FILSPARI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for FILSPARI (FILSPARI).
FILSPARI (sparsentan) is an endothelin receptor antagonist (ERA) and angiotensin II receptor blocker (ARB) with high affinity for the endothelin type A (ETA) receptor and angiotensin II type 1 (AT1) receptor. It reduces proteinuria in IgA nephropathy by inhibiting endothelin-1 mediated vasoconstriction, inflammation, and fibrosis, and by blocking angiotensin II mediated effects.
| Metabolism | Sparsentan is metabolized primarily by CYP3A4 and to a lesser extent by CYP2C8 and CYP2C9. |
| Excretion | Primarily hepatic metabolism; <1% excreted unchanged in urine. ~59% of dose recovered in feces and ~27% in urine as metabolites. |
| Half-life | Terminal half-life ~30 hours in healthy subjects, supporting once-daily dosing. |
| Protein binding | >99% bound to plasma proteins, mainly albumin. |
| Volume of Distribution | Approximately 10 L (≈0.14 L/kg for a 70 kg adult), indicating limited extravascular distribution. |
| Bioavailability | Oral bioavailability ~57% under fasted conditions; reduced with high-fat meal. |
| Onset of Action | Not applicable; clinical effect (reduction in proteinuria) observed after weeks of continuous dosing. |
| Duration of Action | Sustained reduction in proteinuria over 24-hour dosing interval; clinical effect persists with continued treatment. |
200 mg orally once daily, with or without food.
| Dosage form | TABLET |
| Renal impairment | eGFR 30-59 mL/min: 200 mg once daily. eGFR <30 mL/min or dialysis: not recommended. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B or C: not recommended. |
| Pediatric use | Safety and efficacy not established; no recommended dose. |
| Geriatric use | No specific dose adjustment; use caution due to age-related renal decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for FILSPARI (FILSPARI).
| Breastfeeding | There are no data on the presence of FILSPARI in human milk, effects on the breastfed infant, or effects on milk production. The molecular weight and protein binding suggest likely excretion into breast milk. Because of the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended during treatment and for at least 1 month after the last dose. M/P ratio: unknown. |
| Teratogenic Risk | Based on its mechanism of action as an endothelin receptor antagonist, FILSPARI is expected to be teratogenic. There are no adequate and well-controlled studies in pregnant women. In animal studies, endothelin receptor antagonists have caused teratogenicity, including craniofacial and cardiovascular malformations, at clinically relevant exposures. Use in pregnancy is contraindicated. Fetal risk is highest during the first trimester but may extend throughout pregnancy. |
■ FDA Black Box Warning
WARNING: HEPATOTOXICITY. Sparsentan can cause serious and potentially fatal liver injury. Obtain baseline liver enzymes and monitor monthly for the first 12 months, then quarterly. Discontinue if liver enzyme elevation with symptoms or bilirubin >2x ULN.
| Serious Effects |
Concomitant use with angiotensin receptor blockers (ARBs) or endothelin receptor antagonists (ERAs); concomitant use with cyclosporine; pregnancy; baseline liver enzyme elevations (ALT or AST >3x ULN) or severe hepatic impairment; hypersensitivity to sparsentan.
| Precautions | Hepatotoxicity; embryo-fetal toxicity (must exclude pregnancy before initiation and monthly during treatment); hypotension; acute kidney injury; hyperkalemia; fluid retention; edema; anemia; neutropenia. Monitor liver function, blood pressure, renal function, and potassium levels. |
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| Fetal Monitoring | Pregnancy testing must be performed before initiation of treatment, monthly during treatment, and 1 month after discontinuation. Advise females of reproductive age to use effective contraception. Monitor liver function tests (ALT, AST, bilirubin) monthly due to hepatotoxicity risk. Monitor blood pressure regularly as FILSPARI may cause hypotension. Assess renal function periodically. |
| Fertility Effects | Endothelin receptor antagonists have been associated with testicular tubular atrophy and impaired spermatogenesis in animal studies, suggesting potential male fertility impairment. No human data are available. In females, effects on fertility are unknown; however, due to mechanism, potential for ovarian toxicity cannot be excluded. |