Sparsentan

Monitor for signs of worsening renal function with concomitant use with NSAIDs (including selective COX-2 inhibitors). In patients with volume depletion (including those on diuretic therapy) or with impaired kidney function, concomitant use of NSAIDs (including selective COX-2 inhibitors) with drugs that antagonize the angiotensin II receptor may result in deterioration of kidney function, including possible kidney failure. These effects are usually reversible.

Avoid use of sparsentan in patients with any hepatic impairment (Child-Pugh class A-C) because of the potential risk of serious liver injury.

Monitor for efficacy of the concurrently administered CYP2B6, 2C9, and 2C19 substrates and consider dosage adjustment in accordance with the Prescribing Information. Sparsentan is an inducer of CYP2B6, 2C9, and 2C19. Sparsentan decreases exposure of these substrates, which may reduce efficacy related to these substrates.

Avoid concomitant use of sensitive substrates of P-gp and BCRP with sparsentan. Sparsentan is an inhibitor of P-gp and BCRP. Sparsentan may increase exposure of these transporter substrates, which may increase the risk of adverse reactions related to these substrates.

Monitor blood pressure, serum potassium, edema, and kidney function regularly when used concomitantly with moderate CYP3A inhibitors. No sparsentan dose adjustment is needed.

Avoid concomitant use with a strong CYP3A inducer. Sparsentan is a CYP3A substrate. Concomitant use with a strong CYP3A inducer decreases sparsentan C_max and AUC, which may reduce sparsentan efficacy.

Administer sparsentan 2 hours before or after administration of antacids. Avoid concomitant use of acid reducing agents (histamine H₂ receptor antagonist and PPI proton pump inhibitor) with sparsentan. Sparsentan exhibits pH-dependent solubility. Antacids or acid reducing agents may decrease sparsentan exposure which may reduce sparsentan efficacy.

Monitor serum potassium frequently in patients treated with sparsentan and other agents that increase serum potassium. Concomitant use of sparsentan with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that raise serum potassium levels may result in hyperkalemia.

In patients at risk for hypotension, consider eliminating or adjusting other antihypertensive medications and maintaining appropriate volume status.

If hypotension develops, despite elimination or reduction of other antihypertensive medications, consider a dose reduction or dose interruption of sparsentan. A transient hypotensive response is not a contraindication to further dosing of sparsentan, which can be given once blood pressure has stabilized.

Risk Summary

Based on data from animal reproductive toxicity studies, sparsentan can cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy. Available data from reports of pregnancy in clinical trials with sparsentan are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of sparsentan to pregnant rats throughout organogenesis at 10-times the maximum recommended human dose (MRHD) in mg/day caused teratogenic effects in rats, including craniofacial malformations, skeletal abnormalities, increased embryo-fetal lethality, and reduced fetal weights (see Data). Advise pregnant patients of the potential risk to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In embryo-fetal development studies in pregnant rats and rabbits, teratogenicity and/or developmental toxicity were observed, which were attributed to the antagonism of endothelin type A (ET_A) and angiotensin II type 1 (AT₁) receptors.

In pregnant rats, oral administration of sparsentan throughout organogenesis at doses of 80, 160, and 240 mg/kg/day resulted in dose-dependent teratogenic effects in the form of craniofacial malformations, skeletal abnormalities, increased embryo-fetal lethality, and reduced fetal weights at all doses tested. The area under the curve (AUC) at the lowest dose tested (80 mg/kg/day) was approximately 10 times the AUC at the MRHD of 400 mg/day. In pregnant rabbits, oral administration of sparsentan throughout organogenesis at doses of 2.5, 10 and 40 mg/kg/day resulted in maternal death and abortions at 10 and 40 mg/kg/day which provided exposures approximately 0.1 times and 0.2 times the AUC at the MRHD, respectively. An increase in fetal variation (supernumerary cervical ribs) occurred at the high dose of 40 mg/kg/day.

In the pre- and postnatal development study in rats, oral administration of sparsentan during pregnancy and the lactational period at doses of 5, 20, or 80 mg/kg/day resulted in maternal death, body weight loss/reduced body weight gain, and adverse clinical signs at 80 mg/kg/day. An increase in pup deaths occurred at 80 mg/kg/day (approximately 10 times the AUC at MRHD) during the neonatal period through weaning, and decreased growth occurred at ≥20 mg/kg/day (approximately 2.6 times the AUC at the MRHD) after weaning. The NOAEL for pre- and postnatal development in rats was 5 mg/kg/day, approximately 0.7 times the AUC at the MRHD.

There are no data on the presence of sparsentan in human milk, the effects on the breastfed infant, or the effect on milk production. Because of the potential for adverse reactions, such as hypotension in breastfed infants, advise patients not to breastfeed during treatment with sparsentan.

Carcinogenesis

In the two-year rat carcinogenicity study, there was no evidence of increased incidence of neoplasia in male rats orally administered at 15 mg/kg/day (the only dose evaluated) and in female rats orally administered up to 240 mg/kg/day, which provided an exposure approximately 0.7 times and 26 times the AUC at the MRHD, respectively. In the 26-week transgenic mouse study, there was no evidence of increased incidence of neoplasia in male and female mice orally administered sparsentan at doses up to 600 mg/kg/day.

Mutagenesis

There was no evidence of mutagenicity or clastogenicity for sparsentan in in vitro bacteria reverse mutation and chromosomal aberration assays, or in an in vivo rat micronucleus study.

Impairment of fertility

In a fertility and early embryonic development study in rats, oral administration of sparsentan at doses of 20, 80, and 320 mg/kg/day for at least 36 (females) and 49 (males) days did not result in any adverse effects on estrous cycles, mating, fertility, sperm evaluation, or pregnancy incidence at doses up to 320 mg/kg/day, which provided approximately 10 and 14 times the AUC at the MRHD for males and females, respectively. Male reproductive organ toxicity was not evident in chronic toxicity studies with sparsentan at exposures up to 10 times and 1.3 times the AUC at the MRHD in rats and monkeys, respectively.

Clinical trials experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of sparsentan was evaluated in PROTECT (NCT03762850), an ongoing, randomized, double-blind, active-controlled clinical study in adults with IgAN.

The data below reflect sparsentan exposure in 202 patients with a median duration of 73 weeks (up to 110 weeks).

The most common adverse reactions are presented in Table 2.

Table 2. Adverse Reactions¹ Reported in ≥2% in Subjects Treated with Sparsentan:

¹ Data presented include all Treatment-Emergent Adverse Events reported
² Elevations in ALT or AST >3-fold ULN reported as Adverse Events of Interest

Laboratory Tests

Initiation of sparsentan may cause an initial small decrease in estimated glomerular filtration rate (eGFR) that occurs within the first 4 weeks of starting therapy and then stabilizes.

The incidence of a hemoglobin decrease >2 g/dL compared to baseline and below the lower limit of normal was greater for the sparsentan arm (11%) compared to the irbesartan arm (5%). This decrease is thought to be in part due to hemodilution. There were no treatment discontinuations due to anemia or hemoglobin decrease in the PROTECT study.