AHFS Class:

• Monoamine Oxidase B Inhibitors 28:36.32

Generic Name(s):

• Safinamide Mesylate

Chemical Name:

• (2S)-2-[[4-[(3-fluorophenyl)methoxy]phenyl]methylamino]propanamide;methanesulfonic acid

Molecular Formula:

• C₁₈H₂₃FN₂O₅S

Safinamide mesylate, an α-aminoamide derivative, is a selective and reversible inhibitor of monoamine oxidase-B (MAO-B).1,2,5,6,8,14

Parkinsonian Syndrome

Safinamide is 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 (See Uses: Parkinsonian Syndrome, in Levodopa/Carbidopa 28:36.16.) Safinamide has been shown to be effective only in combination with levodopa-carbidopa; efficacy of safinamide monotherapy has not been established.1,2,3

Efficacy of safinamide as adjunctive therapy to levodopa-carbidopa has been established in 2 multicenter, randomized, double-blind, placebo-controlled studies in patients with parkinsonian syndrome (mean duration of disease: 8-9 years) who were experiencing motor fluctuations while receiving levodopa-carbidopa therapy.1,2,3 In these studies, patients were randomized to receive safinamide (50 or 100 mg daily) or placebo for up to 24 weeks.1,2,3 Patients continued to receive levodopa (average daily dose of 630-777 mg) and were permitted to receive stable dosages of other antiparkinsonian agents; 61-74% of patients received a dopamine agonist, 18-24% received a catechol- O -methyltransferase (COMT) inhibitor, 17-37% received an anticholinergic agent, and 14-30% received amantadine.1 The primary efficacy end point of both studies was the change from baseline in total daily “on” time without dyskinesia or with only nontroublesome dyskinesia, as assessed by 18-hour patient-completed diaries.1,2,3 Safinamide (50 or 100 mg daily) was more effective than placebo in increasing total daily “on” time without troublesome dyskinesia when used as add-on therapy to levodopa-carbidopa, and this beneficial effect was accompanied by a reduction in “off” time.1,2,3 An important secondary outcome in these studies was motor function during the “on” period, which was assessed by the mean change in score on the Unified Parkinson's Disease Rating Scale (UPDRS) part III.2,3 Compared with placebo, safinamide was associated with substantial improvements in this outcome measure.1,2,3 In an 18-month extension of one of the principal efficacy studies, improvements in “on” time without troublesome dyskinesia were maintained through 24 months with continued safinamide therapy; however, safinamide did not substantially improve scores on a clinician-rated dyskinesia scale during “on” time (the primary efficacy outcome) compared with placebo.4,6,9 A possible explanation for this observed lack of effect is that the majority of the study population (approximately 74%) had no dyskinesia or only mild dyskinesia at baseline.4 In an ad hoc subgroup analysis of patients with moderate-to-severe dyskinesia at baseline, treatment with safinamide 100 mg once daily substantially improved dyskinesia scores compared with placebo.4,6,9

Administration

Safinamide mesylate is administered orally once daily at the same time each day without regard to meals.1

Dosage

Dosage of safinamide mesylate is expressed in terms of safinamide.1

The recommended initial adult dosage of safinamide as an adjunct to levodopa-carbidopa for the management of parkinsonian syndrome is 50 mg once daily.1 After 2 weeks, dosage may be increased to 100 mg once daily based on individual response and tolerability.1 Safinamide dosages exceeding 100 mg daily have not been shown to provide additional benefit and may increase the risk of adverse effects, including serious hypertensive reactions.1 (See Hypertension under Cautions: Warnings/Precautions.)

Because safinamide may cause or exacerbate dyskinesia, dosage reduction of levodopa or other dopaminergic agents may be needed during concomitant therapy to mitigate this effect.1

If a dose of safinamide is missed, the dose should be skipped and the next dose should be taken at the usual time the following day.1

When discontinuing safinamide therapy in patients receiving a dosage of 100 mg once daily, dosage should be decreased to 50 mg once daily for 1 week prior to discontinuance.1 (See Neuroleptic Malignant Syndrome under Cautions: Warnings/Precautions.)

