ADVERSE REACTIONS SECTION.

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.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 ReactionsThe 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 are shown in Table 1.Table 1: Most Common Adverse ReactionsReported in at least 2% of patients in IBSRELA-treated patients and at an incidence greater than placebo in Patients with IBS-C in Trial (26 Weeks)Adverse ReactionsIBSRELAN=293%PlaceboN=300%Diarrhea164Abdominal Distension3<1Flatulence31Dizziness2<1The adverse reaction profile was similar during the 12-week double-blind placebo-controlled treatment period of Trial (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 and the 12 weeks of Trial [see Warnings and Precautions (5.2)].. Patients with Renal ImpairmentIn Trials and 2, there were 368 patients (31%) with baseline renal impairment (defined as eGFR less than 90 mL/min/1.73m2). 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 DiscontinuationDiscontinuations 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 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 ReactionsAdverse reactions reported in less than 2% of IBSRELA-treated patients and at an incidence greater than placebo during the 26 weeks of Trial and the 12 weeks of Trial were: rectal bleeding and abnormal gastrointestinal sounds.. HyperkalemiaIn trial of another patient population with chronic kidney disease (defined by eGFR from 25 to 70 mL/min/1.73m2) and Type diabetes mellitus, three serious adverse reactions of hyperkalemia resulting in hospitalization were reported in patients (2 IBSRELA-treated patients and placebo-treated patient).

BOXED WARNING SECTION.

WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS. IBSRELA is contraindicated in patients less than years of age; in nonclinical studies in young juvenile rats administration of tenapanor caused deaths presumed to be due to dehydration [see Contraindications (4), Use in Specific Populations (8.4)]. Avoid use of IBSRELA in patients years to less than 12 years of age [see Warnings and Precautions (5.1), Use in Specific Populations (8.4)]. The safety and effectiveness of IBSRELA have not been established in patients less than 18 years of age [see Use in Specific Populations (8.4)]. IBSRELA is contraindicated in patients less than years of age; in nonclinical studies in young juvenile rats administration of tenapanor caused deaths presumed to be due to dehydration [see Contraindications (4), Use in Specific Populations (8.4)]. Avoid use of IBSRELA in patients years to less than 12 years of age [see Warnings and Precautions (5.1), Use in Specific Populations (8.4)]. The safety and effectiveness of IBSRELA have not been established in patients less than 18 years of age [see Use in Specific Populations (8.4)]. WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTSSee full prescribing information for complete boxed warning.IBSRELA is contraindicated in patients less than years of age; in young juvenile rats, tenapanor caused death presumed to be due to dehydration. (4, 8.4)Avoid use of IBSRELA in patients years to less than 12 years of age. (5.1, 8.4)The safety and effectiveness of IBSRELA have not been established in pediatric patients less than 18 years of age. (8.4) IBSRELA is contraindicated in patients less than years of age; in young juvenile rats, tenapanor caused death presumed to be due to dehydration. (4, 8.4). Avoid use of IBSRELA in patients years to less than 12 years of age. (5.1, 8.4). The safety and effectiveness of IBSRELA have not been established in pediatric patients less than 18 years of age. (8.4).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisThe carcinogenic potential of tenapanor was assessed in 6-month carcinogenicity study in Tg rasH2 mice and in 2-year carcinogenicity study in rats.Tenapanor was not tumorigenic at oral doses up to 100 mg/kg/day (approximately 4.5 times the recommended human dose, based on the body surface area) in male mice and 800 mg/kg/day (approximately 39 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 mg/kg/day (approximately 0.5 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 times the maximum recommended human dose, based on the body surface area). MutagenesisTenapanor 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. 