Xphozah (tenapanor HCl)

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

Tenapanor is administered orally as tablets.

Tenapanor should be taken just prior to the first and last meals of the day.

Tenapanor should not be taken right before a hemodialysis session, and instead should be taken right before the next meal following dialysis, as patients may experience diarrhea after taking tenapanor.

If a dose of tenapanor is missed, skip the missed dose and take the next dose at the regular time.

Store tenapanor tablets at 20-25degreesC; excursions permitted between 15-30degreesC. Keep bottle tightly closed to protect from moisture. Store and dispense in original bottle with the desiccant.

No dosing information is available for this tab.

Tenapanor and its primary metabolite, M1, do not inhibit cytochrome P-450 (CYP) 1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Tenapanor and M1 do not induce CYP1A2 and CYP2B6.

Tenapanor is not a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 2B1, and OATP1B3. The primary metabolite, M1, is a substrate of P-gp.

Tenapanor is an inhibitor of intestinal uptake transporter OATP2B1.

Tenapanor is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, and peptide transporter (PEPT) 1. M1 does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, multidrug and toxin extrusion (MATE) 1, and MATE2-K.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Phosphate Reducers/Phosphate Supplements;Urine Ph Modifiers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lanthanum and sevelamer bind to phosphate.(1-2) Tenapanor is a sodium/hydrogen exchanger 3 (NHE3) inhibitor.(3) All three agents are used to lower phosphate absorption in the body.(1-3)

CLINICAL EFFECTS: Concurrent use of phosphate supplements or urinary pH modifiers high in phosphate with agents that reduce serum phosphorus may decrease the effectiveness of both agents.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients should normally not receive phosphate supplements or urinary pH modifiers high in phosphate concurrently with agents that reduce serum phosphorus.

DISCUSSION: Lanthanum, sevelamer, and tenapanor are indicated to control phosphorus levels. Consider discontinuing or holding phosphate supplements and urinary pH modifiers high in phosphate in patients receiving these agents.

Serum Phosphate Level-Altering Drugs/Erdafitinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Medications that alter serum phosphate may interfere with interpretation of phosphate levels that are needed to determine initial erdafitinib dose.(1)

CLINICAL EFFECTS: Serum phosphate levels that are elevated by concomitant medications may result in an inappropriately low dose and decreased effectiveness of erdafitinib. Serum phosphate levels that are decreased by concomitant medications may result in an inappropriately high dose and increased toxicity from erdafitinib.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of erdafitinib states that agents that alter serum phosphate levels should be avoided before the initial dose increase period for erdafitinib based on serum phosphate levels (days 14 to 21).(1)

DISCUSSION: Concomitant administration of serum phosphate level-altering agents during the initial dose increase period of erdafitinib based on serum phosphate levels (days 14 to 21) may interfere with serum phospate levels and lead to incorrect dosing of erdafitinib.(1) Agents that may alter serum phosphate levels linked to this monograph include: aluminum carbonate, aluminum hydroxide, calcium acetate, calcium carbonate, calcium citrate, cod liver oil, ferric citrate, lanthanum, magnesium carbonate, magnesium hydroxide, potassium phosphate, sevelamer, sodium phosphate, sucroferric oxyhydroxide, tenapanor, and vitamin D.(1)

Tenapanor/Laxatives; Stool Softeners

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tenapanor commonly causes diarrhea of mild to moderate severity. Laxatives and stool softeners may increase the incidence or severity of diarrhea.(1)

CLINICAL EFFECTS: Concurrent use of laxatives or stool softeners with tenapanor may increase the risk of severe diarrhea.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of tenapanor states that patients should be instructed to avoid stool softeners and laxatives with tenapanor. If severe diarrhea occurs, tenapanor should be discontinued.(1)

DISCUSSION: In clinical trials, 43-53% of CKD patients on dialysis treated with tenapanor developed diarrhea. Diarrhea usually occurred soon after treatment initiation and was severe in 5% of patients.(1)

There are no moderate interactions for this drug.

*Pediatric patients less than 6 years of age due to risk of diarrhea and severe dehydration.

*Known or suspected mechanical GI obstruction.

• Gastrointestinal obstruction

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

The most common adverse effect of tenapanor reported in clinical trials was diarrhea (43--53%).

