Xadago (Oral)

Dosage Forms And Strengths

• 50 mg tablets: Orange to copper with metallic gloss, round, biconcave shaped embossed with “50” on one side
• 100 mg tablets: Orange to copper with metallic gloss, round, biconcave shaped embossed with “100” on one side

50 mg (orange to copper colored with metallic gloss, round film-coated, biconcave shaped tablet embossed with “50” on one side; approximately 7 mm in diameter).

Bottles of 30 tablets……………………………NDC 27505-110-30
Bottles of 90 tablets……………………………NDC 27505-110-90

100 mg (orange to copper colored with metallic gloss, round film-coated, biconcave shaped tablet embossed with “100” on one side; approximately 9 mm in diameter).

Bottles of 30 tablets……………………………NDC 27505-111-30
Bottles of 90 tablets……………………………NDC 27505-111-90

Storage And Handling

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

Distributed by: US WorldMeds, LLC 4441 Springdale Road Louisville, KY 40241. Revised: Jun 2017

XADAGO is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson's disease (PD) experiencing “off” episodes.

Limitations Of Use

XADAGO has not been shown to be effective as monotherapy for the treatment of PD.

Dosing Information

The recommended starting dosage of XADAGO is 50 mg administered orally once daily (at the same time of day), without regard to meals. After two weeks, the dosage may be increased to 100 mg once daily, based on individual need and tolerability.

Daily dosages of XADAGO above 100 mg have not been shown to provide additional benefit, and higher dosages increase the risk for adverse reactions. XADAGO has been shown to be effective only in combination with levodopa/carbidopa.

If a dose is missed, the next dose should be taken at the same time the next day.

XADAGO 100 mg should be tapered by decreasing the dose to 50 mg for one week before stopping.

Dosing In Patients With Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh B: 7-9), the maximum recommended dosage of XADAGO is 50 mg orally once daily. XADAGO is contraindicated in patients with severe hepatic impairment (Child-Pugh C: 10-15). If a patient taking 50 mg XADAGO progresses from moderate to severe hepatic impairment, discontinue XADAGO.

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.
• 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.
• Concomitant use of dextromethorphan. The combination of MAO inhibitors and dextromethorphan has been reported to cause episodes of psychosis or abnormal behavior.
• 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).

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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.

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. 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.

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 XADAGO with these drugs is contraindicated.

In clinical trials, serotonin syndrome was reported in a patient treated with XADAGO and an 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).

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.

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 Parkinson's disease patients treated with XADAGO 50 mg or 100 mg (1%), compared to placebo (0%).

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

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 Parkinson's disease. Consider dosage reduction or stopping the medication if a patient develops hallucinations or psychotic-like behaviors while taking XADAGO.

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.

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.

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.

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).

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Hypertension

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

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

Advise patients to avoid certain foods (e.g., aged cheese) containing a very large amount of tyramine while taking recommended doses of XADAGO 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.

Serotonin Syndrome

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

Falling Asleep During Activities Of Daily Living And Somnolence

Inform patients about the potential for sedating effects associated with XADAGO and other dopaminergic medications, including somnolence and particularly to 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 XADAGO.

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 XADAGO.

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 XADAGO.

Dyskinesia

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

Hallucinations / Psychotic Behavior

Inform patients that hallucinations or other manifestations of psychotic behavior can occur when taking XADAGO. Advise patients that, if they have a major psychotic disorder, that XADAGO 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 XADAGO.

Impulse Control/Compulsive Behaviors

Advise patients that they may experience intense urges to gamble, increased sexual urges, other intense urges, and the inability to control these urges while taking XADAGO. 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 XADAGO. Patients should inform their physician if they experience these urges while taking XADAGO.

Withdrawal-Emergent Hyperpyrexia And Confusion

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

Missing Dose

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

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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

In carcinogenicity studies in mice and rats, safinamide was administered at oral doses of 0, 50, 100 and 200 mg/kg/day, and 0, 25, 50 and 100 mg/kg/day, respectively, for 2 years. The highest doses tested in both species were approximately 10 times the maximum recommended human dose (MRHD) of 100 mg/day on a body surface area (mg/m²) basis. No evidence of tumorigenic potential was observed in either species.

