Tenapanor is an oral sodium/hydrogen exchanger 3 (NHE3) inhibitor indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults and to reduce serum phosphate concentrations in adults with chronic kidney disease (CKD) on dialysis as add-on therapy in persons who have an inadequate response to phosphate binders or who are intolerant of any dose of phosphate binders. Tenapanor acts locally in the gastrointestinal tract to decrease sodium and phosphate absorption. Unlike other treatments for hyperphosphatemia, tenapanor is not a phosphate binder; it is a phosphate absorption inhibitor. In 2 clinical trials (n = 1,226) for IBS-C, tenapanor demonstrated a statistically significant reduction in constipation and abdominal pain in adults with IBS-C. The primary endpoints were at least a 30% reduction in the weekly average abdominal pain score compared with baseline and an increase of at least 1 complete spontaneous bowel movement (CSBM) in weekly average from baseline, in the same week, for at least 6 of the first 12 treatment weeks. In both trials, subjects receiving tenapanor met the primary endpoints (27% or 37% vs. 19% or 24% placebo). In 3 clinical trials for the treatment of hyperphosphatemia, tenapanor significantly reduced elevated serum phosphorus in subjects with CKD on dialysis. During the randomized withdrawal phase in 2 studies (n = 783), the serum phosphorus concentration significantly increased by 0.7 mg/dL in the placebo group compared to subjects who remained on tenapanor. In another study (n = 236) with tenapanor as add-on therapy in subjects on stable phosphate-binder therapy, the serum phosphorus concentration decreased by 0.7 mg/dL in the add-on tenapanor group compared to the add-on placebo group (95% CI: 0.3 to 1; p = 0.0004). Tenapanor has been shown to increase the proportion achieving target serum phosphorous concentrations in persons not adequately responding to phosphate binder therapy. Diarrhea was the most common adverse reaction reported with tenapanor in clinical trials and may be associated with dehydration.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Administer immediately before breakfast or the first meal of the day and immediately before dinner or the last meal of the day.
-Missed dose: 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.
-Xphozah (for hyperphosphatemia treatment): On dialysis days, administer immediately before the next meal after dialysis. Do not administer right before a hemodialysis session.
Diarrhea (13% to 53%) was the most common adverse reaction in clinical trials with tenapanor. Diarrhea was typically reported soon after initiation but could occur at any time during treatment. The majority of diarrhea events in tenapanor-treated subjects in clinical trials were reported to be mild-to-moderate in severity and resolved over time, or with dose reduction. Severe diarrhea was reported in 2.5% to 5% of tenapanor-treated subjects and was associated with dehydration and hyponatremia in less than 1%. Discontinue tenapanor treatment and initiate rehydration if severe diarrhea occurs. Diarrhea was the most common adverse reaction leading to treatment discontinuation. In clinical trials, diarrhea was reported in 43% to 53% of tenapanor-treated subjects with chronic kidney disease and hyperphosphatemia. Diarrhea was reported more frequently in tenapanor-treated subjects with irritable bowel syndrome with constipation (IBS-C) and renal impairment (20%), defined as eGFR less than 90 mL/minute/1.73 m2, vs. subjects with normal renal function (13%); however, the incidence of diarrhea and severe diarrhea in tenapanor-treated subjects with IBS-C did not correspond to the severity of renal impairment. No other differences in the safety profile were reported in the renally impaired subgroup. Other gastrointestinal-related adverse reactions reported with tenapanor in clinical trials include abdominal distension (2% to 3%), flatulence (3%), rectal GI bleeding (less than 2%), and abnormal gastrointestinal sounds (less than 2%).
In a clinical trial of subjects with chronic kidney disease, defined as eGFR from 25 to 70 mL/minute/1.73 m2, and type 2 diabetes mellitus, serious hyperkalemia resulting in hospitalization was reported in 3 subjects (2 tenapanor-treated subjects vs. 1 placebo-treated subject).
Dizziness was reported in 2% of subjects receiving tenapanor in clinical trials.
Tenapanor is contraindicated in persons with known or suspected mechanical GI obstruction.
