6 ADVERSE REACTIONS

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)].

7 DRUG INTERACTIONS

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 (Cmax) 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

The carcinogenic potential of tenapanor was assessed in a 6-month carcinogenicity study in Tg rasH2 mice and in a 2-year carcinogenicity study in rats. Tenapanor was not tumorigenic at oral doses up to 100 mg/kg/day (approximately 7.5 times the recommended human dose, based on the body surface area) in male mice and 800 mg/kg/day (approximately 65 times the maximum recommended human dose, based on the body surface area) for female mice. Tenapanor was not tumorigenic in male and female rats at oral doses up to 5 mg/kg/day (approximately 0.8 times the recommended human dose, based on the body surface area). The major metabolite of tenapanor, M1, was not tumorigenic in Tg rasH2 mice at oral doses up to 165 mg/kg/day (approximately 13.3 times the maximum recommended human dose, based on the body surface area).

Mutagenesis

Tenapanor was not genotoxic in the in vitro bacterial reverse mutation (Ames) assays, an in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes or the in vivo micronucleus assays in mice and rats. The M1 metabolite of tenapanor was not genotoxic in the Ames assay and in an in vitro micronucleus assay using L5178Y cells.

Impairment of Fertility

Tenapanor had no effect on fertility or reproductive function in male rats at oral doses up to 10 mg/kg/day (approximately 1.6 times the recommended human dose, based on the body surface area) and in female mice at oral doses up to 50 mg/kg/day (approximately 4 times the recommended human dose, based on the body surface area).

17 PATIENT COUNSELING INFORMATION

Advise Patients:

Diarrhea

Instruct patients to contact their healthcare provider if they experience severe diarrhea [see Warnings and Precautions (5.1)].

• Instruct patients not to use stool softeners or laxatives with XPHOZAH.

Administration and Handling Instructions

Instruct Patients:

• To take XPHOZAH just prior to the first and last meals of the day [see Dosage and Administration (2.2)].
• Patients should be counseled not to take XPHOZAH right before a hemodialysis session, and to take XPHOZAH right before the next meal, as some patients may experience diarrhea after taking XPHOZAH.
• If a dose is missed, take the dose just before the next meal. Do not take 2 doses at the same time [see Dosage and Administration (2.2)].
• To keep XPHOZAH in a dry place. Protect from moisture. Keep in the original bottle. Do not remove desiccant from the bottle. Keep bottles tightly closed [see How Supplied/Storage and Handling (16)].