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Tenapanor

Class: GI Drugs, Miscellaneous
- NHE3 Inhibitor
- Sodium/Hydrogen Exchanger Inhibitor
Chemical Name: 1,1′-(Butane-1,4-diyl)bis{3-[2-(2-{2-[({3-[(4S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl}sulfonyl)amino]ethoxy}ethoxy)ethyl]urea} dihydrochloride
Molecular Formula: C50H68Cl6N8O10S2
CAS Number: 1234365-97-9
Brands: Ibsrela

Medically reviewed by Drugs.com. Last updated on May 25, 2020.

Warning

  • Contraindicated in pediatric patients <6 years of age; avoid use in children 6 to <12 years of age.1 Tenapanor caused deaths, presumably due to dehydration, in young juvenile rats.1 (See Pediatric Use under Cautions.)

  • Safety and efficacy not established in patients <18 years of age.1

Introduction

Locally acting inhibitor of sodium/hydrogen exchanger isoform 3 (NHE3), a protein that facilitates absorption of intestinal sodium through proton exchange.1 5 6 7 8

Uses for Tenapanor

Irritable Bowel Syndrome (IBS) with Constipation

Symptomatic treatment of IBS with constipation in adults.1 2 7

Tenapanor Dosage and Administration

Administration

Oral Administration

Administer orally twice daily, immediately prior to breakfast or the first meal of the day and immediately prior to dinner.1 Administration 5–10 minutes before a meal increases 24-hour stool sodium excretion compared with administration under fed or fasting conditions.1 9

If a dose is missed, omit the missed dose and administer the next dose at the regularly scheduled time.1 Do not administer 2 doses at the same time to make up for a missed dose.1

Dosage

Available as tenapanor hydrochloride; dosage expressed in terms of tenapanor.1

Adults

IBS with Constipation
Oral

50 mg twice daily.1

Special Populations

Hepatic Impairment

Manufacturer makes no specific dosage recommendations.1 (See Elimination Route under Pharmacokinetics.)

Renal Impairment

Manufacturer makes no specific dosage recommendations.1 (See Renal Impairment under Cautions.)

Geriatric Patients

Manufacturer makes no specific dosage recommendations.1 (See Geriatric Use under Cautions.)

Cautions for Tenapanor

Contraindications

  • Pediatric patients <6 years of age.1 (See Pediatric Use under Cautions.)

  • Known or suspected mechanical GI obstruction.1

Warnings/Precautions

Warnings

Pediatric Risk

Lethality reported in young juvenile rats.1 Contraindicated in pediatric patients <6 years of age; avoid use in children 6 to <12 years of age.1 (See Pediatric Use under Cautions.)

Other Warnings and Precautions

Diarrhea

In clinical trials in patients with IBS with constipation, diarrhea or severe diarrhea reported in 15–16 or 2.5%, respectively, of patients receiving tenapanor and 2–4 or 0.2%, respectively, of those receiving placebo.1

Suspend tenapanor therapy and rehydrate patient if severe diarrhea develops.1

Specific Populations

Pregnancy

Minimally absorbed following oral administration (see Absorption under Pharmacokinetics); not expected to result in fetal exposure if administered to pregnant women.1 Limited data regarding tenapanor exposure during pregnancy have not identified any drug-associated risk for major birth defects, spontaneous abortion, or adverse maternal or fetal outcomes.1

No adverse fetal or prenatal/postnatal developmental effects observed in animal studies.1

Lactation

Not known whether tenapanor distributes into milk, affects milk production, or affects breast-fed infants.1

Manufacturer states that the minimal systemic absorption following oral administration (see Absorption under Pharmacokinetics) will not result in clinically important exposure to breast-fed infants.1

Consider benefits of breast-feeding along with the woman's clinical need for tenapanor and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1 (See Pediatric Use under Cautions.)