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 0.97 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 2.4 times the recommended human dose, based on the body surface area).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Tenapanor is locally acting inhibitor of the sodium/hydrogen exchanger (NHE3), an antiporter expressed on the apical surface of the small intestine and colon primarily responsible for the absorption of dietary sodium. In vitro and animal studies indicate its major metabolite, M1, is not active against NHE3. By inhibiting NHE3 on the apical surface of the enterocytes, tenapanor reduces absorption of sodium from the small intestine and colon, resulting in an increase in water secretion into the intestinal lumen, which accelerates intestinal transit time and results in softer stool consistency.Tenapanor has also been shown to reduce abdominal pain by decreasing visceral hypersensitivity and by decreasing intestinal permeability in animal models. In rat model of colonic hypersensitivity, tenapanor reduced visceral hyperalgesia and normalized colonic sensory neuronal excitability.. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyAt times the mean maximum exposure of M1 at the recommended dosage, there were no clinically relevant effects on the QTc interval.. Food EffectAdministration of IBSRELA to 10 minutes before meal increased the 24-hour stool sodium excretion compared to taking IBSRELA in the fed or fasting condition [see Dosage and Administration (2)]. In clinical trials, IBSRELA was administered immediately prior to the first meal of the day and immediately prior to dinner.. 12.3 Pharmacokinetics. AbsorptionTenapanor 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 (Cmax), and half-life (t1/2) could not be determined.. DistributionPlasma protein binding of tenapanor and its major metabolite, M1, is approximately 99% and 97%, respectively, in vitro.. Elimination. MetabolismTenapanor is metabolized primarily by CYP3A4/5 and low levels of its major metabolite, M1, are detected in plasma. The Cmax 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.. ExcretionFollowing administration of single 15 mg radiolabeled 14C-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 ImpairmentFollowing 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 Cmax 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 ImpairmentBased on cross-study comparison, plasma concentrations of M1 in end-stage renal disease patients on hemodialysis (eGFR less than 15 mL/min/1.73m2) was not notably different from those of healthy subjects given comparable doses of IBSRELA.. Drug Interaction Studies CYP Metabolism Mediated Drug InteractionsTenapanor 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 substrate was observed when IBSRELA 50 mg was administered twice day for 13 days in healthy subjects.Following co-administration of single dose of IBSRELA 50 mg with repeated doses of itraconazole 200 mg, CYP3A4 inhibitor, the mean AUC and Cmax 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.. Membrane Transporter Mediated Drug InteractionsTenapanor and M1 did not inhibit P-gp, BCRP, OATP1B1, and OATP1B3. M1 did not inhibit OAT1, OAT3, OCT2, MATE1, and MATE2-K.M1 is substrate of P-gp. Tenapanor is not substrate of P-gp, BCRP, OATP1B1, and OATP1B3. M1 is not substrate of BCRP, OAT1, OAT3, OCT2, MATE1 and MATE2-K.No significant effect on PepT1 activity using cefadroxil as substrate was observed when IBSRELA 50 mg was administered twice day for 12 days in healthy subjects.