Skip to Content

Xadago

Generic Name: 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

Introduction

Safinamide mesylate is a monoamine oxidase B inhibitor.

Uses for Xadago

Safinamide mesylate has the following uses:

Safinamide mesylate is a monoamine oxidase type B (MAO-B) inhibitor indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson's disease experiencing “off” episodes.1

Safinamide mesylate has the following limitations of use:

Safinamide mesylate has not been shown to be effective as monotherapy for the treatment of Parkinson's disease.1

Xadago Dosage and Administration

General

Safinamide mesylate is available in the following dosage form(s) and strength(s):

Tablets: 50 mg and 100 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Start with 50 mg administered orally once daily at the same time of day; after two weeks, the dose may be increased to 100 mg once daily, based on individual need and tolerability.1

  • Hepatic Impairment: Do not exceed 50 mg once daily in patients with moderate hepatic impairment; contraindicated in patients with severe hepatic impairment.1

Cautions for Xadago

Contraindications

Safinamide mesylate is contraindicated in patients with: 1

  • Concomitant use of the following drugs:

    Other monoamine oxidase inhibitors or other drugs that are potent inhibitors of monoamine oxidase (e.g., linezolid)1

    Opioid drugs (e.g., tramadol, meperidine and related derivatives); selective norepinephrine-reuptake inhibitors; tricyclic or tetracyclic or triazolopyridine antidepressants; cyclobenzaprine; methylphenidate, amphetamine, and their derivatives; St. John's wort1

    Dextromethorphan1

  • A history of a hypersensitivity to safinamide.1

  • Severe hepatic impairment (Child-Pugh C: 10–15).1

Warnings/Precautions

Hypertension

Safinamide mesylate may cause hypertension or exacerbate existing hypertension. In clinical trials, the incidence of hypertension was 7% for safinamide mesylate 50 mg, 5% for safinamide mesylate 100 mg, and 4% for placebo. Monitor patients for new-onset hypertension or hypertension that is not adequately controlled after starting safinamide mesylate. Medication adjustment may be necessary if elevation of blood pressure is sustained.1

Monitor for hypertension if safinamide mesylate is prescribed concomitantly with sympathomimetic medications, including prescription or nonprescription nasal, oral, and ophthalmic decongestants and cold remedies.1

Safinamide mesylate is a selective inhibitor of MAO-B at the recommended dosages of 50 mg or 100 mg daily. Selectivity for inhibiting MAO-B decreases above the recommended daily dosages. Therefore, safinamide mesylate should not be used at daily dosages exceeding those recommended because of the risks of hypertension, exacerbation of existing hypertension, or hypertensive crisis.1

Dietary tyramine restriction is not required during treatment with recommended doses of safinamide mesylate. However, use with certain foods that contain very high amounts (i.e., more than 150 mg) of tyramine could cause severe hypertension, resulting from an increased sensitivity to tyramine in patients taking recommended dosages of safinamide mesylate, and patients should be advised to avoid such foods.1

Isoniazid has some monoamine oxidase inhibiting activity. Monitor for hypertension and reaction to dietary tyramine in patients treated concomitantly with isoniazid and safinamide mesylate.1

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported in patients on concomitant treatment with MAO inhibitors (including selective MAO-B inhibitors), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants, cyclobenzaprine, opioid drugs (e.g., meperidine and meperidine derivatives, propoxyphene, tramadol), and methylphenidate, amphetamine, and their derivatives. Concomitant use of safinamide mesylate with these drugs is contraindicated.1

In clinical trials, serotonin syndrome was reported in a patient treated with safinamide mesylate and an SSRI. Use the lowest effective dose of SSRIs in patients treated with concomitant safinamide mesylate.1

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).1

Falling Asleep During Activities of Daily Living

Patients treated with dopaminergic medications have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event.1

In clinical studies, sleep attacks/sudden onset of sleep were reported in patients treated with safinamide mesylate 100 mg/day.1

If a patient develops daytime sleepiness or episodes of falling asleep during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), safinamide mesylate should ordinarily be discontinued. If a decision is made to continue these patients on safinamide mesylate, advise them to avoid driving and other potentially dangerous activities.1

Dyskinesia

Safinamide mesylate may cause dyskinesia or exacerbate preexisting dyskinesia.1

In clinical trials, the incidence of dyskinesia was 21% for safinamide mesylate 50 mg, 18% for safinamide mesylate 100 mg, and 9% for placebo. There was a greater incidence of dyskinesia causing study discontinuation in Parkinson's disease patients treated with safinamide mesylate 50 mg or 100 mg (1%), compared to placebo (0%).1