Tenapanor is contraindicated in neonates, infants, and children younger than 6 years because of the risk of diarrhea and serious dehydration. In nonclinical studies, decreased body weight and deaths, presumed to be due to dehydration, occurred in young juvenile rats (younger than 1 week; approximately equivalent to human children younger than 2 years) after administration of tenapanor. Although there are no data in older juvenile rats (human age equivalent 2 to 11 years), given the deaths in younger rats and the lack of clinical safety and efficacy data in pediatric populations, avoid tenapanor use in children 6 to 11 years. The safety and efficacy of tenapanor have not been established in any pediatric patient population.
Maternal use of tenapanor during pregnancy is not expected to result in fetal exposure to the drug. The available data on tenapanor exposure from a small number of pregnant women have not identified any drug associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Tenapanor is minimally absorbed systemically, with plasma concentrations below the limit of quantification (less than 0.5 ng/mL) after oral administration. In reproduction studies with tenapanor in pregnant rats and rabbits, no adverse fetal effects were observed in rats at 0.2 times the maximum recommended human dose (MRHD) and in rabbits at doses up to 15 times the MRHD (based on body surface area).
The minimal maternal systemic absorption of tenapanor when used by the lactating mother during breast-feeding will not result in a clinically relevant exposure to breast-fed infants. Tenapanor is minimally absorbed systemically, with plasma concentrations below the limit of quantification (less than 0.5 ng/mL) after oral administration. However, 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 breast-fed infant. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for tenapanor and any potential adverse effects on the breast-fed infant from tenapanor or the underlying maternal condition.
For the treatment of irritable bowel syndrome with constipation (IBS-C):
Oral dosage (Ibsrela):
Adults: 50 mg PO twice daily.
For the treatment of hyperphosphatemia associated with dialysis-dependent chronic kidney disease as add-on therapy in persons who have inadequate response or are intolerant to phosphate binders:
Oral dosage (Xphozah):
Adults: 30 mg PO twice daily, initially. Adjust dose based on serum phosphorus and gastrointestinal tolerability. Dose range: 10 to 30 mg PO twice daily.
Maximum Dosage Limits:
-Adults
100 mg/day PO for IBS-C (Ibsrela); 60 mg/day PO for hyperphosphatemia (Xphozah).
-Geriatric
100 mg/day PO for IBS-C (Ibsrela); 60 mg/day PO for hyperphosphatemia (Xphozah).
-Adolescents
Safety and efficacy have not been established.
-Children
6 to 12 years: Avoid use.
1 to 5 years: Contraindicated.
-Infants
Contraindicated.
-Neonates
Contraindicated.
Patients with Hepatic Impairment Dosing
No dosage adjustments are needed.
Patients with Renal Impairment Dosing
No dosage adjustments are needed.
*non-FDA-approved indication
Anticholinergics: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Atropine: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Atropine; Difenoxin: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Belladonna; Opium: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Benztropine: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Chlordiazepoxide; Clidinium: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Dicyclomine: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Diphenoxylate; Atropine: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Enalapril, Enalaprilat: (Moderate) Monitor for loss of efficacy of enalapril, including blood pressure, if coadministered with tenapanor and increase the enalapril dose if needed. Coadministration may reduce exposure of enalapril and its active metabolite, enalaprilat. However, in persons with chronic kidney disease (CKD) on dialysis receiving tenapanor for hyperphosphatemia, the decrease in enalaprilat exposure with tenapanor may be offset by the inherently higher exposures observed due to its reduced renal clearance in this population. Therefore, a lower starting dose of enalapril, which is otherwise recommended in persons with CKD on dialysis, is not required when enalapril is coadministered with tenapanor in persons with CKD on dialysis. Tenapanor is an inhibitor of intestinal uptake transporter, OATP2B1 and enalapril is an OATP2B1 substrate. Coadministration decreased the exposure of enalapril by 50% to 65%.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for loss of efficacy of enalapril, including blood pressure, if coadministered with tenapanor and increase the enalapril dose if needed. Coadministration may reduce exposure of enalapril and its active metabolite, enalaprilat. However, in persons with chronic kidney disease (CKD) on dialysis receiving tenapanor for hyperphosphatemia, the decrease in enalaprilat exposure with tenapanor may be offset by the inherently higher exposures observed due to its reduced renal clearance in this population. Therefore, a lower starting dose of enalapril, which is otherwise recommended in persons with CKD on dialysis, is not required when enalapril is coadministered with tenapanor in persons with CKD on dialysis. Tenapanor is an inhibitor of intestinal uptake transporter, OATP2B1 and enalapril is an OATP2B1 substrate. Coadministration decreased the exposure of enalapril by 50% to 65%.
Flavoxate: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Glycopyrrolate: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Glycopyrrolate; Formoterol: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Homatropine; Hydrocodone: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Hyoscyamine: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Indacaterol; Glycopyrrolate: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Methscopolamine: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Neostigmine; Glycopyrrolate: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Oxybutynin: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Propantheline: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Scopolamine: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Sodium Polystyrene Sulfonate: (Moderate) Separate administration of tenapanor and sodium polystyrene sulfonate by at least 3 hours. Sodium polystyrene sulfonate may bind to tenapanor and reduce its efficacy.
Trihexyphenidyl: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Tenapanor is a locally acting inhibitor of the sodium/hydrogen exchanger 3 (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.
Hyperphosphatemia
Inhibition of NHE3 by tenapanor results in decreased phosphate absorption by reducing phosphate permeability through the paracellular pathway.
Irritable bowel syndrome with constipation (IBS-C)
Inhibition NHE3 on the apical surface of the enterocytes 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 a 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 a rat model of colonic hypersensitivity, tenapanor reduced visceral hyperalgesia and normalized colonic sensory neuronal excitability.
Tenapanor is administered orally. Tenapanor and its major metabolite, M1, are highly protein bound (99% and 97%, respectively). Tenapanor is metabolized primarily by CYP3A4/5 and low concentrations of its major metabolite, M1, are detected in plasma. In healthy subjects, the Cmax of M1 is approximately 3 and 13 ng/mL after single doses of tenapanor 30 and 50 mg, respectively. At steady-state, the Cmax of M1 is 14 and 15 ng/mL after repeated twice-daily dosing of tenapanor 30 and 50 mg, respectively. After administration of a single 15 mg radiolabeled 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.
Affected cytochrome P450 isoenzymes (CYP450) and drug transporters: OATP2B1
Tenapanor and its major metabolite, M1, have no clinically significant interactions with CYP450 isoenzymes. Inhibitors and inducers of these enzymes are unlikely to affect tenapanor activity. After oral administration, tenapanor and its metabolite are minimally absorbed into the systemic circulation. Tenapanor is an inhibitor of the intestinal uptake transporter OATP2B1 and may reduce exposures to drugs which are OATP2B1 substrates when given concomitantly.
-Route-Specific Pharmacokinetics
Oral Route
Tenapanor is minimally absorbed into the systemic circulation after repeated twice daily oral administration. The AUC, Cmax, and half-life could not be determined because the plasma concentrations of tenapanor were below the limit of quantitation (less than 0.5 ng/mL) in the majority of samples from healthy subjects after single and repeated oral administration of tenapanor 30 or 50 mg twice daily. Administration of tenapanor 5 to 10 minutes before a meal increased the 24-hour stool sodium and phosphorus excretion compared to taking the drug in the fed or fasting condition. In clinical trials, tenapanor was administered immediately before the first meal of the day and immediately before dinner.
-Special Populations
Hepatic Impairment
After a single dose of tenapanor 100 mg in subjects with moderate hepatic impairment (Child-Pugh B), plasma concentrations of tenapanor were mostly below the limit of quantitation (less than 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 subjects with moderate hepatic impairment compared to those of healthy subjects. However, the decrease in M1 systemic exposure is not clinically relevant.
Renal Impairment
Based on a cross-study comparison, plasma concentrations of the M1 metabolite in subjects with end-stage renal disease on hemodialysis (eGFR less than 15 mL/minute/1.73 m2) were not notably different from those of healthy subjects given comparable doses of tenapanor.