Tenapanor (Xphozah)

7 DRUG INTERACTIONS OATP2B1 Substrates: Potential for reduced exposure of the concomitant drug (e.g., enalapril). Monitor for signs related to loss of efficacy and adjust the dosage of the concomitantly administered drug as needed ( 7.1 ). Sodium Polystyrene Sulfonate (SPS): Separate administration by at least three hours ( 7.2 ).

7.1 OATP2B1 Substrates Tenapanor is an inhibitor of intestinal uptake transporter, OATP2B1 [see Clinical Pharmacology (12.3) ] . Drugs which are substrates of OATP2B1 may have reduced exposures when concomitantly taken with XPHOZAH. Monitor for signs related to loss of efficacy and adjust the dose of concomitantly administered drug as needed. Enalapril is a substrate of OATP2B1.

When enalapril was coadministered with XPHOZAH (30 mg twice daily for five days), the peak exposure (C max ) of enalapril and its active metabolite, enalaprilat, decreased by approximately 70% and total systemic exposures (AUC) decreased by 50 to 65% compared to when enalapril was administered alone [see Clinical Pharmacology (12.3) ] . However, the decrease in enalaprilat's exposure with XPHOZAH may be offset by the inherently higher exposures observed in patients with CKD on dialysis due to its reduced renal clearance. Therefore, a lower starting dose of enalapril, which is otherwise recommended in patients with CKD on dialysis is not required when enalapril is coadministered with XPHOZAH.

7.2 Sodium Polystyrene Sulfonate Separate administration of XPHOZAH and sodium polystyrene sulfonate (SPS) by at least 3 hours. SPS binds to many commonly prescribed oral medicines.

8.1 Pregnancy Risk Summary Tenapanor is essentially non-absorbed systemically, with plasma concentrations below the limit of quantification (less than 0.5 ng/mL) following oral administration [see Clinical Pharmacology (12.3) ]. Therefore, maternal use is not expected to result in fetal exposure to the drug. The available data on XPHOZAH exposure from a small number of pregnant women have not identified any drug associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In reproduction studies with tenapanor in pregnant rats and rabbits, no adverse fetal effects were observed in rats at 0.2 times the maximum recommended human dose and in rabbits at doses up to 15 times the maximum recommended human dose (based on body surface area) [see Nonclinical Toxicology (13.1) ] . The estimated background risk of major birth defects and miscarriage for women with CKD on dialysis with hyperphosphatemia is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Animal Data In an embryofetal development study in rats, tenapanor was administered orally to pregnant rats during the period of organogenesis at dose levels of 1, 10 and 30 mg/kg/day. Tenapanor doses of 10 and 30 mg/kg/day were not tolerated by the pregnant rats and was associated with mortality and moribundity with body weight loss. The 10 and 30 mg/kg dose group animals were sacrificed early, and the fetuses were not examined for intrauterine parameters and fetal morphology.

No adverse fetal effects were observed in rats at 1 mg/kg/day (approximately 0.2 times the maximum recommended human dose) and in rabbits at doses up to 45 mg/kg/day (approximately 15 times the maximum recommended human dose, based on body surface area). In a pre- and post-natal developmental study in mice, tenapanor at doses up to 200 mg/kg/day (approximately 16.5 times the maximum recommended human dose, based on body surface area) had no effect on pre- and post-natal development.