Rare or Very Rare

• Dehydration
• Rectal bleeding

More Frequent

• Abdominal distension
• Diarrhea
• Dizziness
• Flatulence

Rare or Very Rare

• Bowel sounds hyperactive
• Pruritus of skin
• Skin rash
• Urticaria

No enhanced messaging available.

Safety and effectiveness of tenapanor in pediatric patients have not been established. Tenapanor is contraindicated in patients less than 6 years of age.

In nonclinical studies, deaths occurred in young juvenile rats (approximate human age equivalent of less than 2 years) and in older juvenile rats (approximate human age equivalent of 2 years) following oral administration of tenapanor. In a 21-day oral dose range toxicity study in juvenile rats, tenapanor was administered to neonatal rats (post-natal day 5) at doses of 5 and 10 mg/kg per day. Tenapanor was not tolerated in male and female pups and the study was terminated on post-natal day 16 due to mortalities and decreased body weight. Compared to the control group, 24% and 29% of female pups in the 5 mg/kg per day and 10 mg/kg per day groups, respectively, experienced decreased body weight; 33% of male pups that received 10 mg/kg per day experienced decreased body weight. In a second dose range finding study, tenapanor at dosages of 0.1, 0.5, 2.5, or 5 mg/kg per day were administered to neonatal rats from post-natal day 5 through post-natal day 24. Treatment-related mortalities were observed at 0.5, 2.5, and 5 mg/kg per day. Premature deaths were observed as early as post-natal day 8, with the majority of deaths occurring between post-natal day 15 and 25. In the 5 mg/kg per day group, mean body weights were 47% lower for males on post-natal day 23 and 35% lower for females on post-natal day 22 when compared to the control group. Other findings included slightly lower mean tibial lengths; lower spleen, thymus, and/or ovarian weights; GI distension; and microscopic bone findings of increased osteoclasts, eroded bone, and/or decreased bone in sternum and/or femorotibial joint in the 0.5, 2.5, and 5 mg/kg per day groups.

In juvenile rats administered tenapanor at 0.03, 0.1, or 0.3 mg/kg per day on post-natal day 5 through post-natal day 61, treatment-related mortalities were observed at 0.3 mg/kg per day. Lower mean body weight gains were noted in the 0.3 mg/kg per day group in addition to decreased food consumption, resulting in mean body weights up to 15.8% and 16.8% lower in males and females, respectively, compared to the control group. There were no tenapanor-related effects of mean body weights, body weight gains, or food consumption in the 0.03 and 0.1 mg/kg per day groups. A dosage of 0.1 mg/kg per day was considered to be the No Observed Adverse Effect Level (NOAEL) for juvenile toxicity of tenapanor. In weaned juvenile rats administered tenapanor 0.1, 0.3, and 0.7 (males) or 1 (females) mg/kg per day on post-natal days 21 through 80, no mortalities were observed. Significant decreases in mean body weights were observed in the 0.3 and 0.7 mg/kg per day males throughout the dosing period and in the 1 mg/kg per day females between postnatal days 23 to 35, with food consumption notably decreased between post-natal days 21 to 29. The NOAEL was considered to be 0.1 mg/kg per day for juvenile toxicity of tenapanor.

Tenapanor is essentially non-absorbed systemically, with plasma concentrations below the limit of quantification (less than 0.5 ng/mL) following oral administration. Therefore, maternal use 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.

In reproduction studies in pregnant rats and rabbits, no adverse fetal effects were observed in rats at 0.2 times the maximum recommended human dose and in rabbits up to 15 times the maximum recommended human dose (based on body surface area). In a pre- and post-natal development study in mice, tenapanor at doses up to 200 mg/kg per day (approximately 16.5 times the maximum recommended human dose based on body surface area) had no effect on pre- and post-natal development.

There are no data on the presence of tenapanor in human milk, the effects on the breast-fed child, or the effects on milk production. The minimal systemic absorption of tenapanor will not result in a clinically relevant exposure to breast-fed infants. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for tenapanor or any potential adverse effects on the breast-fed infant from tenapanor or from the underlying maternal condition.

The manufacturer makes no specific dosage recommendations for geriatric patients.

Clinical studies with tenapanor did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently than younger patients. Among 1,010 patients with CKD on dialysis who were treated with tenapanor or tenapanor in combination with phosphate binders, 282 (28%) patients were 65 years of age and older.