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XERMELO- telotristat ethyl tablet
Lexicon Pharmaceuticals, Inc.
1 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.
2 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 Clinical Pharmacology (12.3), Clinical Studies (14)].
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)].
3 DOSAGE FORMS AND STRENGTHS
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.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Constipation
Xermelo reduces bowel movement frequency. 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, 10 of 115 patients reported constipation: one developed intestinal perforation and one developed obstruction. 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. 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)].
DESCRIPTION
Xermelo (telotristat ethyl) tablets contain telotristat ethyl as telotristat etiprate, a tryptophan hydroxylase inhibitor. Telotristat etiprate is the hippurate salt of telotristat ethyl [(S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate], which undergoes hydrolysis to the active metabolite, (S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid.
The molecular formula of telotristat etiprate is C27 H26 ClF3 N6 O3 � C9 H9 NO3 and its molecular weight is 754.2. The molecular weight of the free base (telotristat ethyl) is 575.0.
Chemical Structure:
Chemical Structure
(click image for full-size original)
Telotristat etiprate is a white to off-white solid. The solubility is a function of pH at 25�C; at pH 1 (0.1N HCl), the solubility is greater than 71 mg/mL., at pH 3 phosphate buffer, the solubility is 0.30 mg/mL, at a pH of 5 to 9, the solubility is negligible. In organic solvents, telotristat etiprate is freely soluble in methanol, soluble in acetone, and sparingly soluble in ethanol.
Each Xermelo tablet contains 250 mg of telotristat ethyl (free base) which is equivalent to 328 mg telotristat etiprate. The inactive ingredients of Xermelo tablets include: colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, lactose anhydrous, macrogol/PEG, magnesium stearate, polyvinyl alcohol [part hydrolyzed], talc and titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 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.