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Safinamide

Pronunciation

(sa FIN a mide)

Index Terms

  • Safinamide Mesylate
  • Xadago

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Xadago: 50 mg, 100 mg

Brand Names: U.S.

  • Xadago

Pharmacologic Category

  • Anti-Parkinson Agent, MAO Type B Inhibitor

Pharmacology

Inhibitor of MAO-B. Plasma concentrations achieved via administration in recommended doses (≤100 mg/day) confer selective inhibition of MAO-B activity, blocking the catabolism of dopamine, resulting in an increase in dopamine levels and a subsequent increase in dopaminergic activity in the brain. The precise mechanism by which safinamide exerts its effect in Parkinson disease is unknown.

Distribution

Vdss: ~165 L

Metabolism

Predominantly metabolized to inactive metabolites by non-microsomal enzymes (cytosolic amidases/MAO­A); CYP3A4 and other CYP iso-enzymes play only a minor role in its overall biotransformation.

Excretion

Urine (76%, primarily in the form of inactive metabolites; ~5% unchanged)

Time to Peak

2 to 3 hours

Half-Life Elimination

20 to 26 hours

Protein Binding

~88%

Special Populations: Hepatic Function Impairment

An approximately 30% increase in AUC was observed in mild hepatic impairment (Child-Pugh A). Exposure to safinamide was increased by about 80% in moderate hepatic impairment (Child-Pugh B).

Use: Labeled Indications

Parkinson disease: Adjunctive treatment to levodopa/carbidopa in patients with Parkinson disease (PD) experiencing "off" episodes

Limitations of use: Has not been shown to be effective as monotherapy for the treatment of PD

Contraindications

Hypersensitivity (eg, swelling of the tongue and oral mucosa, dyspnea) to safinamide or any component of the formulation; severe hepatic impairment (Child-Pugh class C); concomitant use of other monoamine oxidase inhibitors (MAOIs) or other drugs that are potent inhibitors of monoamine oxidase (including linezolid), opioids (eg, meperidine, methadone, propoxyphene, tramadol), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic, tetracyclic, or triazolopyridine antidepressants, cyclobenzaprine, methylphenidate, amphetamine, and their derivatives, St John's wort, dextromethorphan.

Dosing: Adult

Parkinson disease: Oral: 50 mg once daily; after 2 weeks may increase to 100 mg once daily.

Discontinuation of therapy: Decrease dose to 50 mg for one week before discontinuing therapy.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate impairment (Child-Pugh class B): Maximum dose: 50 mg once daily.

Severe impairment (Child-Pugh class C): Use is contraindicated by the manufacturer (has not been studied).

Administration

Administer without regard to meals at the same time every day. Always administer in association with levodopa/carbidopa.

Dietary Considerations

At doses ≤100 mg/day, interaction with tyramine-containing foods and beverages is unlikely, however patients should avoid foods and beverages with very high (>150 mg) tyramine concentrations. Food's freshness is also an important concern; improperly stored or spoiled food can create an environment where tyramine concentrations may increase (Walker 1996).

Storage

Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

Drug Interactions

Alcohol (Ethyl): May enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

Alpha-/Beta-Agonists (Indirect-Acting): MAO Inhibitors may enhance the hypertensive effect of Alpha-/Beta-Agonists (Indirect-Acting). While linezolid is expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to linezolid specific monographs for details. Avoid combination

Alpha1-Agonists: MAO Inhibitors may enhance the hypertensive effect of Alpha1-Agonists. While linezolid is expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to linezolid specific monographs for details. Avoid combination

Altretamine: May enhance the orthostatic hypotensive effect of MAO Inhibitors. Monitor therapy

Amphetamines: MAO Inhibitors may enhance the hypertensive effect of Amphetamines. While linezolid and tedizolid may interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Avoid combination

Analgesics (Opioid): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antidepressants (Serotonin Reuptake Inhibitor/Antagonist): MAO Inhibitors may enhance the adverse/toxic effect of Antidepressants (Serotonin Reuptake Inhibitor/Antagonist). While methylene blue and linezolid are expected to interact, specific recommendations for their use differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Avoid combination

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antipsychotic Agents: Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Apraclonidine: MAO Inhibitors may enhance the adverse/toxic effect of Apraclonidine. MAO Inhibitors may increase the serum concentration of Apraclonidine. Avoid combination

AtoMOXetine: MAO Inhibitors may enhance the neurotoxic (central) effect of AtoMOXetine. Avoid combination

Atropine (Ophthalmic): MAO Inhibitors may enhance the hypertensive effect of Atropine (Ophthalmic). Avoid combination

Beta2-Agonists: MAO Inhibitors may enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy

