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Telotristat (Monograph)

Brand name: Xermelo
Drug class: Antidiarrhea Agents
- Tryptophan Hydroxylase Inhibitors
Chemical name: Ethyl (S)-2-amino-3-[4-[2-amino-6-[(1R)-1-[4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]phenyl]propanoate
Molecular formula: C27H26ClF3N6O3•C9H9NO3
CAS number: 1137608-69-5

Medically reviewed by on Nov 17, 2023. Written by ASHP.


Tryptophan hydroxylase inhibitor.

Uses for Telotristat

Carcinoid Syndrome Diarrhea

Used (in combination with somatostatin analog therapy) for treatment of carcinoid syndrome diarrhea inadequately controlled by somatostatin analog therapy alone (designated an orphan drug by FDA for the treatment of carcinoid syndrome in patients with neuroendocrine tumors).

Carcinoid syndrome, a condition associated with serotonin overproduction, is characterized by flushing, diarrhea, wheezing, occasionally congestive heart failure, and various other manifestations. Although somatostatin analogs (e.g., octreotide, lanreotide) are standard treatment for carcinoid syndrome and are effective initially in most patients, some patients may not respond adequately or may develop recurrent symptoms, including diarrhea, despite therapy.

In clinical studies, telotristat ethyl reduced the frequency of daily bowel movements in patients with carcinoid syndrome diarrhea. Reductions in other symptoms of carcinoid syndrome (e.g., abdominal pain, flushing) not observed.

Telotristat Dosage and Administration


Restricted Distribution


Oral Administration

Administer orally 3 times daily with food. (See Food under Pharmacokinetics.)


Available as telotristat etiprate (the hippurate salt of telotristat ethyl); dosage expressed in terms of telotristat ethyl (the free base).


Carcinoid Syndrome Diarrhea

250 mg 3 times daily; use in combination with a somatostatin analog.

Higher dosages (e.g., 500 mg 3 times daily) have been studied in some patients, but increase the risk of adverse effects (e.g., severe constipation) without providing additional therapeutic benefit.

Therapy Interruption for Toxicity
GI Effects

If severe constipation or severe persistent or worsening abdominal pain occurs, discontinue therapy.

Prescribing Limits


Carcinoid Syndrome Diarrhea

Dosages >250 mg 3 times daily not recommended.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time. (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations at this time. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time. (See Geriatric Use under Cautions.)

Cautions for Telotristat




Reduces bowel movement frequency; constipation reported. Severe constipation resulting in GI obstruction or perforation reported in patients receiving a higher than recommended dosage (500 mg 3 times daily).

Because the integrity of the GI tract wall may be impaired in patients with metastatic carcinoid tumors, monitor patients for development of constipation and/or severe persistent or worsening abdominal pain. If such manifestations occur, discontinue therapy.

Specific Populations


Adequate data in pregnant women not available.

Embryotoxicity (i.e., post-implantation loss, decreased fetal weight), maternal toxicity (i.e., mortality, impaired weight gain), and an increase in pup mortality on postnatal days 0–4 observed in animals at dosages tested.


Not known whether telotristat ethyl distributes into human milk. Effects of the drug on nursing infants and on milk production also not known. In addition, effects of local GI and systemic exposure to the drug in breast-fed infants are unknown.

Consider benefits of breast-feeding to the infant along with the women's clinical need for the drug and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition. Monitor breast-fed infants for symptoms of constipation. (See Constipation under Cautions.)

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in safety and efficacy observed in patients ≥65 years of age compared with younger adults, but increased sensitivity cannot be ruled out. (See Special Populations under Pharmacokinetics.)

Hepatic Impairment

Mild hepatic impairment does not alter pharmacokinetics of telotristat. Not studied in patients with moderate or severe hepatic impairment. (See Special Populations under Pharmacokinetics.)

Renal Impairment

Mild to moderate renal impairment (Clcr 20–89 mL/minute) does not substantially alter pharmacokinetics.

Not studied in patients with end-stage renal disease requiring dialysis.

Common Adverse Effects

Nausea, headache, increased γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP) concentrations, depression, peripheral edema, flatulence, decreased appetite, pyrexia, abdominal pain, constipation.

Drug Interactions

Metabolized by carboxylesterases to telotristat. Telotristat further metabolized by decarboxylation and deamination, including to a major inactive metabolite; however, drug interaction potential of this metabolite unknown.

Neither telotristat ethyl nor telotristat is a substrate of CYP isoenzymes in vitro. Telotristat ethyl and telotristat not adequately studied in vitro to indicate whether the drug or its active metabolite inhibit CYP isoenzymes 2B6, 2C8, or 2C9 or induce CYP isoenzymes 1A2 or 2B6. Effects on CYP3A4 not fully established. (See Drugs Metabolized by Hepatic Microsomal Enzymes under Interactions.)

