Tenapanor Hydrochloride

1 INDICATIONS AND USAGE IBSRELA is indicated for treatment of irritable bowel syndrome with constipation (IBS-C) in adults. IBSRELA is a sodium/hydrogen exchanger 3 (NHE3) inhibitor indicated for treatment of irritable bowel syndrome with constipation (IBS-C) in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of IBSRELA in adults is 50 mg orally twice daily. The recommended dosage in adults is 50 mg, orally twice daily. ( 2 ) Take immediately prior to breakfast or the first meal of the day and immediately prior to dinner. ( 2 ) Administration Instructions Take IBSRELA immediately prior to breakfast or the first meal of the day and immediately prior to dinner [see Clinical Pharmacology (12.2) ] . If a dose is missed, skip the missed dose and take the next dose at the regular time. Do not take 2 doses at the same time.

6 ADVERSE REACTIONS Most common adverse reactions (≥2%) are diarrhea, abdominal distension, flatulence and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ardelyx at 1-844-427-7352 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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 1203 adult patients with IBS-C in two randomized, double-blind, placebo-controlled clinical trials (Trial 1 and Trial 2). Patients were randomized to receive placebo or IBSRELA 50 mg twice daily for up to 52 weeks. Demographic characteristics were comparable between treatment groups in the two trials [see Clinical Studies (14) ] . Most Common Adverse Reactions The most common adverse reactions reported in at least 2% of patients in IBSRELA-treated patients and at an incidence greater than placebo during the 26-week double-blind placebo-controlled treatment period of Trial 1 are shown in Table 1. Table 1: Most Common Adverse Reactions Reported in at least 2% of patients in IBSRELA-treated patients and at an incidence greater than placebo in Patients with IBS-C in Trial 1 (26 Weeks) Adverse Reactions IBSRELA N=293 % Placebo N=300 % Diarrhea 16 4 Abdominal Distension 3 <1 Flatulence 3 1 Dizziness 2 <1 The adverse reaction profile was similar during the 12-week double-blind placebo-controlled treatment period of Trial 2 (610 patients: 309 IBSRELA-treated and 301 placebo-treated) with diarrhea (15% with IBSRELA vs 2% with placebo) and abdominal distension (2% with IBSRELA vs 0% with placebo) as the most common adverse reactions. Adverse Reaction of Special Interest – Severe Diarrhea Severe diarrhea was reported in 2.5% of IBSRELA-treated patients compared to 0.2% of placebo-treated patients during the 26 weeks of Trial 1 and the 12 weeks of Trial 2 [see Warnings and Precautions (5.2) ] . Patients with Renal Impairment In Trials 1 and 2, there were 368 patients (31%) with baseline renal impairment (defined as eGFR less than 90 mL/min/1.73m 2 ). In patients with renal impairment, diarrhea, including severe diarrhea, was reported in 20% (39/194) of IBSRELA-treated patients and 0.6% (1/174) of placebo-treated patients. In patients with normal renal function at baseline, diarrhea, including severe diarrhea, was reported in 13% (53/407) of IBSRELA-treated patients and 3.5% (15/426) of placebo-treated patients. No other differences in the safety profile were reported in the renally impaired subgroup. The incidence of diarrhea and severe diarrhea in IBSRELA-treated patients did not correspond to the severity of renal impairment. Adverse Reactions Leading to Discontinuation Discontinuations due to adverse reactions occurred in 7.6% of IBSRELA-treated patients and 0.8% of placebo-treated patients during the 26 weeks of Trial 1 and the 12 weeks of Trial 2. The most common adverse reaction leading to discontinuation was diarrhea: 6.5% of IBSRELA-treated patients compared to 0.7% of placebo-treated patients. Less Common Adverse Reactions Adverse reactions reported in less than 2% of IBSRELA-treated patients and at an incidence greater than placebo during the 26 weeks of Trial 1 and the 12 weeks of Trial 2 were: rectal bleeding and abnormal gastrointestinal sounds. Hyperkalemia In a trial of another patient population with chronic kidney disease (defined by eGFR from 25 to 70 mL/min/1.73m 2 ) and Type 2 diabetes mellitus, three serious adverse reactions of hyperkalemia resulting in hospitalization were reported in 3 patients (2 IBSRELA-treated patients and 1 placebo-treated patient). 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of IBSRELA. 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

