Safinamide

Selective Serotonin Reuptake Inhibitors: Monitor patients for serotonin syndrome ( 7.3 ) Sympathomimetic Medications: Monitor patients for hypertension ( 7.5 ) Tyramine: Risk of severe hypertension ( 7.6 )

7.1 MAO Inhibitors (MAOIs) XADAGO is contraindicated for use with other drugs in the MAOIs class or other drugs that are potent inhibitors of monoamine oxidase (e.g., linezolid, an oxazolidinone antibacterial, which also has reversible nonselective MAO inhibition activity). Co-administration increases the risk of nonselective MAO inhibition, which may lead to hypertensive crisis [see Contraindications (4) and Warnings and Precautions (5.1) ] . At least 14 days should elapse between discontinuation of XADAGO and initiation of treatment with other MAOIs. Isoniazid has some monoamine oxidase inhibiting activity.

Monitor for hypertension and reaction to dietary tyramine in patients treated concomitantly with isoniazid and XADAGO.

7.2 Opioid Drugs Because serious, sometimes fatal reactions have been precipitated with concomitant use of opioid drugs (e.g., meperidine and its derivatives, methadone, propoxyphene, or tramadol) and MAOIs, including selective MAO-B inhibitors, concomitant use of these drugs is contraindicated [see Warnings and Precautions (5.2) ] . At least 14 days should elapse between discontinuation of XADAGO and initiation of treatment with these drugs.

7.3 Serotonergic Drugs Concomitant use of XADAGO with SNRIs; triazolopyridine, tricyclic or tetracyclic antidepressants; cyclobenzaprine (a skeletal muscle relaxant that is a tricyclic antidepressant derivative); or St. John's wort is contraindicated [see Warnings and Precautions (5.2) ] . At least 14 days should elapse between discontinuation of XADAGO and initiation of treatment with these drugs. Monitor patients for symptoms of serotonin syndrome if SSRIs are used by patients treated with XADAGO [see Warnings and Precautions (5.2) ] .

7.4 Dextromethorphan The combination of MAOIs and dextromethorphan has been reported to cause episodes of psychosis or bizarre behavior. Therefore, in view of XADAGO's MAO inhibitory activity, dextromethorphan is contraindicated for use with XADAGO.

7.5 Sympathomimetic Medications Severe hypertensive reactions have followed the administration of sympathomimetics and nonselective MAOIs. Hypertensive crisis has been reported in patients taking the recommended doses of selective MAO-B inhibitors and sympathomimetic medications. Concomitant use of XADAGO with methylphenidate, amphetamine, and their derivatives is contraindicated [see Warnings and Precautions (5.1 , 5.2) ] . Monitor patients for hypertension if XADAGO is prescribed concomitantly with prescription or nonprescription sympathomimetic medications, including nasal, oral, or ophthalmic decongestants and cold remedies [see Warnings and Precautions (5.1) ] .

7.6 Tyramine MAO in the gastrointestinal tract and liver (primarily type A) provides protection from exogenous amines (e.g., 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 (e.g., aged cheese, pickled herring) may cause release of norepinephrine resulting in a rise in blood pressure (Tyramine Reaction). Patients should be advised to avoid foods containing a large amount of tyramine while taking recommended doses of XADAGO [see Warnings and Precautions (5.1) ] .

Selectivity for inhibiting MAO-B decreases in a dose-related manner above the highest recommended daily dosage, which may increase the risk for hypertension [see Clinical Pharmacology (12.2) ] . In addition, isoniazid has some monoamine oxidase inhibiting activity. Monitor for hypertension and reaction to dietary tyramine in patients treated with isoniazid and XADAGO [see Warnings and Precautions (5.1) ] .

7.7 Dopaminergic Antagonists Dopamine antagonists, such as antipsychotics or metoclopramide, may decrease the effectiveness of XADAGO and exacerbate the symptoms of PD.

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of XADAGO 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 doses lower than those used clinically when safinamide was administered during pregnancy in combination with levodopa/carbidopa. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data 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. A no-effect dose for adverse effects on embryofetal development was not established. The lowest dose tested (50 mg/kg/day) is approximately 5 times the maximum recommended human dose (MRHD) of 100 mg on a body surface area (mg/m 2 ) basis.

In a combination embryofetal development study of safinamide and levodopa (LD)/carbidopa (CD) in rats (80/20 mg/kg/day LD/CD 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 CD/LD and with safinamide alone. The lowest dose of safinamide tested (25 mg/kg/day) is approximately 2 times the MRHD on a mg/m 2 basis. 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 (0, 4, 12, or 40 mg/kg/day) was administered throughout organogenesis in a combination study of safinamide with LD/CD (80/20 mg/kg/day LD/CD), there was an increased incidence of embryofetal death and cardiac and skeletal malformations, compared to LD/CD 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/m 2 basis.

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…