Betahistine: MAO Inhibitors may increase the serum concentration of Betahistine. Monitor therapy

Bezafibrate: MAO Inhibitors may enhance the adverse/toxic effect of Bezafibrate. Avoid combination

Blood Glucose Lowering Agents: MAO Inhibitors may enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Brimonidine (Ophthalmic): MAO Inhibitors may enhance the adverse/toxic effect of Brimonidine (Ophthalmic). MAO Inhibitors may increase the serum concentration of Brimonidine (Ophthalmic). Monitor therapy

Brimonidine (Topical): MAO Inhibitors may enhance the adverse/toxic effect of Brimonidine (Topical). MAO Inhibitors may increase the serum concentration of Brimonidine (Topical). Monitor therapy

Buprenorphine: May enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

BuPROPion: MAO Inhibitors may enhance the hypertensive effect of BuPROPion. Avoid combination

BusPIRone: May enhance the adverse/toxic effect of MAO Inhibitors. Specifically, blood pressure elevations been reported. Avoid combination

CarBAMazepine: May enhance the adverse/toxic effect of MAO Inhibitors. Management: Avoid concurrent use of carbamazepine during, or within 14 days of discontinuing, treatment with a monoamine oxidase inhibitor. Avoid combination

Cerebrolysin: May enhance the adverse/toxic effect of MAO Inhibitors. Monitor therapy

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of MAO Inhibitors. Monitor therapy

Codeine: MAO Inhibitors may enhance the adverse/toxic effect of Codeine. Monitor therapy

COMT Inhibitors: May enhance the adverse/toxic effect of MAO Inhibitors. Consider therapy modification

Cyclobenzaprine: May enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Avoid combination

Cyproheptadine: MAO Inhibitors may enhance the anticholinergic effect of Cyproheptadine. Cyproheptadine may diminish the serotonergic effect of MAO Inhibitors. Avoid combination

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

Deutetrabenazine: MAO Inhibitors may enhance the adverse/toxic effect of Deutetrabenazine. Avoid combination

Dexmethylphenidate: MAO Inhibitors may enhance the hypertensive effect of Dexmethylphenidate. Avoid combination

Dextromethorphan: MAO Inhibitors may enhance the serotonergic effect of Dextromethorphan. This may cause serotonin syndrome. Avoid combination

Diethylpropion: MAO Inhibitors may enhance the hypertensive effect of Diethylpropion. Avoid combination

Dihydrocodeine: May enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Monitor therapy

Domperidone: MAO Inhibitors may enhance the adverse/toxic effect of Domperidone. MAO Inhibitors may diminish the therapeutic effect of Domperidone. Domperidone may diminish the therapeutic effect of MAO Inhibitors. Monitor therapy

Doxapram: MAO Inhibitors may enhance the hypertensive effect of Doxapram. Monitor therapy

EPINEPHrine (Nasal): MAO Inhibitors may enhance the hypertensive effect of EPINEPHrine (Nasal). Monitor therapy

EPINEPHrine (Oral Inhalation): MAO Inhibitors may enhance the hypertensive effect of EPINEPHrine (Oral Inhalation). Avoid combination

Epinephrine (Racemic): MAO Inhibitors may enhance the hypertensive effect of Epinephrine (Racemic). Monitor therapy

EPINEPHrine (Systemic): MAO Inhibitors may enhance the hypertensive effect of EPINEPHrine (Systemic). Monitor therapy

FentaNYL: May enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Avoid combination

Heroin: MAO Inhibitors may enhance the adverse/toxic effect of Heroin. Avoid combination

HYDROcodone: MAO Inhibitors may enhance the adverse/toxic effect of HYDROcodone. Management: Consider alternatives to this combination when possible. Consider therapy modification

HYDROmorphone: MAO Inhibitors may enhance the adverse/toxic effect of HYDROmorphone. Avoid combination

Indoramin: MAO Inhibitors may enhance the hypotensive effect of Indoramin. Avoid combination

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Isometheptene: MAO Inhibitors may enhance the adverse/toxic effect of Isometheptene. Avoid combination

Isoniazid: Safinamide may enhance the adverse/toxic effect of Isoniazid. Specifically, there is an increased risk for hypertension. Monitor therapy

Levodopa: May enhance the adverse/toxic effect of MAO Inhibitors. Of particular concern is the development of hypertensive reactions when levodopa is used with nonselective MAOI. Management: The concomitant use of nonselective monoamine oxidase inhibitors (MAOIs) and levodopa is contraindicated. Discontinue the nonselective MAOI at least two weeks prior to initiating levodopa. Monitor patients taking a selective MAOIs and levodopa. Consider therapy modification

Levonordefrin: MAO Inhibitors may enhance the hypertensive effect of Levonordefrin. Avoid combination