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of IBSRELA for the treatment of IBS-C was established in two double-blind, placebo-controlled, randomized, multicenter trials in adult patients: Trial (TEN-01-302; NCT02686138) and Trial (TEN-01-301; NCT02621892). The intent-to-treat (ITT) analysis population included 620 patients in Trial and 606 patients in Trial with mean age of 46 years (range 18 to 75 years), 80% females, 64% White and 31% Black/African American. In these clinical trials, IBSRELA was administered immediately prior to breakfast or the first meal of the day and immediately prior to dinner.To enter the trials, all patients met Rome III criteria for IBS-C and were required to meet the following clinical criteria during the 2-week baseline run-in period:a mean abdominal pain score of at least on 0-to-10-point numeric rating scale where score of indicates no pain and 10 indicates very severe painless than complete spontaneous bowel movements (CSBMs) per week, where CSBM is defined as spontaneous bowel movement (SBM) that is associated with sense of complete evacuation (an SBM is bowel movement occurring in the absence of laxative use)less than or equal to SBMs per weekThe trial designs were identical through the first 12 weeks of treatment, and thereafter differed in that Trial continued for an additional 14 weeks of treatment (26 weeks double-blind treatment), whereas Trial included 4-week randomized withdrawal (RW) period.Efficacy of IBSRELA was assessed using responder analyses based on daily diary entries.In both trials, the primary endpoint was the proportion of responders, where responder was defined as patient achieving both the stool frequency and abdominal pain intensity responder criteria in the same week for at least of the first 12 weeks of treatment. The stool frequency (CSBM) and abdominal pain responder criteria assessed each week were defined as:CSBM responder: patient who experienced an increase of at least CSBM in weekly average from baseline.Abdominal pain responder: patient who experienced at least 30% reduction in the weekly average of abdominal pain score compared with baseline.The responder rates for the primary endpoint and components of the primary endpoint (CSBM and abdominal pain), which were pre-specified key secondary endpoints, are shown in Table 2.Table 2:Efficacy Responder Rates in Placebo-Controlled Trials (Trial and Trial 2) in Adults with IBS-C: Responder for at least of the First 12 Weeks of TreatmentTrial 1IBSRELAN=293PlaceboN=300Treatment Difference[95% CICI: Confidence Interval]ResponderA responder for these trials was defined as patient who met both the abdominal pain and CSBM weekly responder criteria for at least of the first 12 weeks. 37%24%13%[6%, 20%]Components of Responder Endpoint: CSBM ResponderA CSBM responder was defined as patient who achieved an increase in at least CSBM per week, from baseline, for least of at least 12 weeks. 47%33% Abdominal Pain ResponderAn abdominal pain responder was defined as patient who met the criteria of at least 30% reduction from baseline in weekly average of the worst daily abdominal pain, for at least of the first 12 weeks. 50%38%Trial 2Responder RatesIBSRELAN=307PlaceboN=299Treatment Difference[95% CI]Responder 27%19%8%[2%, 15%]Components of Responder Endpoint: CSBM Responder 34%29% Abdominal Pain Responder 44%33%In Trials and 2, the proportion of responders for out of the first 12 weeks, including at least of the last weeks, was greater in IBSRELA-treated patients compared to placebo-treated patients. In addition, in Trial 1, the proportion of responders for 13 out of 26 weeks was greater in IBSRELA-treated patients compared to placebo-treated patients.In both trials, improvements from baseline in average weekly CSBMs and abdominal pain were observed by Week 1, with improvement maintained through the end of treatment.In IBSRELA-treated patients re-randomized to placebo in Trial 2, CSBM frequency and abdominal pain severity worsened on average over the 4-week period but remained improved compared to baseline. Patients who continued on IBSRELA maintained their response to therapy on average over the additional weeks. Patients on placebo who were re-randomized to IBSRELA had an average increase in CSBM frequency and decrease in abdominal pain.. mean abdominal pain score of at least on 0-to-10-point numeric rating scale where score of indicates no pain and 10 indicates very severe pain. less than complete spontaneous bowel movements (CSBMs) per week, where CSBM is defined as spontaneous bowel movement (SBM) that is associated with sense of complete evacuation (an SBM is bowel movement occurring in the absence of laxative use). less than or equal to SBMs per week. CSBM responder: patient who experienced an increase of at least CSBM in weekly average from baseline.. Abdominal pain responder: patient who experienced at least 30% reduction in the weekly average of abdominal pain score compared with baseline.