harmacology (12.3) ] . monitor blood pressure and increase the dosage of enalapril, if needed, when ibsrela is coadministered with enalapril.

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.

ported 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).

harmacology (12.3) ] . monitor blood pressure and increase the dosage of enalapril, if needed, when ibsrela is coadministered with enalapril.

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 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 0.1 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 a 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 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 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 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 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 6 years of age. avoid ibsrela in patients 6 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 1 week-old-rats approximate human age equivalent of less than 2 years of age) following oral administration of tenapanor, as described below in juvenile animal toxicity data. 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 [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.

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 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 0.1 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 a 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.

g/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 [see contraindications (4) , warnings and precautions (5.1) ].

imes the mean maximum exposure of m1 at the recommended dosage, there were no clinically relevant effects on the qtc interval. food effect administration of ibsrela 5 to 10 minutes before a 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 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) ] .

le 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) ] .

s) 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).

omosomal 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).

csbm is defined as a spontaneous bowel movement (sbm) that is associated with a sense of complete evacuation (an sbm is a bowel movement occurring in the absence of laxative use) less than or equal to 5 sbms per week the trial designs were identical through the first 12 weeks of treatment, and thereafter differed in that trial 1 continued for an additional 14 weeks of treatment (26 weeks double-blind treatment), whereas trial 2 included a 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 a responder was defined as a patient achieving both the stool frequency and abdominal pain intensity responder criteria in the same week for at least 6 of the first 12 weeks of treatment. the stool frequency (csbm) and abdominal pain responder criteria assessed each week were defined as: csbm responder: a patient who experienced an increase of at least 1 csbm in weekly average from baseline. abdominal pain responder: a patient who experienced at least a 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 1 and trial 2) in adults with ibs-c: responder for at least 6 of the first 12 weeks of treatment trial 1 ibsrela n=293 placebo n=300 treatment difference [95% ci ci: confidence interval ] responder a responder for these trials was defined as a patient who met both the abdominal pain and csbm weekly responder criteria for at least 6 of the first 12 weeks. 37% 24% 13% [6%, 20%] components of responder endpoint: csbm responder a csbm responder was defined as a patient who achieved an increase in at least 1 csbm per week, from baseline, for a least 6 of at least 12 weeks. 47% 33% abdominal pain responder an abdominal pain responder was defined as a patient who met the criteria of at least 30% reduction from baseline in weekly average of the worst daily abdominal pain, for at least 6 of the first 12 weeks. 50% 38% trial 2 responder rates ibsrela n=307 placebo n=299 treatment difference [95% ci ] responder 27% 19% 8% [2%, 15%] components of responder endpoint: csbm responder 34% 29% abdominal pain responder 44% 33% in trials 1 and 2, the proportion of responders for 9 out of the first 12 weeks, including at least 3 of the last 4 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 4 weeks . patients on placebo who were re-randomized to ibsrela had an average increase in csbm frequency and a decrease in abdominal pain.

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) ].