XADAGO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for XADAGO (XADAGO).
XADAGO (safinamide) is a selective, reversible monoamine oxidase B (MAO-B) inhibitor. It also blocks voltage-dependent sodium and calcium channels, and modulates glutamate release. The MAO-B inhibition increases dopamine levels in the striatum, while the other actions may provide neuroprotective and symptomatic benefits.
| Metabolism | Primarily metabolized by amide hydrolysis (non-cytochrome P450) to safinamide acid (NW-1153) and further by oxidation to a lactam (NW-1689). Minor pathways involve CYP1A2 and CYP2B6, but overall CYP involvement is minimal. |
| Excretion | Primarily renal (approximately 70% as unchanged drug and major metabolite O-desmethylsafinamide) and fecal (approximately 30%). |
| Half-life | Terminal elimination half-life is approximately 20-25 hours, supporting once-daily dosing. |
| Protein binding | Approximately 90% bound to plasma proteins (mainly albumin). |
| Volume of Distribution | Approximately 1.3 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 95%. |
| Onset of Action | Oral: Clinical effect on motor fluctuations observed within 1-2 weeks of daily dosing; maximum effect may take several weeks. |
| Duration of Action | Approximately 24 hours due to once-daily dosing; sustained improvement in OFF time with continued administration. |
| Molecular Weight | 302.37 |
XADAGO (safinamide) 50 mg orally once daily, increased to 100 mg orally once daily based on tolerability and efficacy; take at the same time each day.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Not recommended in severe renal impairment (CrCl <30 mL/min) due to lack of data. |
| Liver impairment | No dose adjustment for mild hepatic impairment (Child-Pugh A). Not recommended for moderate to severe hepatic impairment (Child-Pugh B or C). |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustment recommended; elderly patients may have higher plasma exposures but no dose adjustment is required based on age alone. |
| 1st trimester | XADAGO (safinamide) is contraindicated in the first trimester due to teratogenic effects observed in animal studies. Use only if benefit outweighs risk. |
| 2nd trimester | Limited human data; animal studies show teratogenicity at maternal toxic doses. Avoid use unless necessary. |
| 3rd trimester | Avoid in third trimester due to risk of neonatal withdrawal or adverse effects. Use only if clearly needed. |
Clinical note
Comprehensive clinical and safety monograph for XADAGO (XADAGO).
| Placental transfer | Animal studies indicate safinamide crosses the placenta; human data lacking. Molecular weight suggests potential transfer. |
| Breastfeeding | Excretion into human milk is unknown; risk of infant exposure cannot be excluded. Use caution or consider alternatives. |
■ FDA Black Box Warning
None
| Serious Effects |
Hypersensitivity to safinamide or any excipientConcomitant use with MAOIs or other MAO-B inhibitorsSevere hepatic impairment (Child-Pugh C)Pheochromocytoma
| Precautions | Serotonin syndrome risk when used with other serotonergic drugs or MAOIs, Hypertension/hypotension, especially with concomitant use of sympathomimetics or tyramine-rich foods, May cause dyskinesia or exacerbate existing dyskinesia, Risk of hallucinations and psychotic-like behavior, Impulse control disorders (e.g., pathological gambling, hypersexuality), May cause somnolence and sudden sleep onset, Retinal degeneration observed in animal studies; monitor for visual changes, Contraindicated with use of MAOIs, opioids (e.g., meperidine, tramadol), St. John's wort, and selective serotonin reuptake inhibitors (SSRIs) due to risk of serotonin syndrome, Abrupt discontinuation may cause withdrawal emergent hyperpyrexia and confusion |
| Food/Dietary | At therapeutic doses (50-100 mg/day), dietary tyramine restriction is generally not required. However, if doses exceed 100 mg/day or if the patient is particularly sensitive, advise avoiding foods rich in tyramine (aged cheeses, cured meats, sauerkraut, soy sauce, tap beers, red wines, overripe fruits, fermented tofu). Concurrent consumption of tyramine-rich foods with MAO-B inhibitors can rarely precipitate hypertensive crisis, though risk is low with selective MAO-B inhibitors at standard doses. |
Loading safety data…
| Lactation Rating |
| L4 (Possibly Hazardous) |
| Teratogenic Risk | XADAGO (safinamide) is in FDA pregnancy category C. Animal studies show embryotoxicity and teratogenicity at clinically relevant doses. In rats, increased fetal malformations (ventricular septal defects, skeletal abnormalities) and reduced fetal weight occurred. In rabbits, increased post-implantation loss and malformations (omphalocele, gastroschisis). There are no adequate human studies. Risk cannot be excluded in the first trimester. In second and third trimesters, potential for MAO-B inhibition affecting fetal catecholamine metabolism. Use only if benefit outweighs risk. |
| Fetal Monitoring | Monitor for maternal hypertensive crises if concurrent tyramine-rich foods or sympathomimetics. Assess fetal growth and well-being via ultrasound if prolonged use. Monitor for maternal serotonin syndrome symptoms (agitation, hyperthermia, clonus) if used with other serotonergic drugs. No routine fetal monitoring indicated. |
| Fertility Effects | No human data on fertility effects. In animal studies, safinamide did not impair fertility in rats at exposures up to 14 times the human dose. However, reduced corpora lutea and implantation sites were observed at high doses. Potential for hormonal disruption unknown. |
| Clinical Pearls | XADAGO (safinamide) is a monoamine oxidase B (MAO-B) inhibitor used as adjunctive therapy to levodopa/carbidopa for Parkinson's disease. It should not be used with other MAO inhibitors or opioids (especially meperidine and tramadol) due to risk of serotonin syndrome. Monitor for dyskinesias, nausea, and hallucinations. Dose adjustment may be needed in hepatic impairment. Avoid tyramine-rich foods only at doses >100 mg/day, but clinical relevance is low at therapeutic doses (50-100 mg/day). |
| Patient Advice | Take XADAGO exactly as prescribed, usually once daily in the morning. · Do not take XADAGO with other MAO inhibitors (e.g., selegiline, rasagiline) or opioids (especially meperidine, tramadol, and methadone). · Report any symptoms of serotonin syndrome: agitation, hallucinations, fever, sweating, shivering, fast heart rate, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea. · Avoid foods high in tyramine (e.g., aged cheese, cured meats, fermented products) only if directed by your doctor, especially if taking doses above 100 mg/day. · XADAGO may cause dizziness or drowsiness; avoid driving or operating machinery until you know how it affects you. · Do not stop taking XADAGO suddenly; consult your doctor for a gradual taper. · XADAGO is not for use as a monotherapy; it must be taken with levodopa/carbidopa. |