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. IBSRELA is contraindicated in:Patients less than years of age due to the risk of serious dehydration [see Warnings and Precautions (5.1), Use in Specific Populations (8.4)]. Patients with known or suspected mechanical gastrointestinal obstruction. Patients less than years of age due to the risk of serious dehydration [see Warnings and Precautions (5.1), Use in Specific Populations (8.4)]. Patients with known or suspected mechanical gastrointestinal obstruction. Pediatric patients less than years of age. (4, 5.1, 8.4)Patients with known or suspected mechanical gastrointestinal obstruction. (4). Pediatric patients less than years of age. (4, 5.1, 8.4). Patients with known or suspected mechanical gastrointestinal obstruction. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. IBSRELA (tenapanor) tablets contain tenapanor hydrochloride as an active ingredient. Tenapanor hydrochloride is sodium/hydrogen exchanger (NHE3) inhibitor for oral use. The chemical name for tenapanor hydrochloride is 12,15-Dioxa-2,7,9-triazaheptadecanamide, 17-[[[3-[(4S)-6,8-dichloro-1,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]phenyl]sulphonyl]amino]-N-[2-[2-[2-[[[3-[(4S)-6,8-dichloro-1,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]phenyl]sulphonyl]amino]ethoxy]ethoxy]ethyl]-8-oxo-, hydrochloride (1:2). Tenapanor hydrochloride has the molecular formula of C50H68Cl6N8O10S2, the molecular weight of 1218 Daltons, and the chemical structure below: Tenapanor hydrochloride is white to off-white to light brown hygroscopic amorphous solid. It is practically insoluble in water.IBSRELA tablets contain 50 mg of tenapanor (equivalent to 53.2 mg of tenapanor hydrochloride). Inactive ingredients in the tablet are colloidal silicon dioxide, hypromellose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, propyl gallate, stearic acid, tartaric acid powder, titanium dioxide and triacetin.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

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) 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 InstructionsTake IBSRELA immediately prior to breakfast or the first meal of the day and immediately prior to dinner [see Clinical Pharmacology (12.2)].If dose is missed, skip the missed dose and take the next dose at the regular time. Do not take doses at the same time.. Take IBSRELA immediately prior to breakfast or the first meal of the day and immediately prior to dinner [see Clinical Pharmacology (12.2)].. If dose is missed, skip the missed dose and take the next dose at the regular time. Do not take doses at the same time.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Tablets: 50 mg tenapanor supplied as an oval, white to off-white tablet debossed with 50 on one side and 5791 on the other side.. Tablets: 50 mg tenapanor. (3). Image.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 1203 patients in placebo-controlled clinical trials of IBSRELA, 100 (8%) were 65 years of age and older. No overall differences in safety or effectiveness were observed between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. IBSRELA tablets contain 50 mg tenapanor and are oval, white to off-white, debossed with 50 on one side and 5791 on the other side.IBSRELA is supplied in white, opaque, high-density polyethylene bottle containing 60 tablets with silica gel canister (as the desiccant) and screw-top polypropylene child-resistant cap lined and induction-activated aluminum foil liner (NDC 73154-050-60).. StorageStore at room temperature, between 68F and 77F (20C and 25C).Keep in original container and protect from moisture. Keep the container of IBSRELA tightly closed and in dry place.Do not remove desiccant from the bottle. Do not subdivide or repackage.. Image.

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patients to read the FDA-approved patient labeling (Medication Guide).. Diarrhea Instruct patients to stop IBSRELA and contact their healthcare provider if they experience severe diarrhea [see Warnings and Precautions (5.2)].. Accidental Ingestion Accidental ingestion of IBSRELA in children, especially children less than years of age, may result in severe diarrhea and dehydration. Instruct patients to store IBSRELA securely and out of reach of children [see Contraindications (4), Warnings and Precautions (5.1)]. Administration and Handling Instructions Instruct Patients: To take IBSRELA immediately prior to breakfast or the first meal of the day and immediately before dinner [see Dosage and Administration (2)]. If dose is missed, skip the missed dose and take the next dose at the regular time. Do not take doses at the same time [see Dosage and Administration (2)]. To keep IBSRELA in dry place. Protect from moisture. Keep in the original bottle. Do not remove desiccant from the bottle. Do not subdivide or repackage. Keep bottles tightly closed [see How Supplied/Storage and Handling (16)]. To take IBSRELA immediately prior to breakfast or the first meal of the day and immediately before dinner [see Dosage and Administration (2)].. If dose is missed, skip the missed dose and take the next dose at the regular time. Do not take doses at the same time [see Dosage and Administration (2)].. To keep IBSRELA in dry place. Protect from moisture. Keep in the original bottle. Do not remove desiccant from the bottle. Do not subdivide or repackage. Keep bottles tightly closed [see How Supplied/Storage and Handling (16)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 minimally 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 clinically relevant exposure to breastfed infants. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for IBSRELA and any potential adverse effects on the breastfed infant from IBSRELA or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Tenapanor is locally acting inhibitor of the sodium/hydrogen exchanger (NHE3), an antiporter expressed on the apical surface of the small intestine and colon primarily responsible for the absorption of dietary sodium. In vitro and animal studies indicate its major metabolite, M1, is not active against NHE3. By inhibiting NHE3 on the apical surface of the enterocytes, tenapanor reduces absorption of sodium from the small intestine and colon, resulting in an increase in water secretion into the intestinal lumen, which accelerates intestinal transit time and results in softer stool consistency.Tenapanor has also been shown to reduce abdominal pain by decreasing visceral hypersensitivity and by decreasing intestinal permeability in animal models. In rat model of colonic hypersensitivity, tenapanor reduced visceral hyperalgesia and normalized colonic sensory neuronal excitability.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisThe carcinogenic potential of tenapanor was assessed in 6-month carcinogenicity study in Tg rasH2 mice and in 2-year carcinogenicity study in rats.Tenapanor was not tumorigenic at oral doses up to 100 mg/kg/day (approximately 4.5 times the recommended human dose, based on the body surface area) in male mice and 800 mg/kg/day (approximately 39 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 mg/kg/day (approximately 0.5 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 times the maximum recommended human dose, based on the body surface area). MutagenesisTenapanor 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. 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 0.97 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 2.4 times the recommended human dose, based on the body surface area).

OVERDOSAGE SECTION.

10 OVERDOSAGE. Based on nonclinical data, overdose of IBSRELA may result in gastrointestinal adverse effects such as diarrhea as result of exaggerated pharmacology with risk for dehydration if diarrhea is severe or prolonged [see Warnings and Precautions (5.1)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 50 mg Tablet Bottle Label 050-60. NDC 73154-050-60IBSRELA(R) (tenapanor) tablets50 mgATTENTION PHARMACIST:Dispense the accompanyingMedication Guide to each patient.Attention Pharmacist:Dispense IBSRELA(R) in originalcontainer to patient. Do not removethe desiccant from inside the bottle.60 tabletsRx Only. PRINCIPAL DISPLAY PANEL 50 mg Tablet Bottle Label 050-60.