Special Populations

Hepatic Impairment

Patients with moderate hepatic impairment (Child-Pugh class B) should not receive safinamide dosages exceeding 50 mg once daily; safinamide is contraindicated in patients with severe hepatic impairment (Child-Pugh class C).1 If a patient progresses from moderate to severe hepatic impairment while receiving a safinamide dosage of 50 mg daily, the drug should be discontinued.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Renal Impairment

The manufacturer does not provide specific dosage recommendations for patients with renal impairment.1 Data from a pharmacokinetic study indicate that the pharmacokinetics of safinamide are not affected by impaired renal function.1,15 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Contraindications

Concomitant use with other drugs that inhibit monoamine oxidase (MAO) (e.g., other MAO inhibitors, linezolid); opiate agonists (e.g., meperidine, methadone, propoxyphene [no longer commercially available in the US], tramadol); serotonin- and norepinephrine-reuptake inhibitors (SNRIs); tricyclic, tetracyclic, or triazolopyridine antidepressants; cyclobenzaprine; methylphenidate; amphetamines; St. John's wort ( Hypericum perforatum ); or dextromethorphan.1 (See Drug Interactions.)

Known hypersensitivity to safinamide.1 (See Hypersensitivity Reactions under Warnings/Precautions: Sensitivity Reactions, in Cautions.)

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

Warnings/Precautions

Hypertension

Safinamide may cause hypertension or exacerbate existing hypertension.1 In clinical studies, the incidence of hypertension was 7 or 5% in patients receiving safinamide 50 or 100 mg daily, respectively, compared with an incidence of 4% in those receiving placebo.1 Patients receiving safinamide should be monitored for new-onset hypertension or hypertension that is not adequately controlled.1 Dosage adjustment of antihypertensive drugs may be necessary if elevation of blood pressure is sustained.1,15

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 exceeding 100 mg daily, relative selectivity for MAO-B diminishes and the likelihood of hypertensive reactions increases.1 To minimize this risk, patients should not exceed recommended dosages of safinamide.1 (See Dosage and Administration: Dosage.) Concomitant use of safinamide with other MAO inhibitors (e.g., linezolid) also may increase the risk of nonselective MAO inhibition and cause hypertensive crisis.1 (See Cautions: Contraindications and also see Drug Interactions.)

Severe hypertensive reactions have been reported rarely in patients taking recommended dosages of selective MAO-B inhibitors with tyramine-rich foods or with sympathomimetic drugs.1 In an oral tyramine challenge study, safinamide produced a small increase in tyramine sensitivity for increasing blood pressure; these findings suggest that safinamide at a dosage of 50-100 mg once daily is relatively selective for inhibiting MAO-B.1,12 The manufacturer states that restriction of most tyramine-containing foods or beverages generally is not required during safinamide therapy.1 However, because foods that contain very large amounts (i.e., more than 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, patients should be advised to avoid such tyramine-rich foods during safinamide therapy.1 Patients treated concomitantly with safinamide and isoniazid should be monitored for hypertension and reaction to dietary tyramine.1 (For additional information on foods and beverages with high tyramine content, see Drug Interactions: Food and Drugs Associated with Hypertensive Crisis, in the Monoamine Oxidase Inhibitors General Statement 28:16.04.12.)

