safinamide (Rx)

Brand and Other Names:Xadago
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 50mg
  • 100mg

Parkinson Disease

Indicated as add-on treatment for patients with Parkinson disease who are currently taking levodopa/carbidopa and experiencing “off” episodes

Initial: 50 mg PO qDay

After 2 weeks, may increase dose to 100 mg PO qDay, based on individual need and tolerability

Doses >100 mg/day have not shown additional benefit

Dosage Modifications

Liver impairment

  • Moderate (Child-Pugh B: 7-9): Not to exceed 50 mg/day
  • Severe (Child-Pugh C: 10-15): Contraindicated

Dosing Considerations

Limitation of use: Not shown effective as monotherapy for PD

Safety and efficacy not established

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Interactions

Interaction Checker

and safinamide

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      Serious - Use Alternative

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            Adverse Effects

            >10%

            Dyskinesia (17-21%)

            1-10%

            Hypertension (5-7%)

            ALT or AST increased to >ULN (5-7%)

            Fall (4-6%)

            Nausea (3-6%)

            Insomnia (1-4%)

            Orthostatic hypotension (2%)

            Anxiety (2%)

            Cough (2%)

            Dyspepsia (2%)

            Postmarketing Reports

            Swelling of tongue and gingiva

            Dyspnea

            Rash

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            Warnings

            Contraindications

            History of hypersensitivity to safinamide; reactions include swelling of the tongue and oral mucosa, and dyspnea

            Severe hepatic impairment (Child-Pugh C: 10-15)

            Coadministration with other monoamine oxidase inhibitors (MAOIs) or drugs that are potent inhibitors of MAO (eg, linezolid); combination may result in increased blood pressure, including hypertensive crisis

            Coadministration with opioids (eg, meperidine and its derivatives, methadone, tramadol); serotonin-norepinephrine reuptake inhibitors (SNRIs); tricyclic, tetracyclic, or triazolopyridine antidepressants; cyclobenzaprine; methylphenidate, amphetamine, and their derivatives; or St John’s wort; combination could result in life-threatening serotonin syndrome

            Coadministration with dextromethorphan; combination of MAOIs and dextromethorphan has been reported to cause episodes of psychosis or abnormal behavior

            Cautions

            May cause or exacerbate hypertension; monitor patients for new onset hypertension or hypertension not adequately controlled after initiating therapy; medication adjustment may be necessary if blood pressure elevation is sustained

            May cause serotonin syndrome when used with MAOIs, antidepressants, or opioid drugs (see Contraindications)

            May cause falling asleep during activities of daily living

            May cause or exacerbate dyskinesia; consider levodopa dose reduction to mitigate dyskinesia

            May cause hallucinations and psychotic behavior; consider dosage reduction or stopping medication if patient develops hallucinations or psychotic-like behaviors while on therapy

            May cause problems with impulse control/compulsive behaviors; consider dose reduction or stopping medication if a patient develops compulsive behavior while on therapy

            May cause withdrawal-emergent hyperpyrexia and confusion

            Retinal degeneration and loss of photoreceptor cells observed in animal studies (albino and pigmented rats); 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

            Drug interaction overview

            • Safinamide is contraindicated with other drugs in the MAOI class or other drugs that are potent inhibitors of MAO (see Contraindications)
            • Opioids combined with safinamide has caused serious and sometimes fatal reactions and is contraindicated; at least 14 days should elapse between use of safinamide and these drugs to avoid serotonin syndrome (see Contraindications)
            • Dextromethorphan and MAOIs is contraindicated, owing to reports of psychosis or bizarre behavior (see Contraindications)
            • Isoniazid has some monoamine oxidase inhibiting activity; monitor for hypertension and reaction to dietary tyramine in patients treated concomitantly with isoniazid
            • Safinamide and its major metabolite may inhibit intestinal breast cancer resistance protein (BCRP), and therefore could increase plasma concentrations of BCRP substrates (eg, methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan)
            • Dopamine antagonists, such as antipsychotics or metoclopramide, may decrease the effectiveness therapy and exacerbate the symptoms of Parkinson disease
            • Sympathomimetics
              • Severe hypertensive reactions have followed administration of sympathomimetics and nonselective MAOIs
              • Hypertensive crisis has been reported in patients taking recommended doses of selective MAO-B inhibitors and sympathomimetic medications
              • Concomitant use with methylphenidate, amphetamine, and their derivatives is contraindicated; monitor patients for hypertension if therapy is prescribed concomitantly with prescription or nonprescription sympathomimetic medications, including nasal, oral, or ophthalmic decongestants and cold remedies
            • Serotonergic drugs
              • SNRIs; triazolopyridine, tricyclic, or tetracyclic antidepressants; cyclobenzaprine; or St John’s wort are contraindicated with safinamide; at least 14 days should elapse between use of safinamide and these drugs to avoid serotonin syndrome (see Contraindications)
              • Coadministration with SSRIs: Monitor for symptoms of serotonin syndrome
            • Tyramine
              • MAO in the GI tract and liver (primarily type A) provides protection from exogenous amines (eg, tyramine)
              • If tyramine were absorbed intact, it could lead to severe hypertension, including hypertensive crisis
              • Aged, fermented, cured, smoked, and pickled foods containing large amounts of exogenous amines (eg, aged cheese, pickled herring) may cause release of norepinephrine, resulting in a rise in blood pressure (tyramine reaction)
              • Advise patients to avoid foods containing large amounts of tyramine
              • Selectivity for inhibiting MAO-B decreases in a dose-related manner above the highest recommended daily dosage, which may increase the risk for hypertension
              • In addition, isoniazid has some MAO inhibiting activity; monitor for hypertension and reaction to dietary tyramine in patients treated with isoniazid and safinamide
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            Pregnancy

            Pregnancy

            There are no adequate and well-controlled studies of safinamide in pregnant women

            Animal studies

            • 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

            Lactation

            Unknown if distributed in human breast milk

            Rats: 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

            Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            The precise mechanism by which safinamide exerts its effect in PD is unknown

            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

            Absorption

            Peak plasma time: 2-3 hr

            Bioavailability: 95%

            Steady-state: 3-5 days

            Distribution

            Protein bound: Not highly protein bound

            Vd: 165 L

            Metabolism

            Hydrolytic oxidation of the amide moiety leading to the primary metabolite safinamide acid

            Oxidative cleavage of the ether bond forming O-debenzylated safinamide

            Oxidative cleavage of the amine bond of either safinamide or safinamide acid to form N-dealkylated acid; this is further conjugated with glucuronic acid to yield its acyl glucuronide

            Elimination

            Half-life: 20-26 hr

            Total clearance: 4.6 L/hr

            Excretion: Primarily in urine (~5% unchanged; 76% as inactive metabolites)

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            Administration

            Oral Administration

            May take with or without food

            Take one daily dose at approximately the same time each day

            Missed dose: Take the next dose at the same time the next day

            Discontinuing: If taking 100 mg/day, taper by decreasing dose to 50 mg/day for 1 week before stopping

            Storage

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

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.