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. IBSRELA is contraindicated in patients less than years of age. Avoid IBSRELA in patients years to less than 12 years of age [see Contraindications (4), Warnings and Precautions (5.1)]. The safety and effectiveness of IBSRELA in patients less than 18 years of age have not been established.In nonclinical studies, deaths occurred in young juvenile rats (less than week-old-rats approximate human age equivalent of less than years of age) following oral administration of tenapanor, as described below in Juvenile Animal Toxicity Data.. Juvenile Animal Toxicity DataIn 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 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 second dose range finding study, tenapanor doses of 0.1, 0.5, 2.5, or mg/kg/day were administered to neonatal rats from PND through PND 24. Treatment-related mortalities were observed at 0.5, 2.5, and 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 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 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 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 mg/kg/day dose groups [see Contraindications (4), Warnings and Precautions (5.1)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyAt times the mean maximum exposure of M1 at the recommended dosage, there were no clinically relevant effects on the QTc interval.. Food EffectAdministration of IBSRELA to 10 minutes before meal increased the 24-hour stool sodium excretion compared to taking IBSRELA in the fed or fasting condition [see Dosage and Administration (2)]. In clinical trials, IBSRELA was administered immediately prior to the first meal of the day and immediately prior to dinner.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionTenapanor 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 (Cmax), and half-life (t1/2) could not be determined.. DistributionPlasma protein binding of tenapanor and its major metabolite, M1, is approximately 99% and 97%, respectively, in vitro.. Elimination. MetabolismTenapanor is metabolized primarily by CYP3A4/5 and low levels of its major metabolite, M1, are detected in plasma. The Cmax 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.. ExcretionFollowing administration of single 15 mg radiolabeled 14C-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 ImpairmentFollowing 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 Cmax 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 ImpairmentBased on cross-study comparison, plasma concentrations of M1 in end-stage renal disease patients on hemodialysis (eGFR less than 15 mL/min/1.73m2) was not notably different from those of healthy subjects given comparable doses of IBSRELA.. Drug Interaction Studies CYP Metabolism Mediated Drug InteractionsTenapanor 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 substrate was observed when IBSRELA 50 mg was administered twice day for 13 days in healthy subjects.Following co-administration of single dose of IBSRELA 50 mg with repeated doses of itraconazole 200 mg, CYP3A4 inhibitor, the mean AUC and Cmax 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.. Membrane Transporter Mediated Drug InteractionsTenapanor and M1 did not inhibit P-gp, BCRP, OATP1B1, and OATP1B3. M1 did not inhibit OAT1, OAT3, OCT2, MATE1, and MATE2-K.M1 is substrate of P-gp. Tenapanor is not substrate of P-gp, BCRP, OATP1B1, and OATP1B3. M1 is not substrate of BCRP, OAT1, OAT3, OCT2, MATE1 and MATE2-K.No significant effect on PepT1 activity using cefadroxil as substrate was observed when IBSRELA 50 mg was administered twice day for 12 days in healthy subjects.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryTenapanor is minimally 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 IBSRELA exposure from 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 0.1 times the maximum recommended human dose and in rabbits at doses up to 8.8 times the maximum recommended human dose (based on body surface area).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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.. Data. Animal DataIn 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 mg/kg/day (approximately 0.1 times the maximum recommended human dose) and in rabbits at doses up to 45 mg/kg/day (approximately 8.8 times the maximum recommended human dose, based on body surface area).In pre- and post-natal developmental study in mice, tenapanor at doses up to 200 mg/kg/day (approximately 9.7 times the maximum recommended human dose, based on body surface area) had no effect on pre- and post-natal development.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: May 2021Medication GuideIBSRELA(R) (ibs rela)(tenapanor)tablets, for oral useWhat is the most important information should know about IBSRELADo not give IBSRELA to children who are less than years of age. It may harm them.You should not give IBSRELA to patients years to less than 18 years of age. It may harm them.IBSRELA can cause severe diarrhea and your child could get severe dehydration (loss of large amount of body water and salt).See What are the possible side effects of IBSRELA for more information about side effects. What is IBSRELAIBSRELA is prescription medicine used in adults to treat:Irritable bowel syndrome with constipation (IBS-C).It is not known if IBSRELA is safe and effective in children less than 18 years of age.Who should not take IBSRELADo not give IBSRELA to children who are less than years of age. IBSRELA can cause severe diarrhea and your child could get severe dehydration (loss of large amount of body water and salt).Do not take IBSRELA if doctor has told you that you have bowel blockage (intestinal obstruction).Before you take IBSRELA, tell your doctor about all your medical conditions, including if you:are pregnant or plan to become pregnant. It is not known if IBSRELA will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if IBSRELA passes into your breast milk. Talk with your doctor about the best way to feed your baby if you take IBSRELA.