TELOTRISTAT ETHYL: 5,598 Adverse Event Reports & Safety Profile

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 C 27 H 26 ClF 3 N 6 O 3

• C 9 H 9 NO 3 and its molecular weight is 754.2. The molecular weight of the free base (telotristat ethyl) is 575.0.

Chemical

Structure: 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.

Chemical

Structure

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 )

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 )]. 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 , 7.1 )

Discontinue

Xermelo if severe constipation develops. ( 2 , 5.1 )

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 )

REACTIONS Most common adverse reactions (≥5%) are nausea, headache, increased GGT, depression, flatulence, decreased appetite, peripheral edema, and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact TerSera Therapeutics LLC at 1-844-334-4035 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Xermelo was studied in a double-blind, placebo-controlled clinical trial of 90 patients with metastatic neuroendocrine tumors and carcinoid syndrome diarrhea. Patients reported between 4 to 12 bowel movements daily despite the use of SSA therapy at a stable dose for at least 3 months <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . Placebo or Xermelo 250 mg was administered three times daily for 12 weeks. Concomitant anti-diarrheal medications (e.g., loperamide) were used by 43% (36% and 51% in the placebo and Xermelo group, respectively), pancreatic enzyme replacement medications by 39% (36% and 42% in the placebo and Xermelo group, respectively), and opioid analgesics by 29% (24% and 33% in the placebo and Xermelo group, respectively) of patients during the 12-week double-blind period of the trial.

Table

1 below lists adverse reactions occurring at an incidence of at least 5% in the Xermelo group (N=45) and at an incidence greater than placebo (N=45) during the 12-week placebo-controlled period of the trial.

Table

1: Percent Common Adverse Reactions a by Treatment Group at 12-Weeks in a Double-Blind Placebo-Controlled Clinical Trial of Patients with Carcinoid Syndrome Diarrhea a incidence of at least 5% in the Xermelo group and at an incidence greater than placebo b including depression, depressed mood and decreased interest Adverse Reaction Xermelo 250 mg Three Times Daily, N=45 (%) Placebo, N=45 (%)

Nausea

13 11 Headache 11 4 Increased gamma-glutamyl-transferase (GGT) 9 0 Depression b 9 7 Peripheral edema 7 2 Flatulence 7 2 Decreased appetite 7 4 Pyrexia 7 4 In another placebo-controlled clinical trial of patients with carcinoid syndrome diarrhea and less than 4 bowel movements per day, the following additional adverse reactions, not listed in Table 1 , of abdominal pain (including upper and lower abdominal pain, abdominal distention and gastrointestinal pain) and constipation were reported in at least 5% of patients in the Xermelo treated group and at an incidence greater than placebo [see Warnings and Precautions ( 5.1 )] .

Less Common Adverse

Reactions : The following is a list of adverse reactions occurring in less than 5% of patients receiving Xermelo during the 12-week placebo-controlled period of the clinical trial: Investigations : increased alkaline phosphatase, increased alanine aminotransferase, and increased aspartate aminotransferase. Fecaloma was reported in one patient treated with Xermelo (at a higher than recommended dosage) during the 36-week open-label extension period following the 12-week double-blind period of the trial.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Xermelo. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal: intestinal obstruction <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> Immune system disorders: angioedema Skin and subcutaneous tissue disorders: pruritis, rash

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 )] .

INTERACTIONS CYP3A4 Substrates (e.g., midazolam) and CYP2B6 Substrates (e.g., bupropion, efavirenz): Efficacy of concomitant drugs may be decreased; monitor patients’ response and consider increasing the dosage of the concomitant drug, if necessary. ( 7.1 )

7.1 CYP3A4 Substrates Concomitant use of Xermelo may decrease the efficacy of drugs that are CYP3A4 substrates (e.g., midazolam) by decreasing their systemic exposure. Monitor patients’ response to CYP3A4 substrates when co-administered with Xermelo and consider increasing the dosage of the interacting drug, if necessary <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.2 CYP2B6 Substrates Concomitant use of Xermelo may decrease the efficacy of drugs that are CYP2B6 substrates (e.g., bupropion, efavirenz) by decreasing their systemic exposure. Monitor patients’ response to CYP2B6 substrates when co-administered with Xermelo and consider increasing the dosage of the interacting drug, if necessary <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.3 Short-Acting Octreotide Concurrent administration of short-acting octreotide with Xermelo significantly decreased the systemic exposure of telotristat ethyl and telotristat, the active metabolite. If treatment with short-acting octreotide is needed in combination with Xermelo, administer short-acting octreotide at least 30 minutes after administration of Xermelo <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .