Xermelo (Telotristat Ethyl), First-in-Class Tryptophan Hydroxylase Inhibitor, Approved for Carcinoid Syndrome Diarrhea

March 2018, Vol 11, Ninth Annual Payers' Guide - Select Drug Profiles, Payers' Guide

Approximately 8000 individuals are diagnosed annually with gastrointestinal (GI) carcinoid tumors, the most common type of neuroendocrine tumors, in the United States. The average age at diagnosis of carcinoid tumors is the early 60s.1 The majority of carcinoid tumors are located in the GI tract, primarily in the small intestine.1,2 These tumors are also often found in the rectum, colon, appendix, and stomach.1

Less than 10% of patients with carcinoid tumors have carcinoid syndrome, particularly after the tumor has metastasized to the liver.3 Carcinoid syndrome is characterized by the secretion of certain chemicals into the bloodstream, causing a cluster of signs and symptoms.2,3

The uncontrolled diarrhea caused by carcinoid syndrome is associated with multiple complications, including weight loss, dehydration, malnutrition, fatigue, and electrolyte imbalance.3,4 These symptoms can interfere with the patient’s functionality and activities of daily living.4

Carcinoid syndrome can also lead to bowel obstruction, carcinoid heart disease, carcinoid crisis (a severe episode of low blood pressure), breathing difficulty, and flushing that can occur when patients are exposed to anesthesia or other triggers.2

Xermelo Approved for Carcinoid Syndrome Diarrhea

On February 28, 2017, the US Food and Drug Administration (FDA) approved telotristat ethyl (Xermelo; Lexicon), a first-in-class oral tryptophan hydroxylase inhibitor, for the treatment of carcinoid syndrome diarrhea, in combination with somatostatin analog therapy, in adults with carcinoid syndrome diarrhea that is inadequately controlled by somatostatin analog therapy.3-5

“Today’s approval will provide patients whose carcinoid syndrome diarrhea is not adequately controlled with another treatment option,” said Julie Beitz, MD, FDA’s Director of the Office of Drug Evaluation III.3

Mechanism of Action

Telotristat ethyl is a tryptophan hydroxylase inhibitor, an enzyme that mediates the rate-limiting stage of serotonin biosynthesis. Serotonin, a neurotransmitter, plays a role in several GI processes, including secretion, inflammation, motility, and sensation. Excess levels of serotonin are produced in patients with carcinoid syndrome.

Telotristat, the active metabolite of telotristat ethyl, and telotristat ethyl inhibit tryptophan hydroxylase, thereby reducing peripheral serotonin levels and the frequency of carcinoid syndrome diarrhea.5

Dosing and Administration

The recommended dose of oral telotristat ethyl is 250 mg 3 times daily, taken with food. Telotristat ethyl is available as a 250-mg tablet for oral use.5

When used in combination with telotristat ethyl, short-acting octreotide (Sandostatin) should be taken at least 30 minutes after telotristat ethyl.5

Telotristat ethyl should be discontinued if a patient has severe constipation.5

Pivotal Clinical Trial

The efficacy and safety of telotristat ethyl were evaluated in a 12-week, double-blind, placebo-controlled study that included 90 patients with a well-differentiated metastatic neuroendocrine tumor and carcinoid syndrome diarrhea.5,6 Eligible patients had to have 4 to 12 daily bowel movements, despite receiving somatostatin analog treatment for at least 3 months. Patients were randomized to receive telotristat ethyl 250 mg or placebo 3 times daily.5

All patients were required to continue treatment with their baseline somatostatin analog regimen, and were allowed to use rescue medication (short-acting octreotide) and antidiarrheals (eg, loperamide) to alleviate symptoms.5

Treatment with telotristat ethyl plus somatostatin analog achieved significant reductions in the frequency of daily bowel movements during the 12-week treatment period compared with placebo (Table).5,6 The difference in the average weekly reductions of bowel movements between telotristat ethyl and placebo was seen as early as 1 week to 3 weeks in the 12-week study duration.5


In addition, 33% of patients using telotristat ethyl reported a reduction in the overall average bowel movements from baseline of at least 2 bowel movements daily versus 4% of patients who received placebo.5

