or other dopaminergic agents.1 (See Dyskinesia under Cautions.)

When discontinuing therapy in patients receiving a dosage of 100 mg once daily, taper dosage by decreasing to 50 mg once daily for 1 week.1

Special Populations

Hepatic Impairment

Maximum recommended dosage of 50 mg once daily in patients with moderate hepatic impairment (Child-Pugh class B).1

Use contraindicated in patients with severe hepatic impairment (Child-Pugh class C).1 (See Special Populations under Pharmacokinetics.)

If a patient progresses from moderate to severe hepatic impairment while receiving a dosage of 50 mg daily, discontinue therapy.1

Renal Impairment

No specific dosage recommendations.1 15 (See Renal Impairment under Cautions.)

Cautions for Safinamide Mesylate

Contraindications

  • Concomitant use with other drugs that inhibit MAO (e.g., other MAO inhibitors, linezolid); opiate agonists (e.g., meperidine, methadone, propoxyphene [no longer commercially available in the US], tramadol); SNRIs; tricyclic, tetracyclic, or triazolopyridine antidepressants; cyclobenzaprine; methylphenidate; amphetamines; St. John’s wort (Hypericum perforatum); or dextromethorphan.1 (See Specific Drugs and Foods under Interactions.)

  • Known hypersensitivity to safinamide.1 (See Hypersensitivity under Cautions.)

  • Severe hepatic impairment (Child-Pugh class C).1

Warnings/Precautions

Hypertension

May cause hypertension or exacerbate existing hypertension.1 Monitor patients for new-onset or inadequately controlled hypertension.1 Dosage adjustment of antihypertensive agents may be necessary.1

Serious hypertensive reactions associated with nonselective inhibition of MAO may occur with use of higher than recommended dosages of selective MAO-B inhibitors.1 At safinamide dosages >100 mg daily, relative selectivity for MAO-B diminishes and likelihood for hypertensive reactions increases.1 Do not exceed recommended dosages.1 (See Dosage under Dosage and Administration.)

Concomitant use of safinamide with other drugs in the MAO inhibitor class or drugs that are potent inhibitors of MAO (e.g., linezolid) also may increase risk of nonselective MAO inhibition and cause hypertensive crisis.1 (See Contraindications under Cautions.)

Hypertensive crisis reported rarely following concomitant use of recommended dosages of selective MAO-B inhibitors and tyramine-rich foods or sympathomimetic drugs.1 (See Specific Drugs and Foods under Interactions.)

Manufacturer states that restriction of most tyramine-containing foods or beverages generally not required during safinamide therapy.1 However, because foods that contain very large amounts (i.e., >150 mg) of tyramine potentially can cause severe hypertension in some patients (e.g., those with mildly increased sensitivity to tyramine) receiving recommended dosages of safinamide, advise patients to avoid such tyramine-rich foods during safinamide therapy.1

Serotonin Syndrome

Severe, potentially fatal serotonin syndrome reported following concomitant use of MAO inhibitors with certain antidepressants (e.g., SNRIs; SSRIs; tricyclic, tetracyclic, or triazolopyridine antidepressants), cyclobenzaprine, methylphenidate, amphetamine, or certain opiate agonists (i.e., meperidine, tramadol).1 (See Contraindications under Cautions.)

Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile BP, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular aberrations (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1

Sudden Sleep Episodes

Episodes of falling asleep while engaged in activities of daily living (e.g., driving) reported with dopaminergic drugs, sometimes resulting in accidents.1

Some patients perceived no warning signs (e.g., excessive drowsiness) and believed that they were alert immediately prior to the event.1

Generally discontinue therapy if a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., driving a motor vehicle, conversations, eating).1 If the drug is continued, advise patients not to drive and to avoid other potentially dangerous activities.1

Dyskinesia

When used as adjunctive therapy with levodopa, may cause or exacerbate dyskinesia; may be mitigated by reducing levodopa dosage or dosage of other dopaminergic drugs.1

Hallucinations and Psychotic-like Behavior

Use not recommended in patients with major psychotic disorders due to risk of exacerbating psychosis with an increase in central dopaminergic tone.1

Symptoms of parkinsonian syndrome may be exacerbated by antipsychotic agents that antagonize the effects of dopaminergic drugs.1 (See Specific Drugs and Foods under Interactions.)