Serotonin Syndrome

Concomitant use of MAO inhibitors with antidepressants (e.g., selective serotonin-reuptake inhibitors [SSRIs], selective serotonin- and norepinephrine-reuptake inhibitors [SNRIs], tricyclic or tetracyclic antidepressants, triazolopyridine-derivative antidepressants), cyclobenzaprine, methylphenidate, amphetamine, or certain opiate agonists (i.e., meperidine, propoxyphene [no longer commercially available in the US], tramadol) has resulted in severe, sometimes fatal, serotonin syndrome.1 (See Cautions: Contraindications.) Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, 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

Patients receiving dopaminergic drugs have reported falling asleep while engaged in activities of daily living including operating a motor vehicle (which has sometimes resulted in accidents).1 In clinical studies, sleep attacks and sudden onset of sleep were reported in some patients receiving safinamide 100 mg daily.1 Patients may not exhibit warning signs (e.g., excessive drowsiness) or may report feeling alert immediately prior to the sudden sleep event.1

If a patient develops clinically important daytime sleepiness or episodes of falling asleep during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), safinamide generally should be discontinued.1 If a decision is made to continue the drug, patients should be advised not to drive and to avoid other potentially dangerous activities.1

Dyskinesia

When used as adjunctive therapy with levodopa, safinamide may cause or exacerbate dyskinesia; this may be mitigated by reducing the dosage of levodopa or dosage of another dopaminergic drug.1 Dyskinesia was reported in 18-21% of patients receiving safinamide and resulted in discontinuance of the drug in 1% of patients in clinical studies.1

Hallucinations and Psychotic-like Behavior

Patients with major psychotic disorders generally should not receive safinamide due to the risk of exacerbating the psychosis with an increase in central dopaminergic tone.1 Additionally, the symptoms of parkinsonian syndrome may be exacerbated by antipsychotic agents that antagonize the effects of dopaminergic drugs.1 (See Drug Interactions.)

If a patient develops hallucinations or psychotic-like behaviors while receiving safinamide, consideration should be given to reducing the dosage or discontinuing the drug.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 have been reported in some patients receiving antiparkinsonian agents that increase central dopaminergic tone (including safinamide).1 These urges stopped in some cases when dosage was reduced or the drug was discontinued.1 Clinicians should ask patients or their caregivers whether they have developed new or increased gambling urges, sexual urges, or other urges while receiving safinamide.1 If a patient develops such urges while receiving safinamide, consideration should be given to reducing the dosage or discontinuing the drug.1

Neuroleptic Malignant Syndrome

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

Ocular Effects

In animal toxicity studies, retinal degradation and loss of photoreceptor cells were observed when safinamide was administered orally to rats for up to 6 months at dosages lower than the maximum recommended human dosage.1 Retinal scarring and cataracts were observed in albino rats following oral administration of safinamide for 2 years.1 Investigative studies were not able to identify a mechanism underlying the retinal toxicity.1

Patients who may be at increased risk of adverse ocular events (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]) should be periodically evaluated for visual changes while receiving safinamide therapy.1,6

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., swelling of the tongue and oral mucosa, dyspnea) have occurred in patients receiving safinamide.1 (See Cautions: Contraindications.)

Specific Populations

Pregnancy

Category C.1 (See Users Guide.)

There are no adequate and well-controlled studies of safinamide in pregnant women.1 In animal reproduction studies, safinamide produced developmental toxicity and teratogenic effects (e.g., decreased body weight, cardiac and skeletal malformations, embryofetal death, postnatal death) when the drug was administered to pregnant rats and rabbits at clinically relevant dosages.1

Lactation

Studies in rats indicate that safinamide is distributed into milk; skin discoloration, thought to be caused by hepatobiliary toxicity, was observed in nursing pups exposed to safinamide through milk during the lactation period.1,8

It is not known whether safinamide is distributed into human milk; a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1

Pediatric Use

Safety and efficacy of safinamide have not been established in pediatric patients younger than 18 years of age.1

Geriatric Use

Approximately 38% of patients in clinical studies of safinamide were 65 years of age or older.1 No overall differences in safety or efficacy relative to younger adults were observed and other clinical experiences have not identified differences in response with regard to a however, greater sensitivity of some older individuals cannot be ruled out.1

