Xadago (Safinamide Mesylate)
Dosage & administration
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Xadago prescribing information
XADAGO is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson's disease (PD) experiencing "off" episodes.
- Start with 50 mg administered orally once daily at the same time of day; after two weeks, the dose may be increased to 100 mg once daily, based on individual need and tolerability ()
2.1 Dosing InformationThe 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
[see Indications and Usage (1)].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
[see Warnings and Precautions (5.7)]. - Hepatic Impairment: Do not exceed 50 mg once daily in patients with moderate hepatic impairment; contraindicated in patients with severe hepatic impairment (,
2.2 Dosing in Patients with Hepatic ImpairmentIn 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)
[see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)]. If a patient taking 50 mg XADAGO progresses from moderate to severe hepatic impairment, discontinue XADAGO.)4 CONTRAINDICATIONSXADAGO 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)
- 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
- Dextromethorphan
- A history of a hypersensitivity to safinamide
- Severe hepatic impairment (Child-Pugh C: 10-15)
- 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
- 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
Pregnancy: Based on animal data, may cause fetal harm (
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.
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/m2) 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/m2basis.
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/m2basis.
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) for adverse developmental effects is less than the MRHD on a mg/m2basis.
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.and
5.1 HypertensionXADAGO 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
[see Drug Interactions (7.5)].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
[see Clinical Pharmacology (12.2)]. 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
[see Drug Interactions (7.1, 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.
- 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.and
5.2 Serotonin SyndromeThe 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).
,7.2 Opioid DrugsBecause 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 DrugsConcomitant 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)].]7.5 Sympathomimetic MedicationsSevere 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)]. - Concomitant use of dextromethorphan. The combination of MAOIs and dextromethorphan has been reported to cause episodes of psychosis or abnormal behavior [see.]
7.4 DextromethorphanThe 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.
- 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.]
8.6 Hepatic ImpairmentXADAGO plasma concentrations are increased in patients with hepatic impairment
[see Clinical Pharmacology (12.3)].In patients with moderate hepatic impairment (Child-Pugh B: 7-9), the maximum recommended dosage of XADAGO is 50 mg once daily
[see Dosage and Administration (2.2)]. 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.
- May cause or exacerbate hypertension ()
5.1 HypertensionXADAGO 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
[see Drug Interactions (7.5)].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
[see Clinical Pharmacology (12.2)]. 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
[see Drug Interactions (7.1, 7.6)]. - May cause serotonin syndrome when used with MAO inhibitors, antidepressants, or opioid drugs ()
5.2 Serotonin SyndromeThe 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).
- May cause falling asleep during activities of daily living ()
5.3 Falling Asleep During Activities of Daily LivingPatients 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.
- May cause or exacerbate dyskinesia; consider levodopa dose reduction ()
5.4 DyskinesiaXADAGO 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%)
[see Adverse Reactions (6.1)].Reducing the patient's daily levodopa dosage or the dosage of another dopaminergic drug may mitigate dyskinesia.
- May cause hallucinations and psychotic behavior ()
5.5 Hallucinations / Psychotic BehaviorPatients 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
[see Drug Interactions (7.7)].Consider dosage reduction or stopping the medication if a patient develops hallucinations or psychotic-like behaviors while taking XADAGO.
- May cause problems with impulse control/compulsive behaviors ()
5.6 Impulse Control / Compulsive BehaviorsPatients 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.
- May cause withdrawal-emergent hyperpyrexia and confusion ()
5.7 Withdrawal Emergent Hyperpyrexia and ConfusionA 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.