In vitro, telotristat ethyl inhibits P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). In vitro, telotristat is not an inhibitor of P-gp and BCRP, but is a substrate of P-gp at clinically relevant concentrations.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: Possible pharmacokinetic interaction (decreased systemic exposure of CYP3A4 substrate and suboptimal efficacy). Monitor for signs of reduced efficacy of the CYP3A4 substrate, particularly drugs with a narrow therapeutic index, and consider increasing dosage of CYP3A4 substrate, if necessary. (See Specific Drugs under Interactions.)

Drugs Affected by Transport Systems

Clinically important pharmacokinetic interactions unlikely with substrates of P-gp, BCRP, organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT) 1, OAT3, organic anion transport protein (OATP) 1B1, OATP1B3, or bile salt export pump (BSEP). (See Specific Drugs under Interactions.)

Drugs Affecting Gastric Acidity

Solubility of telotristat ethyl dependent on pH. Possible pharmacokinetic interaction with drugs that increase gastric pH. (See Specific Drugs under Interactions.)

Specific Drugs





Telotristat ethyl did not alter AUC and peak concentrations of fexofenadine in healthy individuals


Telotristat ethyl decreased AUC and peak concentrations of midazolam (a CYP3A4 substrate) by 48 and 25%, respectively; AUC and peak concentrations of midazolam's active metabolite decreased by 48 and 34%, respectively

Monitor for signs of reduced efficacy of CYP3A4 substrate; consider dosage increase of CYP3A4 substrate, if necessary

Octreotide acetate

Short-acting octreotide acetate decreased AUC and peak concentrations of telotristat ethyl by 81 and 86%, respectively; AUC and peak concentrations of telotristat decreased by 68 and 79%, respectively

Administer short-acting octreotide acetate ≥30 minutes following administration of telotristat ethyl

Proton-pump inhibitors (e.g., omeprazole)

Not studied; possible pharmacokinetic interaction

In principal efficacy study, 42% of patients received concomitant therapy with telotristat ethyl and drugs affecting gastric acidity

Telotristat Pharmacokinetics



Telotristat ethyl is a prodrug that is converted in vivo to telotristat; peak plasma concentrations and AUC of telotristat ethyl and telotristat attained within 0.5–2 hours and 1–3 hours, respectively, after a single oral dose of telotristat etiprate.

Following a single oral dose (dosage range: 100 mg to 1 g), peak plasma concentrations and AUC of telotristat ethyl and telotristat appear to be dose proportional under fasted conditions.

Following multiple-dose administration of telotristat ethyl 500 mg 3 times daily, negligible accumulation at steady state for both telotristat ethyl and telotristat.

Plasma concentrations of telotristat ethyl and telotristat decline in a biphasic manner.


Administration of telotristat ethyl 500 mg with a high-fat meal increased peak concentrations of telotristat ethyl and telotristat by 112 and 47%, respectively, and increased AUC0–inf of telotristat ethyl and telotristat by 264 and 33%, respectively.

Special Populations

Mild hepatic impairment (total bilirubin concentration ≤1.5 times ULN or AST concentration exceeding ULN): Pharmacokinetics not affected.

Moderate or severe hepatic impairment (total bilirubin concentration >1.5 times the ULN with any AST concentration): Not studied; effect on pharmacokinetics not known.

Renal impairment: In patients with mild to moderate renal impairment (Clcr 20–89 mL/minute), pharmacokinetics similar to those in patients with normal renal function. Not studied in patients with end-stage renal disease who require dialysis.

Age (18–83 years), gender, and body weight (40–115 kg) do not have clinically important effects on pharmacokinetics of telotristat.



Not known whether distributed into human milk.

Plasma Protein Binding

Telotristat ethyl and telotristat: >99%.



Telotristat ethyl is hydrolyzed to telotristat (active metabolite), principally by carboxylesterases in non-CYP-dependent pathways. Further metabolized to a major inactive metabolite (LP-951757).

Elimination Route

Telotristat ethyl is eliminated in feces (92.8%) and urine (<0.4%).


Telotristat ethyl: Approximately 0.6 hours.

Telotristat: Approximately 5 hours.





25°C (may be exposed to 15–30°C).


Advice to Patients


Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of telotristat ethyl is restricted. (See Restricted Distribution under Dosage and Administration.)

Telotristat Etiprate


Dosage Forms


Brand Names




250 mg (of telotristat ethyl)



AHFS DI Essentials™. © Copyright 2024, Selected Revisions November 27, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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