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)].

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.

Risk Summary

There are no data available on the presence of tenapanor in either human or animal milk, its effects on milk production or its effects on the breastfed infant. 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)]. The minimal systemic absorption of tenapanor will not result in a clinically relevant exposure to breastfed infants. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for XPHOZAH and any potential adverse effects on the breastfed infant from XPHOZAH or from the underlying maternal condition.

Risk Summary

XPHOZAH is contraindicated in patients less than 6 years of age. In nonclinical studies, deaths occurred in young juvenile rats (less than 1-week old rats; approximate human age-equivalent of less than 2 years of age) and in older juvenile rats (approximate human age-equivalent of 2 years of age) following oral administration of tenapanor, as described below in Juvenile Animal Toxicity Data.

The safety and effectiveness of XPHOZAH in pediatric patients have not been established.

Juvenile Animal Toxicity Data

In a 21-day oral dose range finding toxicity study in juvenile rats, tenapanor was administered to neonatal rats (post-natal day (PND) 5) at doses of 5 and 10 mg/kg/day. Tenapanor was not tolerated in male and female pups and the study was terminated on PND 16 due to mortalities and decreased body weight (24% to 29% reduction in females at the respective dose groups and 33% reduction in males in the 10 mg/kg/day group, compared to control).

In a second dose range finding study, tenapanor doses of 0.1, 0.5, 2.5, or 5 mg/kg/day were administered to neonatal rats from PND 5 through PND 24. Treatment-related mortalities were observed at 0.5, 2.5, and 5 mg/kg/day doses. These premature deaths were observed as early as PND 8, with majority of deaths occurring between PND 15 and 25. In the 5 mg/kg/day group, mean body weights were 47% lower for males on PND 23 and 35% lower for females on PND 22 when compared to the controls. Slightly lower mean tibial lengths (5% to 11%) were noted in males and females in the 0.5, 2.5, and 5 mg/kg/day dose groups on PND 25 and correlated with the decrements in body weight noted in these groups. Lower spleen, thymus, and/or ovarian weights were noted at the 0.5, 2.5, and 5 mg/kg/day doses. Tenapanor-related gastrointestinal distension and microscopic bone findings of increased osteoclasts, eroded bone, and/or decreased bone in sternum and/or femorotibial joint were noted in males and females in the 0.5, 2.5, and 5 mg/kg/day dose groups.

In juvenile rats administered tenapanor at 0.03, 0.1, or 0.3 mg/kg/day on PND 5 through PND 61, treatment-related mortalities were observed at 0.3 mg/kg/day. Lower mean body weight gains were noted in the 0.3 mg/kg/day group males and females compared to the control group primarily during PND 12–24 but continuing sporadically during the remainder of the dosing period; corresponding lower mean food consumption was noted in this group during PND 21–33. As a result, mean body weights were up to 15.8% and 16.8% lower in males and females, respectively, compared to the control group; the greatest difference was on PND 24 for males and PND 21 for females. Mean body weight in the 0.3 mg/kg/day group males was only 3.9% lower than the control group on PND 61. There were no tenapanor-related effects on mean body weights, body weight gains, or food consumption in the 0.03 and 0.1 mg/kg/day group males and females. A dosage level of 0.1 mg/kg/day was considered to be the no-observed-adverse-effect level (NOAEL) for juvenile toxicity of tenapanor [see Contraindications (4), Warnings and Precautions (5.1)].

In a 21-day oral dose range finding study in older (weaned) juvenile rats administered tenapanor at 0.1, 1, or 5 mg/kg/day on PND 21 through PND 41 (approximate human age-equivalent of 2 to 12 years of age), treatment-related mortalities or moribundities were observed during the first two days of the study in the 1 mg/kg/day males and the 5 mg/kg/day males and females. Watery feces, decreased food consumption, and lower mean body weight were also observed in the 1 and 5 mg/kg/day groups.

In weaned juvenile rats administered tenapanor at 0.1, 0.3, and 0.7 (males) or 1 (females) mg/kg/day on PND 21 through PND 80, no mortalities were observed. Significant decreases in mean body weights were observed in the 0.3 and 0.7 mg/kg/day males throughout the dosing period (up to 20.3% lower than control) and in the 1 mg/kg/day females between PND 23 to 35 (up to 16.7% lower than control), with food consumption notably decreased on PND 21 to 29. There were also reductions in tibia length between PND 76 and 80 in the 0.3 and 0.7 mg/kg/day males, and between PND 36 and 64 in the 0.7 mg/kg/day males, which were not observed during the 14-day recovery period. The NOAEL was considered to be 0.1 mg/kg/day for juvenile toxicity of tenapanor.

Cardiac Electrophysiology

At 3 times the mean maximum exposure of the major pharmacologically inactive metabolite of tenapanor (M1) at the recommended dosage, there were no clinically relevant effects on the QTc.

Food Effect

Administration of XPHOZAH 5 to 10 minutes before a meal increased the 24-hour stool phosphorus excretion compared to taking XPHOZAH in the fed or fasting condition [see Dosage and Administration (2.2)]. In clinical trials, XPHOZAH was administered just prior to the first meal and just prior to dinner.

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of XPHOZAH was studied in 20 subjects with normal or moderate hepatic impairment function (Child-Pugh B) after a single 100-mg dose. Compared to subjects with normal hepatic function, the geometric mean Cmax of the pharmacologically inactive metabolite M1, was approximately 27% to 35% lower in subjects with moderate hepatic impairment. Tenapanor exhibited minimal systemic bioavailability in subjects with both normal hepatic function and moderate hepatic impairment, with plasma concentrations below the limit of quantitation (less than 0.5 ng/mL) in the majority of samples.

Absorption

Tenapanor is minimally absorbed following repeated twice daily oral administration. Plasma concentrations of tenapanor were below the limit of quantitation (less than 0.5 ng/mL) in the majority of samples from subjects following single and repeated oral administration of tenapanor 30 mg twice daily. Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (Cmax), and half-life (t1/2) could not be determined.

Distribution

Plasma protein binding of tenapanor and its major metabolite, M1, is approximately 99% and 97%, respectively, in vitro.

Elimination

Drug Interaction Studies

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).