Pediatric Use

Contraindicated in pediatric patients <6 years of age; avoid use in children 6 to <12 years of age.1 Safety and efficacy in patients <18 years of age not established.1

Deaths reported in juvenile rats (age approximately equivalent to human age of <2 years).1 Data lacking in older juvenile rats (age approximately equivalent to human age of 2 to <12 years).1

One toxicology study in neonatal rats terminated early because of deaths and decreased body weight at dosages of 5–10 mg/kg daily.1

In second study in neonatal rats receiving tenapanor (0.1–5 mg/kg daily on postnatal days 5–24), deaths observed at dosages of 0.5–5 mg/kg daily as early as postnatal day 8; most deaths occurred between postnatal days 15 and 25.1 At 5-mg/kg dosage, mean body weight decreased by 35–47% compared with controls.1 At dosages of 0.5–5 mg/kg daily, slight (5–11%) reductions in mean tibial length (correlated with decrements in body weight); decreased spleen, thymus, and/or ovary weight; GI distension; and microscopic findings of increased osteoclasts, eroded bone, and/or decreased bone in sternum and/or femorotibial joint observed.1

Geriatric Use

No overall differences in efficacy or safety observed between geriatric patients and younger adults; however, possibility of increased sensitivity to the drug cannot be ruled out.1

Renal Impairment

Diarrhea reported in 20 or 0.6% of patients with renal impairment (eGFR <90 mL/minute per 1.73 m2) receiving tenapanor or placebo, respectively, compared with 13 or 3.5% of patients with normal renal function receiving these respective treatments.1 Incidence of diarrhea and severe diarrhea in tenapanor-treated patients did not correspond to severity of renal impairment.1 No other differences in safety observed in patients with renal impairment.1 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Diarrhea, abdominal distension, flatulence, dizziness.1

Interactions for Tenapanor

Metabolized principally by CYP3A4/5.1

Tenapanor and M1 (major metabolite) do not inhibit CYP isoenzyme 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 and do not induce CYP isoenzyme 1A2 or 2B6 in vitro.1

Tenapanor does not appear to inhibit or induce CYP3A4 in vivo.1 4

Tenapanor and M1 do not inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or organic anion transport polypeptide (OATP) 1B1 or 1B3.1 M1 does not inhibit organic anion transporter (OAT) 1 or 3, organic cation transporter (OCT) 2, or multidrug and toxin extrusion transporter (MATE) 1 or 2-K.1

Tenapanor is not a substrate of P-gp, BCRP, OATP1B1, or OATP1B3.1 M1 is a substrate of P-gp but is not a substrate of BCRP, OAT1, OAT3, OCT2, MATE-1, or MATE2-K.1

Specific Drugs

Drug

Interaction

Comments

Cefadroxil

No change in pharmacokinetics of cefadroxil (peptide transporter 1 substrate)1 4 8

Itraconazole

Decreased AUC and peak plasma concentration of M1 metabolite1 4

Effect of itraconazole (CYP3A4 inhibitor) on M1 exposure not considered clinically important since M1 is pharmacologically inactive4

Midazolam

No change in pharmacokinetics of midazolam (CYP3A4 substrate)1 4

Tenapanor Pharmacokinetics

Absorption

Bioavailability

Minimally absorbed following oral administration.1 Plasma tenapanor concentrations below limit of quantitation in most samples obtained following oral administration of single or repeated (50 mg twice daily) doses.1

AUC and peak plasma concentration not determined because of minimal systemic absorption.1

Distribution

Extent

Not known whether distributed into milk.1

Plasma Protein Binding

Tenapanor: Approximately 99% (in vitro).1

M1: Approximately 97% (in vitro).1

Elimination

Metabolism

Metabolized principally by CYP3A4/5; major metabolite, M1 (not active against NHE3), is detected at low concentrations in plasma.1

Elimination Route

Approximately 70 or 79% of dose eliminated in feces within 120 or 240 hours, respectively, mostly (65% within 144 hours) as unchanged drug.1 Approximately 9% of dose recovered in urine, mainly as metabolites; 1.5% recovered in urine as M1 within 144 hours.1

Half-life

Half-life not determined because of minimal systemic absorption.1

Special Populations

End-stage renal disease requiring hemodialysis (eGFR <15 mL/minute per 1.73 m2): Plasma concentrations of M1 not substantially different from those in healthy individuals.1

Stability

Storage

Oral

Tablets

20–25°C in original container in a dry place, with lid tightly closed, to protect from moisture; do not remove desiccant from container; do not subdivide or repackage.1

Actions

  • Locally acting inhibitor of sodium/hydrogen exchanger isoform 3 (NHE3), which is expressed on apical surface of the small intestine and colon and is primarily responsible for absorption of dietary sodium from the intestinal lumen through proton exchange.1 3 5 6 7 8