Hepatic Impairment

The area under the plasma concentration-time curve (AUC) of safinamide was increased by 30 or 80% in individuals with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, respectively.1

Dosage adjustment is recommended in patients with moderate hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration: Special Populations.) Use of safinamide is contraindicated in patients with severe hepatic impairment (Child-Pugh class C); safety and efficacy have not been established in this population.1 If patients progress from moderate to severe hepatic impairment during therapy, the drug should be discontinued.1

Renal Impairment

In an open-label single-dose study in patients with normal renal function or moderate to severe renal impairment, the pharmacokinetics of safinamide were not affected by impaired renal function.1

Common Adverse Effects

Adverse effects reported in 2% or more of patients receiving safinamide and occurring more frequently than with placebo include dyskinesia,1,2,3 fall,1,3 nausea,1,3 insomnia,1,3 orthostatic hypotension,1 anxiety,1,3 cough,1,3 and dyspepsia.1,3

Safinamide is minimally metabolized by cytochrome P-450 (CYP) 3A4 and other CYP isoenzymes.1 Safinamide and its major metabolites are neither inhibitors nor inducers of CYP isoenzymes at therapeutic concentrations.1

In vitro studies indicate that safinamide and its metabolites are not inhibitors of the efflux transporters P-glycoprotein (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 Safinamide and its major metabolite may inhibit intestinal breast cancer resistance protein (BCRP).1 Safinamide is not a substrate of P-gp.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Safinamide is not expected to interact with drugs metabolized by hepatic microsomal enzymes.1 In specific drug interaction studies using probe substrates for CYP1A2 (caffeine) and CYP3A4 (midazolam), clinically important changes were not observed in the pharmacokinetics of safinamide or the coadministered substrate drug.1

Drugs Affected by Breast Cancer Resistance Protein

Concomitant use of safinamide and BCRP substrates (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan) may result in increased plasma concentrations of the BCRP substrate.1 If safinamide is used concomitantly with a BCRP substrate, patients should be monitored for increased pharmacologic or adverse effects of the BCRP substrate.1

Antidepressant Agents

Concomitant use of safinamide and serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic or tetracyclic antidepressants, or triazolopyridine-derivative antidepressants may cause life-threatening serotonin syndrome; such concomitant use is contraindicated.1 (See Serotonin Syndrome under Cautions: Warnings/Precautions.) At least 14 days should elapse between discontinuance of safinamide and initiation of these antidepressants.1

In clinical studies, serotonin syndrome was reported in a patient who received safinamide in conjunction with a selective serotonin-reuptake inhibitor (SSRI).1 If safinamide is used concomitantly with an SSRI, the lowest effective dosage of the SSRI should be used.1

Cyclobenzaprine

Concomitant use of safinamide with cyclobenzaprine (a tricyclic antidepressant derivative) may result in life-threatening serotonin syndrome; such concomitant use is contraindicated.1 (See Serotonin Syndrome under Cautions: Warnings/Precautions.) At least 14 days should elapse between discontinuance of safinamide and initiation of cyclobenzaprine.1

Dextromethorphan

Concomitant use of monoamine oxidase (MAO) inhibitors and dextromethorphan has caused episodes of psychosis or bizarre behavior; concomitant use of safinamide and dextromethorphan is contraindicated.1

Dopamine Antagonists

Concomitant use of safinamide and dopamine antagonists (e.g., metoclopramide, antipsychotic agents) may result in decreased efficacy of safinamide.1

Isoniazid

Isoniazid possesses some MAO-inhibiting activity and can increase the risk of hypertensive reactions when used concomitantly with safinamide.1 Patients receiving such concomitant therapy should be monitored for hypertensive reactions when consuming foods containing tyramine.1 (See Hypertension under Cautions: Warnings/Precautions.)