Mutagenesis

Safinamide was negative for genotoxicity in in vitro (Ames, mouse lymphoma) and in vivo (mouse micronucleus) assays.

Impairment Of Fertility

In a rat fertility study in which males and females were orally administered safinamide (0, 50, 100, 150 mg/kg/day) prior to and during mating and continuing through early pregnancy in females, adverse effects on reproductive function were observed in both males (sperm abnormalities) and females (decreased corpora lutea, increased pre-implantation loss). The no-effect dose for reproductive toxicity (50 mg/kg/day) is approximately 5 times the MRHD on a mg/m² basis.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies 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 safinamide doses lower than those used clinically when safinamide was administered during pregnancy in combination with levodopa/carbidopa. XADAGO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 m²of 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/m² 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 (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/m² 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 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.

Nursing Mothers

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 mother.

Pediatric Use

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

Geriatric Use

Of the 1516 subjects exposed to XADAGO 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.

Hepatic Impairment

XADAGO plasma concentrations are increased in patients with hepatic impairment.

In patients with moderate hepatic impairment (Child-Pugh B: 7-9), the maximum recommended dosage of XADAGO is 50 mg once daily. XADAGO 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 XADAGO should be stopped.

SIDE EFFECTS

The following serious adverse reactions are discussed in greater detail in other sections of labeling:

• Hypertension
• Serotonin Syndrome
• Falling Asleep During Activities of Daily Living
• Dyskinesia
• Hallucinations / Psychotic Behavior
• Impulse Control / Compulsive Behaviors
• Withdrawal-Emergent Hyperpyrexia and Confusion
• Retinal Pathology

Clinical Trials Experience

Clinical trials are conducted under widely varying conditions; therefore, adverse reactions observed in the clinical trials of a drug cannot be directly compared to the incidence in the clinical trials of another drug and may not reflect the incidence observed in clinical practice.

Common Adverse Reactions In Placebo-Controlled Parkinson's Disease Studies

Table 1 shows the incidence of adverse reactions with an incidence of at least 2% on XADAGO 100 mg/day and greater than placebo in controlled studies in Parkinson's disease (Study 1 and Study 2). The most common adverse reactions associated with XADAGO treatment in which the incidence for XADAGO 100 mg/day was at least 2% greater than the incidence for placebo were dyskinesia, fall, nausea, and insomnia.

Adverse Reactions Reported As Reason For Discontinuation From Study

In pooled placebo-controlled studies (Study 1 and Study 2) in patients with Parkinson's disease taking a stable dose of carbidopa/levodopa with or without other PD medications, there was an increase in the incidence of XADAGO-treated patients who discontinued from the study because of adverse reactions. The incidence of patients discontinuing from Study 1 and Study 2 for any adverse reaction was 5% for XADAGO 50 mg/day, 6% for XADAGO 100 mg/day, and 4% for placebo. The most frequently reported adverse reaction causing study discontinuation was dyskinesia (1% of patients treated with XADAGO 50 mg/day or XADAGO 100 mg/day vs. 0% for placebo).

Table 1: Percentage of Patients with Adverse Reactions with an Incidence ≥ 2% in the XADAGO 100 mg/day Group and Greater than Placebo in Studies 1 and 2.

Abnormal Laboratory Changes

In Study 1 and Study 2, the proportion of patients who experienced a shift from normal to above the upper limit of normal for serum alanine aminotransferase (ALT) was 5% for XADAGO 50 mg, 7% for XADAGO 100 mg, and 3% for placebo. No patient treated with XADAGO experienced an increase in ALT that was 3 times the upper limit of normal or higher.

The proportion of patients with a shift from normal to above the upper limit of normal for serum aspartate aminotransferase (AST) was 7% for XADAGO 50 mg, 6% for XADAGO 100 mg, and 3% for placebo. The incidence of patients with an increase in AST to at least 3 times the upper limit of normal was similar for XADAGO and placebo.