Consider reducing dosage or discontinuing safinamide if patient develops hallucinations or psychotic-like behavior.1

Intense Urges

Intense urges (e.g., urge to gamble, increased sexual urges, binge eating, urge to spend money, other intense urges) and inability to control these urges reported in some patients receiving antiparkinsonian agents that increase central dopaminergic tone (including safinamide).1 Urges stopped in some cases when dosage was reduced or drug was discontinued.1

Consider reducing dosage or discontinuing safinamide if a patient develops such urges.1

Neuroleptic Malignant Syndrome

A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability) reported following rapid dosage reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone.1

Ocular Effects

Retinal degradation, retinal scarring, cataracts, and loss of photoreceptor cells observed in animal toxicity studies.1

Periodically evaluate patients who may be at increased risk (e.g., those with a history of retinal/macular degeneration, uveitis, inherited retinal conditions, family history of hereditary retinal disease, albinism, retinitis pigmentosa, or active retinopathy [e.g., diabetic retinopathy]) for visual changes during therapy.1 6

Sensitivity Reactions

Hypersensitivity

Hypersensitivity reactions (e.g., swelling of the tongue and oral mucosa, dyspnea) reported.1 (See Contraindications under Cautions.)

Specific Populations

Pregnancy

Category C.1

No adequate and well-controlled studies of safinamide in pregnant women.1 In animal reproduction studies, developmental toxicity and teratogenic effects (e.g., decreased body weight, cardiac and skeletal malformations, embryofetal death, postnatal death) observed at clinically relevant dosages.1

Lactation

Distributed into milk in rats; skin discoloration, thought to be caused by hepatobiliary toxicity, observed in nursing pups exposed to safinamide through milk.1 8 Not known whether distributed into human milk; discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1

Geriatric Use

No overall differences in safety or efficacy relative to younger adults.1

Hepatic Impairment

Dosage adjustment recommended in patients with moderate hepatic impairment (Child-Pugh class B).1

Use contraindicated in patients with severe hepatic impairment (Child-Pugh class C).1 (See Special Populations under Pharmacokinetics.)

Renal Impairment

Pharmacokinetics not affected by impaired renal function.1

Common Adverse Effects

Dyskinesia,1 2 3 fall,1 3 nausea,1 3 insomnia,1 3 orthostatic hypotension,1 anxiety,1 3 cough,1 3 dyspepsia.1 3

Interactions for Safinamide Mesylate

Minimally metabolized by CYP3A4 and other CYP isoenzymes.1 14 Does not inhibit or induce CYP isoenzymes at therapeutic concentrations.1

Not a substrate of P-glycoprotein (P-gp).1 Does not inhibit P-gp, organic cation transporter 2 (OCT2), organic anion transport proteins (OATP) 1B1 or 1B3, bile salt export pump (BSEP), or organic anion transporter (OAT) 1, OAT3, or OAT4.1

May inhibit intestinal breast cancer resistance protein (BCRP).1

Drugs Metabolized by Hepatic Microsomal Enzymes

Interactions not expected.1

Drugs Affected by BCRP

Concomitant use with BCRP substrates may result in increased plasma concentrations of the BCRP substrate.1 Monitor patients for increased pharmacologic or adverse effects of the BCRP substrate.1

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Antidepressants (e.g., SNRIs, SSRIs, tetracyclics, tricyclics, triazolopyridine derivatives)

Potential for serious, possibly fatal serotonin syndrome1

SNRIs, tetracyclics, tricyclics, triazolopyridine derivatives: Concomitant use contraindicated; allow ≥14 days to elapse between discontinuance of safinamide and initiation of antidepressant1