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.How should take IBSRELATake IBSRELA exactly as your doctor tells you to take it.Take IBSRELA tablet by mouth, times each day.Take IBSRELA immediately before breakfast or the first meal of the day and immediately before dinner.If dose is missed, skip the missed dose and take the next dose at the regular time. Do not take doses at the same time.What are the possible side effects of IBSRELAIBSRELA can cause serious side effects, including:See What is the most important information should know about IBSRELA Diarrhea is the most common side effect of IBSRELA, and it can sometimes be severe. Stop taking IBSRELA and call your doctor if you develop severe diarrhea.The other most common side effects of IBSRELA include:swelling, or feeling of fullness or pressure in your abdomen (distension).gas (flatulence).dizziness.These are not all the possible side effects of IBSRELA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to www.fda.gov/medwatch.How should store IBSRELAStore IBSRELA at room temperature, between 68F and 77F (20C and 25C).Keep IBSRELA in the original container and protect from moisture. Keep the container of IBSRELA tightly closed and in dry place.Do not put IBSRELA in another container (repackage). The IBSRELA bottle contains desiccant canister to help keep your medicine dry (protect it from moisture). Do not remove the desiccant from the bottle.Keep IBSRELA and all medicines out of the reach of children.General information about the safe and effective use of IBSRELA.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use IBSRELA for condition for which it was not prescribed. Do not give IBSRELA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about IBSRELA that is written for health professionals.What are the ingredients in IBSRELAActive ingredient: tenapanor hydrochloride Inactive ingredients: colloidal silicon dioxide, hypromellose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, propyl gallate, stearic acid, tartaric acid, titanium dioxide, and triacetin. Manufactured for and distributed by Ardelyx, Inc. Waltham, MA 02451 USA IBSRELA(R) is registered trademark of Ardelyx, Inc.Patent: www.IBSRELA-patents.comFor more information, go to www.ardelyx.com or call 1-844-427-7352 Do not give IBSRELA to children who are less than years of age. It may harm them.. You should not give IBSRELA to patients years to less than 18 years of age. It may harm them.. Irritable bowel syndrome with constipation (IBS-C).. Do not give IBSRELA to children who are less than years of age. IBSRELA can cause severe diarrhea and your child could get severe dehydration (loss of large amount of body water and salt).. Do not take IBSRELA if doctor has told you that you have bowel blockage (intestinal obstruction).. are pregnant or plan to become pregnant. It is not known if IBSRELA will harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if IBSRELA passes into your breast milk. Talk with your doctor about the best way to feed your baby if you take IBSRELA.. Take IBSRELA exactly as your doctor tells you to take it.. Take IBSRELA tablet by mouth, times each day.. Take IBSRELA immediately before breakfast or the first meal of the day and immediately before dinner.. If dose is missed, skip the missed dose and take the next dose at the regular time. Do not take doses at the same time.. See What is the most important information should know about IBSRELA . Diarrhea is the most common side effect of IBSRELA, and it can sometimes be severe. Stop taking IBSRELA and call your doctor if you develop severe diarrhea.. swelling, or feeling of fullness or pressure in your abdomen (distension).. gas (flatulence).. dizziness.. Store IBSRELA at room temperature, between 68F and 77F (20C and 25C).. Keep IBSRELA in the original container and protect from moisture. Keep the container of IBSRELA tightly closed and in dry place.. Do not put IBSRELA in another container (repackage). The IBSRELA bottle contains desiccant canister to help keep your medicine dry (protect it from moisture). Do not remove the desiccant from the bottle.

SPL UNCLASSIFIED SECTION.

Administration InstructionsTake IBSRELA immediately prior to breakfast or the first meal of the day and immediately prior to dinner [see Clinical Pharmacology (12.2)].If dose is missed, skip the missed dose and take the next dose at the regular time. Do not take doses at the same time.. Take IBSRELA immediately prior to breakfast or the first meal of the day and immediately prior to dinner [see Clinical Pharmacology (12.2)].. If dose is missed, skip the missed dose and take the next dose at the regular time. Do not take doses at the same time.

STORAGE AND HANDLING SECTION.

