Xermelo
(telotristat ethyl)Dosage & Administration
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Xermelo Prescribing Information
Xermelo is indicated for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy.
The recommended dosage of Xermelo in adult patients is 250 mg three times daily for patients whose diarrhea is inadequately controlled by SSA therapy.
Administration
- Take Xermelo with food [see Clinical Pharmacology , Clinical Studies ].
- When short-acting octreotide is used in combination with Xermelo, administer short-acting octreotide at least 30 minutes after administering Xermelo [see Drug Interactions ].
- If a dose is missed, take the next dose at the regular time. Do not take 2 doses at the same time to make up for a missed dose.
- Discontinue Xermelo if severe constipation develops [see Warnings and Precautions ].
Tablets: 250 mg telotristat ethyl; white to off-white, coated and oval with “T-E” debossed on one side and “250” debossed on the other side.
Pregnancy
Risk Summary
There are no human data with Xermelo use in pregnant women to inform a drug-associated risk. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of oral telotristat ethyl to rats during organogenesis at doses up to 750 mg/kg/day (approximately 9 times the exposure at the RHD [recommended human dose]). Treatment of pregnant rabbits with oral telotristat ethyl during organogenesis produced maternal toxicity and post-implantation loss at doses of 250 mg/kg/day or higher (approximately 15 times the exposure at the RHD), and reduced fetal weight at 500 mg/kg/day (approximately 33 times the exposure at the RHD). In a pre-/postnatal development study, an increased incidence of mortality in rat offspring was observed during postnatal days 0 to 4 at the maternal oral dose of 500 mg/kg/day (approximately 5 times the exposure at the RHD), given during organogenesis through lactation (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. 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
An embryo-fetal development study performed in rats with oral telotristat ethyl at doses up to 750 mg/kg/day (approximately 9 times the AUC [area under the plasma concentration-time curve] for the active metabolite at the RHD) during organogenesis produced no harm to embryo-fetal development.
In pregnant rabbits treated orally with telotristat ethyl during organogenesis, an increased incidence of post-implantation loss at doses of 250 and 500 mg/kg/day (approximately 15 times the AUC for the active metabolite at RHD) and a decrease in fetal weight at 500 mg/kg/day (approximately 33 times the AUC for the active metabolite at the RHD) was observed. The adverse effects on embryo-fetal development were associated with maternal toxicity (impaired weight gain and/or mortality) at 250 and 500 mg/kg/day. No adverse effects on embryo-fetal development were observed at 125 mg/kg/day (approximately 5 times the AUC for the active metabolite at the RHD).
A pre-/postnatal development study was conducted in rats using oral administration of 100, 200, and 500 mg/kg/day telotristat ethyl during organogenesis through lactation. An increased incidence of pup mortality was observed during postnatal days 0 to 4 at the maternal dose of 500 mg/kg/day (approximately 5 times the AUC for the active metabolite at the RHD). No developmental abnormalities or effects on growth, learning and memory, or reproductive performance were observed through maturation of offspring at maternal doses of up to 500 mg/kg/day in surviving offspring.
Lactation
Risk Summary
There are no data on the presence of telotristat ethyl in human or animal milk, the effects on the breastfed infant, or the effects on milk production. The effects of local gastrointestinal and systemic exposure to telotristat ethyl on breastfed infants are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Xermelo and any potential adverse effects on the breastfed infant from Xermelo or from the underlying maternal condition.
Clinical Considerations
Monitor the breastfed infant for symptoms of constipation.
Pediatric Use
The safety and effectiveness of Xermelo in pediatric patients have not been established.
Geriatric Use
Of 45 patients in a clinical trial of Xermelo, 19 (42%) patients were 65 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Renal Impairment
No dosage adjustment of Xermelo is necessary in patients with mild, moderate or severe renal impairment who are not requiring dialysis.
There is no information on Xermelo in patients with end-stage renal disease who require dialysis (eGFR <15 mL/min/1.73 m2).
Hepatic Impairment
Systemic exposure of telotristat ethyl and its active metabolite, telotristat, were substantially increased in patients with moderate hepatic impairment (Child-Pugh Class B) and severe hepatic impairment (Child-Pugh C) (3.2- and 5.0-fold, respectively) compared to patients with normal hepatic function [see Clinical Pharmacology ]. Xermelo is not recommended in patients with moderate and severe hepatic impairment.
No dosage adjustment of Xermelo is necessary in patients with mild hepatic impairment (Child-Pugh A); however, additional monitoring of Xermelo-associated adverse reactions (e.g., constipation) is recommended in these patients [see Warnings and Precautions ].
Xermelo is contraindicated in patients with a history of a hypersensitivity reaction to telotristat. Reactions have included angioedema, rash and pruritis.
5.1 Constipation
Xermelo reduces bowel movement frequency and may lead to constipation. Serious complications of constipation have been reported during clinical trials and postmarketing.
In a 12-week, placebo-controlled trial, in which patients had 4 or greater bowel movements per day, 2 out of 45 patients treated with a higher than recommended dosage of Xermelo reported constipation. In one patient the constipation was serious, resulting in hospitalization. During the 36-week extension period with higher than the recommended dosage of Xermelo, 10 of 115 patients reported constipation, with individual reports of intestinal perforation, obstruction, and fecaloma. In another 12-week, placebo-controlled trial in which patients had less than 4 bowel movements per day, 4 out of 25 patients treated with the recommended dosage of Xermelo reported constipation.
Serious complications of constipation in patients treated with Xermelo at the recommended dosage (e.g., intestinal obstruction) have also been reported in the postmarket setting. Most patients had additional risk factors, including underlying disease and concomitant constipating medications.
Given that patients with metastatic carcinoid tumors may have impaired integrity of the gastrointestinal tract wall, monitor for the development of constipation and/or severe, persistent, or worsening abdominal pain in patients taking Xermelo. Discontinue Xermelo if severe constipation or severe persistent or worsening abdominal pain develops [see Dosage and Administration , Adverse Reactions ].