SSRIs: Use lowest effective dosage of SSRI1

Antipsychotics (i.e., dopamine antagonists)

Possible reduced efficacy of safinamide1

Cyclobenzaprine

Potential for serious, possibly fatal serotonin syndrome1

Concomitant use contraindicated1

Allow ≥14 days to elapse between discontinuance of safinamide and initiation of cyclobenzaprine1

Dextromethorphan

Possible episodes of psychosis or bizarre behavior1

Concomitant use contraindicated1

Foods, tyramine-containing

Possible hypertensive crisis1

Avoid foods containing very large amounts of tyramine (e.g., aged cheeses, picked herring)1 (see Advice to Patients)

Imatinib

Possible increased imatinib plasma concentrations1

Monitor patients for increased pharmacologic or adverse effects of imatinib1

Irinotecan

Possible increased irinotecan plasma concentrations1

Monitor patients for increased pharmacologic or adverse effects of irinotecan1

Isoniazid

Because isoniazid has some MAO-inhibiting properties, possible increased risk of hypertension1

Monitor patients for hypertension and reaction to dietary tyramine1

Ketoconazole

Clinically important changes in pharmacokinetics not observed with either drug1

Lapatinib

Possible increased lapatinib plasma concentrations1

Monitor patients for increased pharmacologic or adverse effects of lapatinib1

Levodopa

Clinically important changes in pharmacokinetics not observed with either drug1

Possible increased risk of dyskinesia1

May consider reduction of levodopa dosage1

Combination used to therapeutic advantage1

Linezolid

Possible increased risk of nonselective MAO inhibition, resulting in hypertensive crisis1

Concomitant use contraindicated1

Allow ≥14 days to elapse between discontinuance of safinamide and initiation of linezolid1

MAO inhibitors

Possible increased risk of nonselective MAO inhibition, resulting in hypertensive crisis1

Concomitant use contraindicated1

Allow ≥14 days to elapse between discontinuance of safinamide and initiation of other MAO inhibitors1

Methotrexate

Possible increased methotrexate plasma concentrations1

Monitor patients for increased pharmacologic or adverse effects of methotrexate1

Metoclopramide

Possible reduced efficacy of safinamide1

Mitoxantrone

Possible increased mitoxantrone plasma concentrations1

Monitor patients for increased pharmacologic or adverse effects of mitoxantrone1

Opiate agonists (e.g., meperidine, methadone, propoxyphene [no longer commercially available in US], tramadol)

Potential for serious, possibly fatal serotonin syndrome1

Concomitant use contraindicated1

Allow ≥14 days to elapse between discontinuance of safinamide and initiation of opiate agonist1

Rosuvastatin

Possible increased rosuvastatin plasma concentrations1

Monitor patients for increased pharmacologic or adverse effects of rosuvastatin1

St. John's wort (Hypericum perforatum)

Potential for serious, possibly fatal serotonin syndrome1

Concomitant use contraindicated1

Allow ≥14 days to elapse between discontinuance of safinamide and initiation of St. John's wort1

Sulfasalazine

Possible increased sulfasalazine plasma concentrations1

Monitor patients for increased pharmacologic or adverse effects of sulfasalazine1

Sympathomimetic drugs (e.g., amphetamines, methylphenidate, pseudoephedrine)

Possible severe hypertension or hypertensive crisis1 6

Amphetamines, methylphenidate: Concomitant use contraindicated1

Other prescription or OTC sympathomimetic drugs (e.g., decongestants), including oral, nasal and ophthalmic preparations: Monitor patients for hypertension1 6

Topotecan

Possible increased topotecan plasma concentrations1

Monitor patients for increased pharmacologic or adverse effects of topotecan1

Safinamide Mesylate Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration, with peak plasma concentration attained within approximately 2–3 hours.1 8 11

Absolute bioavailability is 95%.1 8 10

Special Populations

Mild hepatic impairment (Child-Pugh class A) increases safinamide AUC by 30%; moderate hepatic impairment (Child-Pugh class B) increases safinamide AUC by 80%.1 Pharmacokinetic data lacking in patients with severe hepatic impairment (Child-Pugh class C).1 (See Hepatic Impairment under Dosage and Administration.)