StorageStore at room temperature, between 68F and 77F (20C and 25C).Keep in original container and protect from moisture. Keep the container of IBSRELA tightly closed and in dry place.Do not remove desiccant from the bottle. Do not subdivide or repackage.. Image.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryTenapanor is minimally 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 IBSRELA exposure from 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 0.1 times the maximum recommended human dose and in rabbits at doses up to 8.8 times the maximum recommended human dose (based on body surface area).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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.. Data. Animal DataIn 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 mg/kg/day (approximately 0.1 times the maximum recommended human dose) and in rabbits at doses up to 45 mg/kg/day (approximately 8.8 times the maximum recommended human dose, based on body surface area).In pre- and post-natal developmental study in mice, tenapanor at doses up to 200 mg/kg/day (approximately 9.7 times the maximum recommended human dose, based on body surface area) had no effect on pre- and post-natal development.. 8.2 Lactation. Risk SummaryThere 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 minimally 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 clinically relevant exposure to breastfed infants. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for IBSRELA and any potential adverse effects on the breastfed infant from IBSRELA or from the underlying maternal condition.. 8.4 Pediatric Use. IBSRELA is contraindicated in patients less than years of age. Avoid IBSRELA in patients years to less than 12 years of age [see Contraindications (4), Warnings and Precautions (5.1)]. The safety and effectiveness of IBSRELA in patients less than 18 years of age have not been established.In nonclinical studies, deaths occurred in young juvenile rats (less than week-old-rats approximate human age equivalent of less than years of age) following oral administration of tenapanor, as described below in Juvenile Animal Toxicity Data.. Juvenile Animal Toxicity DataIn 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 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 second dose range finding study, tenapanor doses of 0.1, 0.5, 2.5, or mg/kg/day were administered to neonatal rats from PND through PND 24. Treatment-related mortalities were observed at 0.5, 2.5, and 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 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 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 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 mg/kg/day dose groups [see Contraindications (4), Warnings and Precautions (5.1)]. 8.5 Geriatric Use. Of the 1203 patients in placebo-controlled clinical trials of IBSRELA, 100 (8%) were 65 years of age and older. No overall differences in safety or effectiveness were observed between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Diarrhea: Patients may experience severe diarrhea. If severe diarrhea occurs, suspend dosing and rehydrate patient. (5.2). 5.1Risk of Serious Dehydration in Pediatric Patients. IBSRELA is contraindicated in patients below years of age. The safety and effectiveness of IBSRELA in patients less than 18 years of age have not been established. In young juvenile rats (less than week old; approximate human age equivalent of less than years of age), decreased body weight and deaths occurred, presumed to be due to dehydration, following oral administration of tenapanor. There are no data available in older juvenile rats (human age equivalent years to less than 12 years).Avoid the use of IBSRELA in patients years to less than 12 years of age. Although there are no data in older juvenile rats, given the deaths in younger rats and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of IBSRELA in patients years to less than 12 years of age [see Contraindications (4), Warnings and Precautions (5.2), Use in Specific Populations (8.4)].. 5.2 Diarrhea Diarrhea was the most common adverse reaction in two randomized, double-blind, placebo-controlled trials of IBS-C. Severe diarrhea was reported in 2.5% of IBSRELA-treated patients [see Adverse Reactions (6.1)]. If severe diarrhea occurs, suspend dosing and rehydrate patient.

DRUG INTERACTIONS SECTION.

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). 7.1OATP2B1 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 IBSRELA. Monitor for signs related to loss of efficacy and adjust the dosage of concomitantly administered drug as needed.Enalapril is substrate of OATP2B1. When enalapril was coadministered with tenapanor (30 mg twice daily for five days, dosage 0.6 times the recommended dosage), the peak exposure (Cmax) of enalapril and its active metabolite, enalaprilat, decreased by approximately 70% and total systemic exposures (AUC) decreased by approximately 50% to 65% compared to when enalapril was administered alone [see Clinical Pharmacology (12.3)].Monitor blood pressure and increase the dosage of enalapril, if needed, when IBSRELA is coadministered with enalapril.