telotristat ethyl 250 MG Oral Tablet [Xermelo]

INDICATIONS AND USAGE Xermelo is indicated for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy. Xermelo is a tryptophan hydroxylase inhibitor indicated for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy. ( 1 )

DOSAGE AND ADMINISTRATION 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 ( 12.3 ), Clinical Studies ( 14 )] . When short-acting octreotide is used in combination with Xermelo, administer short-acting octreotide at least 30 minutes after administering Xermelo [see Drug Interactions ( 7.3 )] . 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 ( 5.1 )]. The recommended dosage of Xermelo in adult patients is 250 mg three times daily for patients whose diarrhea is inadequately controlled by a SSA therapy. ( 2 ) Take Xermelo with food. ( 2 ) When short-acting octreotide is used in combination with Xermelo, administer short-acting octreotide at least 30 minutes after administering Xermelo. ( 2 , 7.3 ) Discontinue Xermelo if severe constipation develops. ( 2 , 5.1 )

WARNINGS AND PRECAUTIONS Constipation: Xermelo reduces bowel movement frequency; monitor patients for constipation, and/or severe persistent or worsening abdominal pain. Discontinue Xermelo if constipation or abdominal pain develops. ( 5.1 ) 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 ( 2 ), Adverse Reactions ( 6.1 )] .

CONTRAINDICATIONS Xermelo is contraindicated in patients with a history of a hypersensitivity reaction to telotristat. Reactions have included angioedema, rash and pruritis. History of hypersensitivity to telotristat. ( 4 )

Mechanism of Action Telotristat, the active metabolite of telotristat ethyl, is an inhibitor of tryptophan hydroxylase, which mediates the rate limiting step in serotonin biosynthesis. The in vitro inhibitory potency of telotristat towards tryptophan hydroxylase is 29 times higher than that of telotristat ethyl. Serotonin plays a role in mediating secretion, motility, inflammation, and sensation of the gastrointestinal tract, and is over-produced in patients with carcinoid syndrome. Through inhibition of tryptophan hydroxylase, telotristat and telotristat ethyl reduce the production of peripheral serotonin, and the frequency of carcinoid syndrome diarrhea.