Moderate to severe renal impairment does not affect pharmacokinetics of safinamide.1

Distribution

Extent

Distributed into milk in rats; not known if distributed into human milk.1

Plasma Protein Binding

Approximately 88–90%.1 10

Elimination

Metabolism

Predominantly metabolized by nonmicrosomal enzymes (cytosolic amidases/MAO-A); minimally metabolized by CYP3A4 and other CYP isoenzymes.1 Major metabolite (safinamide acid) produced by amide hydroxylation.1 Other routes of metabolism include ether bond oxidation to form O-debenzylated safinamide and oxidation of safinamide or safinamide acid to N-dealkylated acid.8

Elimination Route

Eliminated mainly in urine (76%) as inactive metabolites.1

Half-life

Mean terminal half-life 20–26 hours.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15-30°C).1

Actions

  • Selective reversible MAO-B inhibitor.1 2 5 6 8 14

  • Precise mechanism of action not fully characterized, but thought to involve both dopaminergic and nondopaminergic effects; such effects include selective inhibition of MAO-B, blockade of voltage-dependent sodium and calcium channels, and inhibition of neuronal glutamate release.6 8 11 13 14

  • Compared with the irreversible MAO-B inhibitors selegiline and rasagiline, safinamide binds reversibly to MAO-B and exhibits greater selectivity for MAO-B (i.e., inhibits MAO-B with >1000-fold selectivity over MAO-A).1 8 10 13 However, selectivity for MAO-B is dose related and diminishes as dosage increases above recommended daily dosages.1

  • Inhibition of MAO-B results in increased extracellular concentrations of dopamine and, therefore, enhanced dopaminergic activity in the striatum.1 11 158

Advice to Patients

  • Risk of elevated BP or hypertension; advise patients to contact their clinician if their BP increases.1 Risk of hypertensive crisis; importance of not exceeding the maximum recommended daily dosages of safinamide and of avoiding foods containing very large amounts of tyramine (e.g., aged cheese).1 Advise patients to contact their clinician if they do not feel well after eating foods rich in tyramine.1

  • Risk of new or worsening dyskinesia when used concomitantly with levodopa.1

  • Risk of hallucinations or psychotic-like behavior.1 Importance of informing patients that safinamide generally should not be used in patients with major psychotic disorders due to the risk of exacerbating psychosis.1 Importance of informing patients that many drugs used to treat psychosis may decrease the efficacy of safinamide.1

  • Risk of somnolence and the possibility of falling asleep during activities of daily living.1 Patients should avoid driving or engaging in other potentially dangerous activities until the effects of safinamide on the individual are known.1

  • Importance of advising patients that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car) occur at any time during therapy, they should not drive or participate in potentially dangerous activities until they have contacted their clinician.1 Patients should not drive, operate machinery, or work at heights during therapy if they have previously experienced somnolence and/or have fallen asleep without warning prior to use of safinamide.1 Importance of advising patients of the increased risk of somnolence when safinamide is used concomitantly with other sedating drugs, alcohol, or other CNS depressants (e.g., benzodiazepines, antipsychotics, antidepressants).1

  • Importance of taking safinamide as prescribed.1 If a dose is missed, omit the dose and administer the next dose at the regularly scheduled time the following day.1 Importance of not abruptly discontinuing therapy and advising patients to contact their clinician if they wish to discontinue therapy.1

  • Importance of asking patients whether they have developed any new or increased gambling urges, sexual urges, or other urges while receiving safinamide and of advising them of the importance of reporting such urges.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., analgesics, antidepressants) and OTC drugs (e.g., decongestants, dextromethorphan), dietary supplements, and/or herbal products (e.g., St. John’s wort), as well as any concomitant illnesses (e.g., major psychotic disorder).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Safinamide Mesylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