Reducing the patient's daily levodopa dosage or the dosage of another dopaminergic drug may mitigate dyskinesia.1

Hallucinations / Psychotic Behavior

Patients with a major psychotic disorder should ordinarily not be treated with safinamide mesylate because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone. In addition, treatments for psychosis that antagonize the effects of dopaminergic medications may exacerbate the symptoms of Parkinson's disease.1

Consider dosage reduction or stopping the medication if a patient develops hallucinations or psychotic-like behaviors while taking safinamide mesylate.1

Impulse Control / Compulsive Behaviors

Patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including safinamide mesylate, that increase central dopaminergic tone. In some cases, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with safinamide mesylate. Consider dose reduction or stopping the medication if a patient develops such urges while taking safinamide mesylate.1

Withdrawal-emergent Hyperpyrexia And Confusion

A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone.1

Retinal Pathology

Retinal degeneration and loss of photoreceptor cells were observed in albino and pigmented rats administered safinamide orally in toxicity studies of up to 6 months' duration. In albino rats administered safinamide orally for two years, retinal scarring and cataracts were observed at all doses tested.1

Periodically monitor patients for visual changes in patients with a history of retinal/macular degeneration, uveitis, inherited retinal conditions, family history of hereditary retinal disease, albinism, retinitis pigmentosa, or any active retinopathy (e.g., diabetic retinopathy).1

Specific Populations

Pregnancy

Pregnancy Category C.1

There are no adequate and well-controlled studies of safinamide mesylate in pregnant women. In animals, developmental toxicity, including teratogenic effects, was observed when safinamide was administered during pregnancy at clinically relevant doses. Developmental toxicity was observed at safinamide doses lower than those used clinically when safinamide was administered during pregnancy in combination with levodopa/carbidopa. Safinamide mesylate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.1

In an embryofetal development study in rats, oral administration of safinamide (0, 50, 100, or 150 mg/kg/day) throughout organogenesis resulted in dose-related increases in fetal abnormalities (primarily urogenital malformations) at all doses. The lowest dose tested is approximately 5 times the maximum recommended human dose (MRHD) of 100 mg on a body surface area (mg/m2) basis. In a combination embryofetal development study of safinamide and levodopa /carbidopa- in rats (80/20 mg/kg/day levodopa/carbidopa in combination with 0, 25, 50, or 100 mg/kg/day safinamide or 100 mg/kg/day safinamide alone) increased incidences of fetal visceral and skeletal malformations and variations were observed at all doses of safinamide in combination with carbidopa/levodopa and with safinamide alone. The lowest dose of safinamide tested (25 mg/kg/day) is approximately 2 times the MRHD on a mg/m2 basis.1

In embryofetal development studies in rabbits, no developmental toxicity was observed at up to the highest oral dose of safinamide tested (100 mg/kg/day). However, when safinamide (4, 12, or 40 mg/kg/day) was administered throughout organogenesis in a combination study of safinamide with levodopa/carbidopa (80/20 mg/kg/day levodopa/carbidopa) there was an increased incidence of embryofetal death and cardiac and skeletal malformations, compared to levodopa/carbidopa alone. A no-effect dose for safinamide was not established; the lowest effect dose of safinamide tested (4 mg/kg/day) is less than the MRHD on a mg/m2 basis.1

In a rat pre- and postnatal development study, oral administration of safinamide (0, 4, 12.5, or 37.5 mg/kg/day) throughout pregnancy and lactation resulted in skin discoloration of the offspring, presumed to be due to hepatobiliary toxicity, at the mid and high doses and decreased body weight and increased postnatal mortality in offspring at the highest dose tested. The no effect dose (4 mg/kg/day) is less than the MRHD on a mg/m2 basis.1

Lactation

Skin discoloration, presumed to be caused by hyperbilirubinemia resulting from hepatobiliary toxicity, was observed in rat pups indirectly exposed to safinamide through the milk during the lactation period. It is not known whether this drug is present in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from safinamide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the woman.1

Pediatric Use

The safety and effectiveness of safinamide mesylate in pediatric patients have not been established. No juvenile toxicity studies have been performed in animals.1

Geriatric Use

Of the 1516 subjects exposed to safinamide mesylate in clinical studies, 38% were 65 and over, while 4% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.1

Hepatic Impairment

Safinamide mesylate plasma concentrations are increased in patients with hepatic impairment.1

In patients with moderate hepatic impairment (Child-Pugh B: 7–9), the maximum recommended dosage of safinamide mesylate is 50 mg once daily. Safinamide mesylate has not been studied in patients with severe hepatic impairment (Child-Pugh C: 10–15), and is contraindicated in these patients. If patients progress from moderate to severe hepatic impairment, treatment with safinamide mesylate should be stopped.1