Adverse Reactions

The most common (≥5%) adverse reactions associated with telotristat ethyl were nausea (13%), headache (11%), increased gamma-glutamyl-transferase levels (9%), depression (9%), flatulence (7%), decreased appetite (7%), peripheral edema (7%), and pyrexia (7%).5

Telotristat ethyl has no contraindications.5

Drug Interactions

The concomitant use of telotristat ethyl with a cytochrome (CY) P3A4 substrate (eg, midazolam) may decrease the efficacy of the CYP3A4 substrate by decreasing its systemic exposure. Patients should be monitored for suboptimal efficacy; a dose increase of the concomitant CYP3A4 substrate may be required.5

Use in Specific Populations

The effects of telotristat ethyl on breastfed infants are unknown. The benefits of breastfeeding should be weighed against the mother’s clinical need for telotristat ethyl and any potential adverse effects on the infant.5

In clinical experience and in a clinical trial that included 19 patients aged ≥65 years, no overall differences were seen in the safety or efficacy of telotristat ethyl between older and younger patients.5

Warnings and Precautions

The frequency of bowel movements is reduced with telotristat ethyl; patients should be monitored for constipation and/or severe persistent or worsening abdo­minal pain.5

Telotristat ethyl should be discontinued if severe constipation or abdominal pain occurs.5


Telotristat ethyl became the first-in-class tryptophan hydroxylase inhibitor and the first oral treatment, to be used in combination with somatostatin analog, for the treatment of adults with carcinoid syndrome diarrhea that is inadequately controlled by somatostatin analog treatment alone. Telotristat ethyl reduces the excess serotonin produced by carcinoid tumors, thereby reducing the frequency of carcinoid syndrome diarrhea.

1. American Cancer Society. What are the key statistics about gastrointestinal carcinoid tumors? Revised February 8, 2016. Accessed August 1, 2017.
2. Mayo Clinic staff. Carcinoid syndrome. Accessed August 1, 2017.
3. US Food and Drug Administration. FDA approves Xermelo for carcinoid syndrome diarrhea. Press release. February 28, 2017. Accessed August 1, 2017.
4. Lexicon Pharmaceuticals. FDA approves Lexicon drug XERMELO (telotristat ethyl) 250 mg as first and only oral treatment for carcinoid syndrome diarrhea in cancer patients with metastatic neuroendocrine tumors. Press release. February 28, 2017. Accessed August 8, 2017.
5. Xermelo (telotristat ethyl) tablets [prescribing information]. The Woodlands, TX: Lexicon Pharmaceuticals; February 2017.
6. Kulke MH, Hörsch D, Caplin ME, et al. Telotristat ethyl, a tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome. J Clin Oncol. 2017;35:14-23.

Related Items
Eylea (Aflibercept), a VEGF Receptor Inhibitor, Receives New Indication for All Stages of Diabetic Retinopathy
Lilly Ostrovsky
2019 Payers' Guide Mid-Year Addendum published on August 13, 2019 in Select Drug Profiles
Imbruvica (Ibrutinib) plus Gazyva (Obinutuzumab) First Chemotherapy-Free Combination Approved as First-Line Treatment for Patients with CLL or SLL
Lilly Ostrovsky
2019 Payers' Guide Mid-Year Addendum published on August 13, 2019 in Select Drug Profiles
Mavenclad (Cladribine) First Short-Course Oral Therapy Approved for Relapsing-Remitting Multiple Sclerosis and Active Secondary Progressive Disease
Lilly Ostrovsky
2019 Payers' Guide Mid-Year Addendum published on August 13, 2019 in Select Drug Profiles
Skyrizi (Risankizumab-rzaa) a New Treatment Option Approved by the FDA for Patients with Moderate-to-Severe Plaque Psoriasis
Loretta Fala
2019 Payers' Guide Mid-Year Addendum published on August 13, 2019 in Select Drug Profiles
Balversa (Erdafitinib), First-in-Class FGFR Kinase Inhibitor, Approved for Patients with Metastatic Urothelial Carcinoma and FGFR Mutations
Loretta Fala
2019 Payers' Guide Mid-Year Addendum published on August 13, 2019 in Select Drug Profiles
Last modified: August 30, 2021
Copyright © Engage Healthcare Communications, LLC. All rights reserved.