SAFINAMIDE Drug Interactions: What You Need to Know

INTERACTIONS 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 <span class="opacity-50 text-xs">[see Contraindications (4) and Warnings and Precautions (5.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> . 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&apos;s wort is contraindicated <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> .

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&apos;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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1 , 5.2) ]</span> . Monitor patients for hypertension if XADAGO is prescribed concomitantly with prescription or nonprescription sympathomimetic medications, including nasal, oral, or ophthalmic decongestants and cold remedies <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> .

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> . Selectivity for inhibiting MAO-B decreases in a dose-related manner above the highest recommended daily dosage, which may increase the risk for hypertension <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . In addition, isoniazid has some monoamine oxidase inhibiting activity. Monitor for hypertension and reaction to dietary tyramine in patients treated with isoniazid and XADAGO <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> .

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

XADAGO is contraindicated in patients with: Concomitant use of other drugs in the monoamine oxidase inhibitor (MAOI) class or other drugs that are potent inhibitors of monoamine oxidase, including linezolid. The combination may result in increased blood pressure, including hypertensive crisis [see Warnings and Precautions (5.1) and Drug Interactions (7.1) ] . Concomitant use of opioid drugs (e.g., meperidine and its derivatives, methadone, propoxyphene, or tramadol); serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic, tetracyclic, or triazolopyridine antidepressants; cyclobenzaprine; methylphenidate, amphetamine, and their derivatives; or St John's wort. Concomitant use could result in life-threatening serotonin syndrome [see Warnings and Precautions (5.2) and Drug Interactions (7.2 , 7.3 , 7.5) ] . Concomitant use of dextromethorphan. The combination of MAOIs and dextromethorphan has been reported to cause episodes of psychosis or abnormal behavior [see Drug Interactions (7.4) ] . A history of a hypersensitivity to safinamide. Reactions have included swelling of the tongue and oral mucosa, and dyspnea. Severe hepatic impairment (Child-Pugh C: 10-15) [see Use in Specific Populations (8.6) ] . XADAGO is contraindicated in patients with: Concomitant use of the following drugs: Other monoamine oxidase inhibitors or other drugs that are potent inhibitors of monoamine oxidase (e.g., linezolid) ( 4 , 7.1 ) Opioid drugs (e.g., tramadol, meperidine and related derivatives); serotonin-norepinephrine reuptake inhibitors; tri-or tetra-cyclic or triazolopyridine antidepressants; cyclobenzaprine; methylphenidate, amphetamine, and their derivatives; St. John's wort ( 4 , 7.2 , 7.3 , 7.5 ) Dextromethorphan ( 4 , 7.4 ) A history of a hypersensitivity to safinamide ( 4 ) Severe hepatic impairment (Child-Pugh C: 10-15) ( 4 )

AND PRECAUTIONS May cause or exacerbate hypertension ( 5.1 ) May cause serotonin syndrome when used with MAO inhibitors, antidepressants, or opioid drugs ( 5.2 ) May cause falling asleep during activities of daily living ( 5.3 ) May cause or exacerbate dyskinesia; consider levodopa dose reduction ( 5.4 ) May cause hallucinations and psychotic behavior ( 5.5 ) May cause problems with impulse control/compulsive behaviors ( 5.6 ) May cause withdrawal-emergent hyperpyrexia and confusion ( 5.7 )

5.1 Hypertension XADAGO may cause hypertension or exacerbate existing hypertension. In clinical trials, the incidence of hypertension was 7% for XADAGO 50 mg, 5% for XADAGO 100 mg, and 4% for placebo. Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting XADAGO. Medication adjustment may be necessary if elevation of blood pressure is sustained. Monitor for hypertension if XADAGO is prescribed concomitantly with sympathomimetic medications, including prescription or nonprescription nasal, oral, and ophthalmic decongestants and cold remedies <span class="opacity-50 text-xs">[see Drug Interactions (7.5) ]</span> . XADAGO 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . Therefore, XADAGO should not be used at daily dosages exceeding those recommended because of the risks of hypertension, exacerbation of existing hypertension, or hypertensive crisis. Dietary tyramine restriction is not required during treatment with recommended doses of XADAGO. 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 XADAGO, and patients should be advised to avoid such foods. Isoniazid has some monoamine oxidase inhibiting activity. Monitor for hypertension and reaction to dietary tyramine in patients treated concomitantly with isoniazid and XADAGO <span class="opacity-50 text-xs">[see Drug Interactions (7.1 , 7.6) ]</span> .

5.2 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported in patients on concomitant treatment with MAOIs (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 XADAGO with these drugs is contraindicated. In clinical trials, serotonin syndrome was reported in a patient treated with XADAGO and a selective serotonin reuptake inhibitor (SSRI). Use the lowest effective dose of SSRIs in patients treated with concomitant XADAGO. 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).

5.3 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. In clinical studies, sleep attacks/sudden onset of sleep were reported in patients treated with XADAGO 100 mg/day. 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), XADAGO should ordinarily be discontinued. If a decision is made to continue these patients on XADAGO, advise them to avoid driving and other potentially dangerous activities.

5.4 Dyskinesia XADAGO may cause dyskinesia or exacerbate pre-existing dyskinesia. In clinical trials, the incidence of dyskinesia was 21% for XADAGO 50 mg, 18% for XADAGO 100 mg, and 9% for placebo. There was a greater incidence of dyskinesia causing study discontinuation in patients treated with XADAGO 50 mg or 100 mg (1%), compared to placebo (0%) <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Reducing the patient&apos;s daily levodopa dosage or the dosage of another dopaminergic drug may mitigate dyskinesia.

5.5 Hallucinations / Psychotic Behavior Patients with a major psychotic disorder should ordinarily not be treated with XADAGO 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 PD <span class="opacity-50 text-xs">[see Drug Interactions (7.7) ]</span> . Consider dosage reduction or stopping the medication if a patient develops hallucinations or psychotic-like behaviors while taking XADAGO.

5.6 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 XADAGO, 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 XADAGO. Consider dose reduction or stopping the medication if a patient develops such urges while taking XADAGO.

5.7 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.

5.8 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 <span class="opacity-50 text-xs">[see Nonclinical Toxicology (13.2) ]</span> . 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).