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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for XADAGO (XADAGO).
| Breastfeeding | No data on safinamide excretion in human milk. M/P ratio unknown. Animal studies indicate drug is excreted in rat milk. Potential for serious adverse reactions in nursing infants due to MAO-B inhibition. Decision to breastfeed or discontinue drug should consider importance of drug to mother and risk to infant. |
| 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. |
■ FDA Black Box Warning
None
| Serious Effects |
["Concurrent use of monoamine oxidase inhibitors (MAOIs) including rasagiline, selegiline, phenelzine, tranylcypromine","Concurrent use of meperidine, tramadol, propoxyphene, and other opioids","Concurrent use of St. John's wort","Concurrent use of amphetamines and other sympathomimetics","Severe hepatic impairment (Child-Pugh class 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"] |
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| 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. |