Linezolid: MAO Inhibitors may enhance the adverse/toxic effect of Linezolid. Avoid combination

Lithium: MAO Inhibitors may enhance the adverse/toxic effect of Lithium. Management: This combination should be undertaken with great caution. When combined treatment is clinically indicated, monitor closely for signs of serotonin toxicity/serotonin syndrome. Consider therapy modification

MAO Inhibitors: May enhance the hypertensive effect of other MAO Inhibitors. MAO Inhibitors may enhance the serotonergic effect of other MAO Inhibitors. This could result in serotonin syndrome. Avoid combination

Maprotiline: May enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

Meperidine: MAO Inhibitors may enhance the serotonergic effect of Meperidine. This may cause serotonin syndrome. Avoid combination

Meptazinol: MAO Inhibitors may enhance the adverse/toxic effect of Meptazinol. Avoid combination

Mequitazine: MAO Inhibitors may enhance the anticholinergic effect of Mequitazine. Avoid combination

Metaraminol: MAO Inhibitors may enhance the hypertensive effect of Metaraminol. Monitor therapy

Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Methyldopa: MAO Inhibitors may enhance the adverse/toxic effect of Methyldopa. Avoid combination

Methylene Blue: MAO Inhibitors may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination

Methylphenidate: MAO Inhibitors may enhance the hypertensive effect of Methylphenidate. Avoid combination

Metoclopramide: Serotonin Modulators may enhance the adverse/toxic effect of Metoclopramide. This may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Monitor therapy

Mianserin: MAO Inhibitors may enhance the neurotoxic effect of Mianserin. Avoid combination

Mirtazapine: MAO Inhibitors may enhance the neurotoxic (central) effect of Mirtazapine. While methylene blue and linezolid are expected to interact, specific recommendations for their use differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Avoid combination

Moclobemide: MAO Inhibitors may enhance the adverse/toxic effect of Moclobemide. Avoid combination

Morphine (Liposomal): MAO Inhibitors may enhance the adverse/toxic effect of Morphine (Liposomal). Avoid combination

Morphine (Systemic): MAO Inhibitors may enhance the adverse/toxic effect of Morphine (Systemic). Avoid combination

Nefopam: MAO Inhibitors may enhance the adverse/toxic effect of Nefopam. Avoid combination

Norepinephrine: MAO Inhibitors may enhance the hypertensive effect of Norepinephrine. Monitor therapy

OxyCODONE: May enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Management: Seek alternatives when possible. Avoid use of oxycodone/naltrexone during and within 14 days after monoamine oxidase inhibitor treatment. Non-US labeling for some oxycodone products states that such use is contraindicated. Consider therapy modification

OxyMORphone: May enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

Pheniramine: May enhance the anticholinergic effect of MAO Inhibitors. Avoid combination

Pholcodine: May enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Avoid combination

Pindolol: MAO Inhibitors may enhance the hypotensive effect of Pindolol. Management: Canadian labeling for pindolol states that concurrent use with a monoamine oxidase inhibitor is not recommended. Consider therapy modification

Pipamperone [INT]: May diminish the therapeutic effect of Anti-Parkinson Agents (Monoamine Oxidase Inhibitor). Anti-Parkinson Agents (Monoamine Oxidase Inhibitor) may diminish the therapeutic effect of Pipamperone [INT]. Monitor therapy

Pizotifen: MAO Inhibitors may enhance the anticholinergic effect of Pizotifen. Avoid combination

Reboxetine: MAO Inhibitors may enhance the adverse/toxic effect of Reboxetine. Avoid combination

Reserpine: MAO Inhibitors may enhance the adverse/toxic effect of Reserpine. Existing MAOI therapy can result in paradoxical effects of added reserpine (e.g., excitation, hypertension). Management: Monoamine oxidase inhibitors (MAOIs) should be avoided or used with great caution in patients who are also receiving reserpine. Consider therapy modification

Selective Serotonin Reuptake Inhibitors: MAO Inhibitors may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. While methylene blue and linezolid are expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Avoid combination

Serotonin 5-HT1D Receptor Agonists: MAO Inhibitors may decrease the metabolism of Serotonin 5-HT1D Receptor Agonists. Management: If MAO inhibitor therapy is required, naratriptan, eletriptan or frovatriptan may be a suitable 5-HT1D agonist to employ. Exceptions: Eletriptan; Frovatriptan; Naratriptan. Avoid combination

Serotonin Modulators: Anti-Parkinson Agents (Monoamine Oxidase Inhibitor) may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity if selegiline, rasagiline, or safinamide is combined with a serotonin modulator. Use of transdermal selegiline with serotonin modulators is contraindicated. Exceptions: Nicergoline. Consider therapy modification