  • Intestinal inhibition of NHE3 by tenapanor reduces sodium absorption from the small intestine and colon, resulting in increased water secretion into the intestinal lumen, which accelerates intestinal transit and softens stool.1 3 5 6 7

  • Reduced abdominal pain by decreasing visceral hypersensitivity and intestinal permeability in animal models.1 Reduced visceral hyperalgesia and normalized colonic sensory neuronal excitability in rat model of colonic hypersensitivity.1

Advice to Patients

  • Importance of reading the manufacturer's patient information (medication guide).1

  • Instruct patients to discontinue tenapanor and contact their clinician if severe diarrhea occurs.1

  • Importance of advising patients that accidental ingestion of tenapanor by a child, especially a child <6 years of age, may result in severe diarrhea and dehydration; importance of storing tenapanor securely out of the reach of children.1

  • Instruct patients to take tenapanor twice daily, immediately prior to breakfast or the first meal of the day and immediately before dinner.1

  • Advise patients that if a dose is missed, the missed dose should be omitted and the next dose taken at the regularly scheduled time.1 Two doses should not be taken at the same time to make up for a missed dose.1

  • Importance of storing tenapanor in the original container in a dry place, with the lid tightly closed, to protect the contents from moisture; importance of not removing the desiccant from the container and of not repackaging the tablets or subdividing the contents of the container.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Tenapanor Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

50 mg (of tenapanor)

Ibsrela

Ardelyx

AHFS DI Essentials™. © Copyright 2021, Selected Revisions May 25, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Ardelyx, Inc. Ibsrela (tenapanor hydrochloride) tablets prescribing information. Fremont, CA; 2019 Sep.

2. Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020; 115:281-293. http://www.ncbi.nlm.nih.gov/pubmed/31934897?dopt=AbstractPlus

3. Zielinska M, Wasilewski A, Fichna J. Tenapanor hydrochloride for the treatment of constipation-predominant irritable bowel syndrome. Expert Opin Investig Drugs. 2015; 24:1093-9. http://www.ncbi.nlm.nih.gov/pubmed/26065434?dopt=AbstractPlus

4. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 211801Orig1s000: Multi-discipline review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211801Orig1s000MultidisciplineR.pdf

5. Nusrat S, Miner PB. New pharmacological treatment options for irritable bowel syndrome with constipation. Expert Opin Emerg Drugs. 2015; 20:625-36. http://www.ncbi.nlm.nih.gov/pubmed/26548544?dopt=AbstractPlus

6. Rosenbaum DP, Yan A, Jacobs JW. Pharmacodynamics, Safety, and Tolerability of the NHE3 Inhibitor Tenapanor: Two Trials in Healthy Volunteers. Clin Drug Investig. 2018; 38:341-351. http://www.ncbi.nlm.nih.gov/pubmed/29363027?dopt=AbstractPlus

7. Chey WD, Lembo AJ, Rosenbaum DP. Tenapanor Treatment of Patients With Constipation-Predominant Irritable Bowel Syndrome: A Phase 2, Randomized, Placebo-Controlled Efficacy and Safety Trial. Am J Gastroenterol. 2017; 112:763-774. http://www.ncbi.nlm.nih.gov/pubmed/28244495?dopt=AbstractPlus

8. Johansson S, Rosenbaum DP, Palm J et al. Tenapanor administration and the activity of the H+-coupled transporter PepT1 in healthy volunteers. Br J Clin Pharmacol. 2017; 83:2008-2014. http://www.ncbi.nlm.nih.gov/pubmed/28432691?dopt=AbstractPlus

9. Johansson SA, Knutsson M, Leonsson-Zachrisson M et al. Effect of Food Intake on the Pharmacodynamics of Tenapanor: A Phase 1 Study. Clin Pharmacol Drug Dev. 2017; 6:457-465. http://www.ncbi.nlm.nih.gov/pubmed/28339149?dopt=AbstractPlus

10. A 26-week study to evaluate the efficacy and safety of tenapanor in IBS-C (T3MPO-2). From ClinicalTrials.gov website. Accessed 2020 Feb 20. https://clinicaltrials.gov/ct2/show/NCT02686138