Ketoconazole

In drug interaction studies, clinically important changes were not observed in the pharmacokinetics of safinamide or ketoconazole when the drugs were coadministered.1

Levodopa

In drug interaction studies, clinically important changes were not observed in the pharmacokinetics of safinamide or levodopa when the drugs were coadministered.1

Linezolid

Concomitant use of safinamide and linezolid (a potent inhibitor of MAO) may increase the risk of nonselective MAO inhibition, possibly resulting in hypertensive crisis; concomitant use is contraindicated.1 (See Hypertension under Cautions: Warnings/Precautions.) At least 14 days should elapse between discontinuance of safinamide and initiation of linezolid.1

Monoamine Oxidase Inhibitors

Concomitant use of safinamide with other MAO inhibitors may increase the risk of nonselective MAO inhibition, possibly resulting in hypertensive crisis; concomitant use is contraindicated.1 (See Hypertension under Cautions: Warnings/Precautions.) At least 14 days should elapse between discontinuance of safinamide and initiation of other MAO inhibitors.1

Opiate Agonists

Severe, sometimes fatal reactions (serotonin syndrome) have been reported following concomitant use of safinamide and opiates.1 Therefore, concomitant use of safinamide with meperidine, methadone, propoxyphene (no longer commercially available in the US), or tramadol is contraindicated.1 (See Serotonin Syndrome under Cautions: Warnings/Precautions.) At least 14 days should elapse between discontinuance of safinamide and initiation of these drugs.1

St. John's Wort

Due to the risk of life-threatening serotonin syndrome, concomitant use of safinamide and St. John's wort ( Hypericum perforatum) is contraindicated.1 (See Serotonin Syndrome under Cautions: Warnings/Precautions.) At least 14 days should elapse between discontinuance of safinamide and initiation of St. John's wort.1

Sympathomimetic Drugs

Severe hypertension or hypertensive crisis may occur following concomitant use of safinamide with sympathomimetic drugs.1 Therefore, patients should be monitored for hypertension when safinamide is used concomitantly with preparations containing sympathomimetic drugs such as prescription and nonprescription (OTC) decongestants and drugs used for the common cold (e.g., pseudoephedrine), including oral, nasal, and ophthalmic preparations; concomitant use of safinamide with amphetamines or methylphenidate is contraindicated.1,6 (See Hypertension under Cautions: Warnings/Precautions.)

Tyramine-rich Foods or Beverages

Concomitant use of safinamide with tyramine-rich foods or beverages may result in substantially elevated blood pressure or hypertensive crisis.1 (See Hypertension under Cautions: Warnings/Precautions and also see Description.) The manufacturer states that while it is generally not necessary to restrict ingestion of most foods or beverages that may contain tyramine, ingestion of certain foods containing very large amounts of tyramine (e.g., aged cheese, pickled herring) potentially may result in a hypertensive crisis and, thus, should be avoided during safinamide therapy.1 For additional information on foods and beverages with high tyramine content, see Drug Interactions: Food and Drugs Associated with Hypertensive Crisis, in the Monoamine Oxidase Inhibitors General Statement 28:16.04.12.