Serotonin/Norepinephrine Reuptake Inhibitors: MAO Inhibitors may enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This may cause serotonin syndrome. While methylene blue and linezolid are expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Avoid combination

Tapentadol: May enhance the adverse/toxic effect of MAO Inhibitors. Specifically, the additive effects of norepinephrine may lead to adverse cardiovascular effects. Tapentadol may enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Avoid combination

Tetrabenazine: May enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

Tetrahydrozoline (Nasal): MAO Inhibitors may enhance the hypertensive effect of Tetrahydrozoline (Nasal). Avoid combination

Tricyclic Antidepressants: MAO Inhibitors may enhance the serotonergic effect of Tricyclic Antidepressants. This may cause serotonin syndrome. While methylene blue and linezolid are expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Avoid combination

Tryptophan: May enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

Valbenazine: May enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

Adverse Reactions

>10%: Neuromuscular & skeletal: Dyskinesia (17% to 21%)

1% to 10%:

Cardiovascular: Hypertension (including exacerbation of hypertension: 5% to 7%), orthostatic hypotension (2%)

Central nervous system: Falling (6%), insomnia (4%), anxiety (2%)

Gastrointestinal: Nausea (6%), dyspepsia (2%)

Hepatic: Increased serum ALT (5% to 7%), increased serum AST (6% to 7%)

Respiratory: Cough (2%)

Frequency not defined: Central nervous system: Impulse control disorder

<1% (Limited to important or life-threatening): Sudden onset of sleep (high dose)

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving). Somnolence and falling asleep while engaged in activities of daily living (including operation of motor vehicles) have been reported; some cases reported that there were no warning signs for the onset of symptoms. Monitor for drowsiness or sleepiness. If significant daytime sleepiness or episodes of falling asleep during activities that require active participation occur (eg, driving, conversations, eating), discontinue safinamide or instruct patient to avoid driving or other potentially dangerous activities.

• Dyskinesia: May cause or exacerbate preexisting dyskinesia. Reducing the dose of safinamide or other dopaminergic medications may mitigate this effect.

• Hypertension: May cause or exacerbate preexisting hypertension. Monitor for new-onset or worsening hypertension. Increasing the dose above 100 mg/day decreases specificity for the MAO-B receptor and increases the risk for hypertension.

• Impulse control disorders: Dopaminergic agents used for Parkinson disease have been associated with compulsive behaviors and/or loss of impulse control, which has manifested as pathological gambling, libido increases (hypersexuality), uncontrolled spending of money, binge eating, and/or other intense urges. Causality has not been established, and controversy exists as to whether this phenomenon is related to the underlying disease, prior behaviors/addictions, and/or drug therapy. Dose reduction or discontinuation of therapy has been reported to reverse these behaviors in some, but not all, cases.

• Serotonin syndrome: Potentially life-threatening serotonin syndrome (SS) has occurred with concomitant use of serotonergic agents (eg, SSRIs, SNRIs, triptans, TCAs, fentanyl, lithium, tramadol, buspirone, St John's wort, tryptophan) or agents that impair metabolism of serotonin (eg, MAO inhibitors intended to treat psychiatric disorders, other MAO inhibitors [ie, linezolid and intravenous methylene blue]). Monitor patients closely for signs of SS such as mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis); neuromuscular changes (eg, tremor, rigidity, myoclonus); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with moderate hepatic impairment (Child-Pugh class B); use is contraindicated in patients with severe hepatic impairment (Child-Pugh class C).

• Ophthalmic disorder: Use with caution in patients with ophthalmic disorders, including a history of retinal/macular degeneration, uveitis, inherited retinal conditions, albinism, retinitis pigmentosa, any active retinopathy or family history of hereditary retinal disease. Monitor periodically for visual changes.

• Psychotic disorder: May exacerbate psychosis in patients with a major psychiatric disorder; consider discontinuing treatment or lowering dose in patients who develop hallucinations or psychotic behavior.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Antiparkinsonian discontinuation syndrome: Abrupt discontinuation or interruption of antiparkinsonian therapy has been associated with a discontinuation syndrome, which may resemble neuroleptic malignant syndrome; symptoms may include elevated temperature, muscular rigidity, altered consciousness and autonomic instability.

• Tyramine-containing products: Nonselective MAO inhibition may occur with doses greater than 100 mg/day. Hypertensive crisis as a result of ingesting tyramine-rich foods is always a concern with nonselective MAO inhibition. Discontinue therapy immediately if hypertensive crisis occurs.

Monitoring Parameters

Blood pressure; signs and symptoms of serotonin syndrome; visual changes.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies.

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