Common Adverse Effects

Most common adverse reactions (incidence on safinamide mesylate 100 mg/day at least 2% greater than placebo) were dyskinesia, fall, nausea, and insomnia.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Selective serotonin reuptake inhibitors: Monitor patients for serotonin syndrome1

  • Sympathomimetic medications: Monitor patients for hypertension1

  • Tyramine: Risk of severe hypertension1

  • Substrates of breast cancer resistance protein (BCRP): Potential increase in plasma concentration of BCRP substrate1

Actions

Mechanism Of Action

The precise mechanism by which safinamide mesylate exerts its effect in Parkinson's disease is unknown. Safinamide mesylate is an inhibitor of monoamine oxidase B (MAO-B). Inhibition of MAO-B activity, by blocking the catabolism of dopamine, is thought to result in an increase in dopamine levels and a subsequent increase in dopaminergic activity in the brain.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

Hypertension

Advise patients that treatment with recommended doses of safinamide mesylate may be associated with elevations of blood pressure or onset of hypertension. Tell patients who experience elevation of blood pressure while taking safinamide mesylate to contact their healthcare provider.1

Explain the risk of using higher than recommended daily doses of safinamide mesylate, and provide a brief description of the tyramine associated hypertensive reaction.1

Advise patients to avoid certain foods (e.g., aged cheese) containing a very large amount of tyramine while taking recommended doses of safinamide mesylate because of the potential for large increases in blood pressure. If patients eat foods very rich in tyramine and do not feel well soon after eating, they should contact their healthcare provider.1

Serotonin Syndrome

Tell patients to inform their physician if they are taking, or planning to take, any prescription or over-the-counter drugs, especially antidepressants and over-the-counter cold medications, because there is a potential for interaction with safinamide mesylate. Because patients should not use meperidine or certain other analgesics with safinamide mesylate, they should contact their healthcare provider before taking new medications including antidepressants, analgesics, and prescription or nonprescription decongestants.1

Falling Asleep During Activities of Daily Living and Somnolence

Inform patients about the potential for sedating effects associated with safinamide mesylate and other dopaminergic medications, including somnolence and particularly the possibility of falling asleep while engaged in activities of daily living. Because somnolence can be a frequent adverse reaction with potentially serious consequences, patients should not operate a motor vehicle or engage in other potentially dangerous activities until they have gained sufficient experience with safinamide mesylate.1

Advise patients that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Patients should not drive, operate machinery, or work at heights during treatment if they have previously experienced somnolence and/or have fallen asleep without warning prior to use of safinamide mesylate.1

Because of possible additive effects, advise patients about the potential for increased somnolence when patients are taking other sedating medications, alcohol, or other central nervous system depressants (e.g., benzodiazepines, antipsychotics, antidepressants) in combination with safinamide mesylate.1

Dyskinesia

Advise patients taking safinamide mesylate as adjunct to levodopa that there is a possibility of dyskinesia or increased dyskinesia.1

Hallucinations / Psychotic Behavior

Inform patients that hallucinations or other manifestations of psychotic behavior can occur when taking safinamide mesylate. Advise patients that, if they have a major psychotic disorder, safinamide mesylate should not ordinarily be used because of the risk of exacerbating the psychosis. Patients with a major psychotic disorder should also be aware that many treatments for psychosis may decrease the effectiveness of safinamide mesylate.1

Impulse Control/Compulsive Behaviors

Advise patients that they may experience intense urges to gamble, increased sexual urges, or other intense urges, and the inability to control these urges while taking safinamide mesylate. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges, or other urges while being treated with safinamide mesylate. Patients should inform their physician if they experience these urges while taking safinamide mesylate.1

Withdrawal-Emergent Hyperpyrexia and Confusion

Tell patients to contact their healthcare provider if they wish to discontinue safinamide mesylate and seek guidance for tapering safinamide mesylate instead of abruptly discontinuing safinamide mesylate.1

Missing Dose

Instruct patients to take safinamide mesylate as prescribed. If a dose is missed, instruct patients to take the next dose at the usual time on the following day.1

Concomitant Medications

Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications because of a potential for interactions.1

Additional Information

AHFS First Release. For additional information 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 uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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

Tablet, Film-coated

50 mg

Xadago

US WorldMeds

100 mg

Xadago

US WorldMeds

AHFS Drug Information. © Copyright 2018, Selected Revisions May 22, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. US WorldMeds, LLC. Xadago (safinamide mesylate) oral tablets prescribing information. 2017 Mar.

Hide