Postmarketing Experience

The following adverse reactions have been identified during post-approval of use of safinamide outside of the United States. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

A postmarketing report describes a patient who developed a hypersensitivity reaction consisting of swelling of the tongue and gingiva, dyspnea and skin rash. The symptoms resolved shortly after XADAGO was discontinued, but reappeared following rechallenge a month later.

DRUG INTERACTIONS

MAO Inhibitors

XADAGO is contraindicated for use with other drugs in the MAO inhibitor 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. 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.

Opioid Drugs

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

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. 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 selective serotonin re-uptake inhibitors are used by patients treated with XADAGO.

Dextromethorphan

The combination of MAO inhibitors 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.

Sympathomimetic Medications

Severe hypertensive reactions have followed the administration of sympathomimetics and nonselective MAO inhibitors. 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.

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

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.

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 monoamine oxidase inhibiting activity. Monitor for hypertension and reaction to dietary tyramine in patients treated with isoniazid and XADAGO.

Substrates Of Breast Cancer Resistance Protein (BCRP)

Safinamide and its major metabolite may inhibit intestinal breast cancer resistance protein (BCRP). Inhibition of BCRP could increase plasma concentrations of BCRP substrates. Examples of substrates of BCRP include methotrexate, mitoxantrone, imatinib, irrinotecan, lapatinib, rosuvastatin, sulfasalazine, and topotecan. Monitor patients for increased pharmacologic or adverse effect of the BCRP substrates if XADAGO is used concomitantly.

Dopaminergic Antagonists

Dopamine antagonists, such as antipsychotics or metoclopramide, may decrease the effectiveness of XADAGO and exacerbate the symptoms of Parkinson's disease.

Pregnancy Category C

There are no adequate and well-controlled studies 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 safinamide doses lower than those used clinically when safinamide was administered during pregnancy in combination with levodopa/carbidopa. XADAGO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 m²of 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/m² 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 (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/m² 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 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.

The following serious adverse reactions are discussed in greater detail in other sections of labeling:

• Hypertension
• Serotonin Syndrome
• Falling Asleep During Activities of Daily Living
• Dyskinesia
• Hallucinations / Psychotic Behavior
• Impulse Control / Compulsive Behaviors
• Withdrawal-Emergent Hyperpyrexia and Confusion
• Retinal Pathology

Clinical Trials Experience

Clinical trials are conducted under widely varying conditions; therefore, adverse reactions observed in the clinical trials of a drug cannot be directly compared to the incidence in the clinical trials of another drug and may not reflect the incidence observed in clinical practice.

Common Adverse Reactions In Placebo-Controlled Parkinson's Disease Studies

Table 1 shows the incidence of adverse reactions with an incidence of at least 2% on XADAGO 100 mg/day and greater than placebo in controlled studies in Parkinson's disease (Study 1 and Study 2). The most common adverse reactions associated with XADAGO treatment in which the incidence for XADAGO 100 mg/day was at least 2% greater than the incidence for placebo were dyskinesia, fall, nausea, and insomnia.

Adverse Reactions Reported As Reason For Discontinuation From Study

In pooled placebo-controlled studies (Study 1 and Study 2) in patients with Parkinson's disease taking a stable dose of carbidopa/levodopa with or without other PD medications, there was an increase in the incidence of XADAGO-treated patients who discontinued from the study because of adverse reactions. The incidence of patients discontinuing from Study 1 and Study 2 for any adverse reaction was 5% for XADAGO 50 mg/day, 6% for XADAGO 100 mg/day, and 4% for placebo. The most frequently reported adverse reaction causing study discontinuation was dyskinesia (1% of patients treated with XADAGO 50 mg/day or XADAGO 100 mg/day vs. 0% for placebo).

Table 1: Percentage of Patients with Adverse Reactions with an Incidence ≥ 2% in the XADAGO 100 mg/day Group and Greater than Placebo in Studies 1 and 2.

Abnormal Laboratory Changes

In Study 1 and Study 2, the proportion of patients who experienced a shift from normal to above the upper limit of normal for serum alanine aminotransferase (ALT) was 5% for XADAGO 50 mg, 7% for XADAGO 100 mg, and 3% for placebo. No patient treated with XADAGO experienced an increase in ALT that was 3 times the upper limit of normal or higher.