12.3 Pharmacokinetics 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 healthy subjects following single and repeated oral administration of IBSRELA 50 mg twice daily. Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (C max ), and half-life (t 1/2 ) could not be determined. Distribution Plasma protein binding of tenapanor and its major metabolite, M1, is approximately 99% and 97%, respectively, in vitro. Elimination Metabolism Tenapanor is metabolized primarily by CYP3A4/5 and low levels of its major metabolite, M1, are detected in plasma. The C max of M1 is approximately 13 ng/mL after single dose of IBSRELA 50 mg and 15 ng/mL at steady state following repeated dosing of IBSRELA 50 mg twice daily in healthy subjects. Excretion Following administration of a single 15 mg radiolabeled 14 C-tenapanor dose to healthy subjects, approximately 70% of the radioactivity was excreted in feces within 120 hours post-dose and 79% within 240 hours post-dose, mostly as the parent drug accounting for 65% of dose within 144 hours post-dose. Approximately 9% of the administered dose was recovered in urine, primarily as metabolites. M1 is excreted in urine unchanged accounting for 1.5% of dose within 144 hours post-dose. Specific Populations Patients with Hepatic Impairment Following a single dose of tenapanor 100 mg in patients with moderate hepatic impairment (Child-Pugh B), plasma concentrations of tenapanor were mostly below the limit of quantitation (< 0.5 ng/mL) and the pharmacokinetic parameters for tenapanor could not be determined. The geometric mean AUC and C max of the major metabolite, M1, were approximately 33% and 27% lower, respectively, in patients with moderate hepatic impairment compared to those of healthy subjects. The decrease in M1 systemic exposure is not clinically relevant. Patients with Renal Impairment Based on a cross-study comparison, plasma concentrations of M1 in end-stage renal disease patients on hemodialysis (eGFR less than 15 mL/min/1.73m 2 ) was not notably different from those of healthy subjects given comparable doses of IBSRELA. Drug Interaction Studies CYP Metabolism Mediated Drug Interactions Tenapanor and M1 did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 in vitro. Tenapanor and M1 did not induce CYP1A2 and CYP2B6 in vitro. No significant inhibition or induction of CYP3A4 enzyme using midazolam as a substrate was observed when IBSRELA 50 mg was administered twice a day for 13 days in healthy subjects. Following co-administration of a single dose of IBSRELA 50 mg with repeated doses of itraconazole 200 mg, a CYP3A4 inhibitor, the mean AUC and C max of M1 was decreased 50% in healthy subjects. The decrease in M1 systemic exposure is not clinically relevant. Plasma concentrations of tenapanor were mostly below the limit of quantitation (less than 0.5 ng/mL) after co-administration of itraconazole. No significant effect on CYP2C9 activity using warfarin as a substrate was observed when tenapanor 30 mg was administered twice a day (a dosage 0.6 times the recommended dosage) for 12 days in healthy subjects. Membrane Transporter Mediated Drug Interactions Tenapanor inhibited OATP2B1, but is not an inhibitor of P-gp, BCRP, OATP1B1, and OATP1B3. M1 did not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, and MATE2-K. M1 is a substrate of P-gp. Tenapanor is not a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. M1 is not a substrate of BCRP, OAT1, OAT3, OCT2, MATE1 and MATE2-K. No significant effect on PepT1 activity using cefadroxil as a substrate was observed when IBSRELA 50 mg was administered twice a day for 12 days in healthy subjects. No significant effect on P-gp activity using digoxin as a substrate was observed when tenapanor 30 mg was administered twice a day (a dosage 0.6 times the recommended dosage) for 12 days in healthy subjects. Following administration of a single 20 mg dose of enalapril (OATP2B1 substrate) with tenapanor 30 mg administered twice a day (a dosage 0.6 times the recommended dosage) at steady state in healthy subjects, the mean AUC and C max of enalapril was decreased by 64% and 69%, respectively. The mean AUC and C max of enalaprilat was decreased by 52% and 68%, respectively [see Drug Interactions (7.1) ] .