Description

Safinamide mesylate, an α-aminoamide derivative, is a selective and reversible inhibitor of monoamine oxidase-B (MAO-B).1,2,5,6,8,14 MAO is a mitochondrial enzyme that regulates the metabolic degradation of catecholamines and serotonin in the CNS and peripheral tissues.5 There appear to be at least 2 isoforms of MAO, MAO-A and MAO-B, which differ in localization and substrate specificity.8,158 MAO-A, predominantly found in the GI tract and liver, regulates the metabolic degradation of circulating catecholamines and dietary amines (e.g., tyramine).158 MAO-B, predominantly found in the brain, regulates the metabolic degradation of dopamine and phenylethylamine.158 Inhibition of MAO-A in the periphery results in systemic absorption of dietary amines (e.g., tyramine), which, in substantial amounts, can cause release of norepinephrine and subsequent substantial increases in blood pressure.158 (See Hypertension under Cautions: Warnings/Precautions.) Inhibition of MAO-B results in increased extracellular concentrations of dopamine and, therefore, enhanced dopaminergic activity in the striatum.1,11,158 While the precise mechanism of action of safinamide in parkinsonian syndrome has not been fully characterized, the drug has both dopaminergic and nondopaminergic effects that are thought to contribute to its therapeutic activity.1,6,8,11,13 In addition to its MAO-B inhibiting effects, safinamide also blocks voltage-dependent sodium and calcium channels and inhibits the release of neuronal glutamate, which is thought to play a role in dyskinesia.6,8,11,13,14 Compared with selegiline and rasagiline, safinamide inhibits MAO-B in a reversible manner and has higher selectivity for MAO-B (more than 1000-fold greater selectivity for MAO-B than for MAO-A).1,8,10,13 Selectivity for MAO-B is dose related and diminishes as dosage of safinamide is increased above recommended dosages.1,10

Safinamide exhibits linear pharmacokinetics over the dose range of 50-300 mg.1 Safinamide is rapidly absorbed;11 following oral administration, peak plasma concentrations of the drug are achieved in approximately 2-3 hours.1,8 Absolute bioavailability of safinamide is 95%.1,8,10 Following administration with food, the rate of absorption was slightly delayed, but peak plasma concentrations and area under the plasma concentration-time curve (AUC) of safinamide were unchanged.1,8 The mean terminal half-life of safinamide is 20-26 hours.1 The drug is approximately 88-90% bound to plasma proteins.1,10 Safinamide is principally metabolized by nonmicrosomal enzymes (cytosolic amidases/MAO-A) and only minimally metabolized by cytochrome P-450 (CYP) 3A4 and other CYP isoenzymes.1,14 The major metabolite, safinamide acid, is 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 the N -dealkylated acid.8,10 The N -dealkylated acid metabolite, which is the main circulating metabolite in human plasma (exceeding exposure of the parent compound), undergoes further conjugation with glucuronic acid.1 None of the metabolites of safinamide possess pharmacologic activity.1,8 Safinamide is eliminated mainly in urine (approximately 76%), primarily as inactive metabolites.1

Advice to Patients

Risk of elevated blood pressure or hypertension; advise patients to contact their clinician if they experience an increase in blood pressure.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

Importance of advising patients of the potential for sedating effects, including somnolence and the possibility of falling asleep without feeling drowsy or without warning while engaged in 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, it should be omitted and the next dose should be administered at the regularly scheduled time the following day.1 Importance of not abruptly discontinuing therapy and of 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.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. US WorldMeds. Xadago^® (safinamide mesylate) tablets prescribing information. Louisville, KY; 2017 May. From DailyMed website. [Web]

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. [PubMed 24323641]

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. [PubMed 27942720]

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. [PubMed 25044402]

5. Finberg JP, Rabey JM. Inhibitors of MAO-A and MAO-B in Psychiatry and Neurology. Front Pharmacol . 2016; 7:340. [PubMed 27803666]

6. . Safinamide (Xadago) for Parkinson's disease. Med Lett Drugs Ther . 2017; 59:151-153. [PubMed 28880847]

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. [PubMed 26587996]

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. [PubMed 26406127]

10. Müller T, Foley P. Clinical Pharmacokinetics and Pharmacodynamics of Safinamide. Clin Pharmacokinet . 2017; 56:251-261. [PubMed 27665574]

11. Deeks ED. Safinamide: first global approval. Drugs . 2015; 75:705-11. [PubMed 25851099]

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. [PubMed 22948897]

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. [PubMed 17030736]

14. Onofrj M, Bonanni L, Thomas A. An expert opinion on safinamide in Parkinson's disease. Expert Opin Investig Drugs . 2008; 17:1115-25. [PubMed 18549347]

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. [PubMed 18041937]