The proportion of patients with a shift from normal to above the upper limit of normal for serum aspartate aminotransferase (AST) was 7% for XADAGO 50 mg, 6% for XADAGO 100 mg, and 3% for placebo. The incidence of patients with an increase in AST to at least 3 times the upper limit of normal was similar for XADAGO and placebo.

Postmarketing Experience

The following adverse reactions have been identified during post-approval of use of safinamide outside of the United States. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

A postmarketing report describes a patient who developed a hypersensitivity reaction consisting of swelling of the tongue and gingiva, dyspnea and skin rash. The symptoms resolved shortly after XADAGO was discontinued, but reappeared following rechallenge a month later.

There is no human experience with XADAGO overdose.

There is no known antidote to XADAGO nor any specific treatment for XADAGO overdose. If an important overdose occurs, XADAGO treatment should be discontinued and supportive treatment should be administered as clinically indicated. In cases of overdose with XADAGO, dietary tyramine restriction should be observed for several weeks.

The Poison Control Center should be called at 1-800-222-1222 for the most current treatment guidelines.

XADAGO inhibits monoamine oxidase B (MAO-B), with more than 1000-fold selectivity over MAO-A. In clinical studies, complete inhibition ( > 90%) of MAO-B was measured at doses > 20 mg.

Tyramine Challenge Test

In an oral tyramine challenge study, XADAGO produced a distinct but relatively small increase in tyramine sensitivity to increase blood pressure. The results suggest that XADAGO at a dose of 50 mg or 100 mg is relatively selective for inhibiting MAO-B and can be used without dietary tyramine restriction. Relative selectivity of XADAGO for inhibiting MAO-B decreases above the highest recommended daily dosage (100 mg).

Cardiac Electrophysiology

The effect of XADAGO on the QTc interval was evaluated in a randomized placebo and positive controlled double-blind, multiple-dose parallel thorough QTc study in 240 healthy subjects. At a dose of 350 mg (3.5 times the maximum recommended dosage), XADAGO did not prolong the QTc interval.

Pharmacokinetics of safinamide is linear over a range of 50 mg to 300 mg (3 times the maximum recommended daily dose). Steady state is reached within 5 to 6 days.

Absorption

After single and multiple oral dosing under fasting conditions, Tmax of safinamide ranges from 2 to 3 hours. Absolute bioavailability of safinamide is 95% after oral administration, and first pass metabolism is negligible. A slight delay in Tmax was observed in the fed state relative to the fasted condition, but there was no effect on safinamide AUC0-∞ and Cmax.

Distribution

The volume of distribution (Vss) is approximately 165 L, indicating extensive extravascular distribution. Safinamide is not highly protein bound (unbound fraction is 11 to 12%).

Metabolism And Excretion

In humans, safinamide is almost exclusively eliminated via metabolism (~5% of the drug is eliminated unchanged, mainly in urine), through three main metabolic pathways. One pathway involves hydrolytic oxidation of the amide moiety leading to the primary metabolite 'safinamide acid' (NW-1153). Another pathway is oxidative cleavage of the ether bond forming 'Odebenzylated safinamide' (NW-1199). Finally, the 'N-dealkylated acid' (NW-1689) is formed by oxidative cleavage of the amine bond of either safinamide or the primary safinamide acid metabolite (NW-1153). The 'N-dealkylated acid' (NW-1689) undergoes further conjugation with glucuronic acid yielding its acyl glucuronide. NW-1689 is the main circulating metabolite in human plasma, exceeding the exposure of the parent (161% of parent). NW-1689 AG and NW-1153 account for about 18% and 11% of the parent drug exposure, respectively. None of the metabolites has pharmacological activity.

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

The total clearance of safinamide was determined to be 4.6 L/h. Terminal half-life is 20-26 h. The primary route of excretion is through the kidney (76% of safinamide dose recovered in the urine, primarily in the form of inactive metabolites).