XPHOZAH 10 mg

1 INDICATIONS AND USAGE XPHOZAH is indicated to reduce serum phosphorus in adults with chronic kidney disease (CKD) on dialysis as add-on therapy in patients who have an inadequate response to phosphate binders or who are intolerant of any dose of phosphate binder therapy. XPHOZAH is a sodium hydrogen exchanger 3 (NHE3) inhibitor indicated to reduce serum phosphorus in adults with chronic kidney disease (CKD) on dialysis as add-on therapy in patients who have an inadequate response to phosphate binders or who are intolerant of any dose of phosphate binder therapy ( 1 ).

2 DOSAGE AND ADMINISTRATION Recommended dosage: 30 mg orally twice daily before the morning and evening meals ( 2.1 ). Manage serum phosphorus levels and tolerability with dosage adjustments ( 2.1 ). Take just prior to the first and last meals of the day ( 2.2 ). Instruct patients not to take right before a hemodialysis session, and instead take right before the next meal following dialysis ( 2.2 ). 2.1 Recommended Dosage The recommended dosage is 30 mg orally twice daily before the morning and evening meals. Monitor serum phosphorus and adjust the dosage as needed to manage gastrointestinal tolerability. 2.2 Administration Instructions Instruct patients to take XPHOZAH just prior to the first and last meals of the day [see Clinical Pharmacology (12.2) ] . Instruct patients not to take XPHOZAH right before a hemodialysis session, and instead take right before the next meal following dialysis, as patients may experience diarrhea after taking XPHOZAH [see Warnings and Precautions (5.1) ] . Instruct patients who miss a dose to skip the missed dose and take the next dose at the regular time.

5 WARNINGS AND PRECAUTIONS Patients may experience severe diarrhea ( 5.1 ). 5.1 Diarrhea Diarrhea was the most common adverse reaction in XPHOZAH-treated patients with CKD on dialysis [see Dosage and Administration (2) , Contraindications (4) and Adverse Reactions (6.1) ]. In clinical trials, diarrhea was reported in up to 53% of patients, reported as severe in 5%, and associated with dehydration and hyponatremia in less than 1% of patients. Treatment with XPHOZAH should be discontinued in patients who develop severe diarrhea.

4 CONTRAINDICATIONS XPHOZAH is contraindicated in patients under 6 years of age because of the risk of diarrhea and serious dehydration [see Warnings and Precautions (5.1) , Use in Specific Populations (8.5) ]. XPHOZAH is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. Pediatric patients under 6 years of age ( 4 ). Patients with known or suspected mechanical gastrointestinal obstruction ( 4 ).

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.

6 ADVERSE REACTIONS Most common adverse reaction in the combined clinical trials was diarrhea, reported by 43-53% of patients ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Ardelyx at 1-844-974-6924 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described below reflect data from 754 adults with CKD on dialysis taking XPHOZAH in clinical trials as monotherapy and in combination with phosphate binders. Among the 754 patients, 258 patients were exposed to tenapanor for at least 26 weeks and 75 were exposed to tenapanor for at least one year. [see Clinical Studies (14) ] . Most Common Adverse Reaction Diarrhea, which occurred in 43-53% of patients, was the only adverse reaction reported in at least 5% of XPHOZAH-treated patients with CKD on dialysis across trials. The majority of diarrhea events in the XPHOZAH-treated patients were reported to be mild-to-moderate in severity and resolved over time, or with dose reduction. Diarrhea was typically reported soon after initiation but could occur at any time during treatment with XPHOZAH. Severe diarrhea was reported in 5% of XPHOZAH-treated patients in these trials [see Warnings and Precautions (5.1) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of XPHOZAH. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions: pruritis, rash, and urticaria