50 mg (of safinamide)

Xadago

US WorldMeds

100 mg (of safinamide)

Xadago

US WorldMeds

AHFS DI Essentials. © Copyright 2018, Selected Revisions May 7, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. US WorldMeds. Xadago (safinamide mesylate) tablets prescribing information. Louisville, KY; 2017 May. From DailyMed website. https://dailymed.nlm.nih.gov

2. 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; 29:229-37. http://www.ncbi.nlm.nih.gov/pubmed/24323641?dopt=AbstractPlus

3. Schapira AH, Fox SH, Hauser RA et al. Assessment of Safety and Efficacy of Safinamide as a Levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial. JAMA Neurol. 2017; 74:216-224. http://www.ncbi.nlm.nih.gov/pubmed/27942720?dopt=AbstractPlus

4. Borgohain R, Szasz J, Stanzione P et al. Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson's disease. Mov Disord. 2014; 29:1273-80. http://www.ncbi.nlm.nih.gov/pubmed/25044402?dopt=AbstractPlus

5. Finberg JP, Rabey JM. Inhibitors of MAO-A and MAO-B in Psychiatry and Neurology. Front Pharmacol. 2016; 7:340. http://www.ncbi.nlm.nih.gov/pubmed/27803666?dopt=AbstractPlus

6. . Safinamide (Xadago) for Parkinson's disease. Med Lett Drugs Ther. 2017; 59:151-153. http://www.ncbi.nlm.nih.gov/pubmed/28880847?dopt=AbstractPlus

8. Fabbri M, Rosa MM, Abreu D et al. Clinical pharmacology review of safinamide for the treatment of Parkinson's disease. Neurodegener Dis Manag. 2015; 5:481-96. http://www.ncbi.nlm.nih.gov/pubmed/26587996?dopt=AbstractPlus

9. Cattaneo C, Ferla RL, Bonizzoni E et al. Long-Term Effects of Safinamide on Dyskinesia in Mid- to Late-Stage Parkinson's Disease: A Post-Hoc Analysis. J Parkinsons Dis. 2015; 5:475-81. http://www.ncbi.nlm.nih.gov/pubmed/26406127?dopt=AbstractPlus

10. Müller T, Foley P. Clinical Pharmacokinetics and Pharmacodynamics of Safinamide. Clin Pharmacokinet. 2017; 56:251-261. http://www.ncbi.nlm.nih.gov/pubmed/27665574?dopt=AbstractPlus

11. Deeks ED. Safinamide: first global approval. Drugs. 2015; 75:705-11. http://www.ncbi.nlm.nih.gov/pubmed/25851099?dopt=AbstractPlus

12. Marquet A, Kupas K, Johne A et al. The effect of safinamide, a novel drug for Parkinson's disease, on pressor response to oral tyramine: a randomized, double-blind, clinical trial. Clin Pharmacol Ther. 2012; 92:450-7. http://www.ncbi.nlm.nih.gov/pubmed/22948897?dopt=AbstractPlus

13. Caccia C, Maj R, Calabresi M et al. Safinamide: from molecular targets to a new anti-Parkinson drug. Neurology. 2006; 67(7 Suppl 2):S18-23. http://www.ncbi.nlm.nih.gov/pubmed/17030736?dopt=AbstractPlus

14. Onofrj M, Bonanni L, Thomas A. An expert opinion on safinamide in Parkinson's disease. Expert Opin Investig Drugs. 2008; 17:1115-25. http://www.ncbi.nlm.nih.gov/pubmed/18549347?dopt=AbstractPlus

15. APCER Life Sciences, on behalf of US WorldMeds; Personal communication.

158. Fernandez HH, Chen JJ. Monoamine oxidase-B inhibition in the treatment of Parkinson's disease. Pharmacotherapy. 2007; 27:174S-185S. http://www.ncbi.nlm.nih.gov/pubmed/18041937?dopt=AbstractPlus

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