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 Drugs.com on Nov 17, 2023. Written by ASHP.

Introduction

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

General

Use in combination with a somatostatin analog (e.g., octreotide). (See Carcinoid Syndrome Diarrhea under Uses.)
In the pivotal efficacy study, rescue therapy with short-acting octreotide and antidiarrheals (e.g., loperamide) was allowed and unrestricted.
When used in combination with short-acting octreotide acetate, administer octreotide ≥30 minutes following administration of telotristat etiprate. (See Specific Drugs under Interactions.)

Restricted Distribution

Available only through specialty pharmacies. Consult the Xermelo website for specific information ([Web]).

Administration

Oral Administration

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

Dosage

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

Adults

Carcinoid Syndrome Diarrhea

Oral

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

Oral

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

Prescribing Limits

Adults

Carcinoid Syndrome Diarrhea

Oral

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

Contraindications

Manufacturer states none known.

Warnings/Precautions

Constipation

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

Pregnancy

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.

Lactation

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 (Cl_cr 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

Drug	Interaction	Comments
Fexofenadine	Telotristat ethyl did not alter AUC and peak concentrations of fexofenadine in healthy individuals
Midazolam	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

Absorption

Bioavailability

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.

Food

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 AUC_0–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 (Cl_cr 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.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

Telotristat ethyl and telotristat: >99%.

Elimination

Metabolism

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%).

Half-life

Telotristat ethyl: Approximately 0.6 hours.

Telotristat: Approximately 5 hours.

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).

Actions

Telotristat ethyl is a prodrug of telotristat, a tryptophan hydroxylase inhibitor.
Tryptophan hydroxylase is the rate-limiting enzyme in the biosynthesis of serotonin from tryptophan in the GI tract.
Serotonin plays a role in mediating secretion, motility, inflammation, and sensation of the GI tract. In carcinoid syndrome, a condition associated with overproduction of serotonin, inhibition of tryptophan hydroxylase activity by telotristat and telotristat ethyl reduces peripheral serotonin production and frequency of carcinoid syndrome diarrhea.
Telotristat is 29-fold more potent than telotristat ethyl in its inhibition of tryptophan hydroxylase in vitro.

Advice to Patients

Risk of constipation, which may be severe. Advise patients to discontinue telotristat ethyl and contact their clinician if severe constipation or severe persistent or worsening abdominal pain occurs.
Importance of taking telotristat ethyl tablets with food.
When short-acting octreotide is used in combination with telotristat ethyl, importance of administering short-acting octreotide acetate ≥30 minutes after administration of telotristat ethyl.
If a dose is missed or vomited, importance of administering the next dose at the regularly scheduled time; an additional dose should not be administered to make up for a missed dose.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

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.)