Filspari

  Pregnancy

Risk Summary

Based on data from animal reproductive toxicity studies, FILSPARI can cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy [see Contraindications ]. Available data from reports of pregnancy in clinical trials with FILSPARI 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 (ETA) 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 a 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.

  Lactation

Risk Summary

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 FILSPARI.

  Females and Malesof Reproductive Potential

Based on data from animal reproductive toxicity studies, FILSPARI can cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy [see Contraindications , Use in Specific Populations ].

Pregnancy Testing
Verify that patients who can become pregnant are not pregnant prior to initiating FILSPARI, monthly during treatment, and one month after discontinuation of treatment. The patient should contact their physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient must discuss the risks to their pregnancy and the fetus.

Contraception
Patients who can become pregnant who are using FILSPARI must use an effective method of contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with FILSPARI to prevent pregnancy [see Warnings and Precautions ].

  Pediatric Use

The safety and efficacy of FILSPARI in pediatric patients have not been established.

  Geriatric Use

Of the total number of subjects in the PROTECT study of FILSPARI, 15 (7.4%) were 65 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

  Hepatic Impairment

Avoid use of FILSPARI in patients with any hepatic impairment (Child-Pugh class A-C) because of the potential risk of serious liver injury [see Warnings and Precautions , Clinical Pharmacology ].