Telotristat (monograph)

Telotristat (monograph)

Telotristat (monograph)

introduction

Uses for Telotristat

Carcinoid syndrome diarrhea

Used (in combination with somatostatin analogue therapy) to treat carcinoid syndrome diarrhea that is not adequately controlled by somatostatin analogue therapy alone (designated as an orphan drug by the FDA for the treatment of carcinoid syndrome in patients with neuroendocrine tumors).

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

In clinical trials, telotristat ethyl reduced the frequency of daily bowel movements in patients with carcinoid syndrome diarrhea. A reduction in other symptoms of carcinoid syndrome (e.g., abdominal pain, hot flashes) was not observed.

Telotristat dosage and administration

Generally

• Use in combination with a somatostatin analogue (e.g. octreotide). (See “Carcinoid Syndrome Diarrhea” under “Uses.”)

• In the crucial efficacy study, emergency therapy with short-acting octreotide and antidiarrheal drugs (e.g. loperamide) was permitted and unrestricted.

• When used in combination with short-acting octreotide acetate, octreotide should be administered ≥ 30 minutes after telotristat-etiprate administration. (See “Specific Medications” under “Interactions.”)

Limited distribution

• Only available in specialty pharmacies. Specific information can be found on the Xermelo website ([Web]).

Administration

Oral administration

Administer orally 3 times daily with meals. (See Foods under Pharmacokinetics.)

dosage

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

Adult

Carcinoid syndrome diarrhea

Orally

250 mg 3 times daily; Use in combination with a somatostatin analogue.

Higher doses (e.g., 500 mg three 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 due to toxicity

GI effects

Orally

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

Prescription Limits

Adult

Carcinoid syndrome diarrhea

Orally

Dosages >250 mg 3 times daily not recommended.

Special populations

Liver dysfunction

There are currently no specific dosage recommendations. (See “Hepatic Impairment” under “Precautions.”)

Renal dysfunction

There are currently no specific dosage recommendations. (See Renal Impairment under “Precautions.”)

Geriatric patients

There are currently no specific dosage recommendations. (See “Geriatric Use” under “Precautions.”)

Precautions for Telotristat

Contraindications

• Manufacturer information: none known.

Warnings/Precautions

constipation

Reduces the frequency of bowel movements; Constipation reported. Severe constipation resulting in obstruction or perforation of the gastrointestinal tract has been reported in patients receiving higher than the recommended dosage (500 mg three times daily).

Because the integrity of the gastrointestinal tract wall may be compromised in patients with metastatic carcinoid tumors, patients should be monitored for the development of constipation and/or severe persistent or worsening abdominal pain. If such symptoms occur, discontinue therapy.

Specific populations

pregnancy

There are insufficient data for pregnant women.

Embryotoxicity (i.e., postimplantation loss, reduced fetal weight), maternal toxicity (i.e., mortality, impaired weight gain), and an increase in pup mortality on postnatal days 0–4 were observed in animals at doses tested.

lactation

It is not known whether telotristat ethyl is excreted in breast milk. Effects of the drug on breast-fed infants and on milk production are also unknown. In addition, effects of local gastrointestinal and systemic exposure to the drug in breast-fed infants are unknown.

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

Pediatric use

Safety and effectiveness not proven.

Geriatric use

Overall, no differences in safety and effectiveness were observed in patients aged 65 years and older compared to younger adults, but increased sensitivity cannot be excluded. (See “Special Populations” under “Pharmacokinetics.”)

Liver dysfunction

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

Renal dysfunction

Mild to moderate renal impairment (Clcr 20-89 ml/minute) does not significantly alter pharmacokinetics.

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

Common side effects

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

Interactions with other medications

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

Neither telotristat ethyl nor telotristat is a substrate of CYP isoenzymes in vitro. Telotristat ethyl and telotristat have not been adequately studied in vitro to determine whether the drug or its active metabolite inhibits CYP 2B6, 2C8, or 2C9 isoenzymes or induces CYP 1A2 or 2B6 isoenzymes. Effects on CYP3A4 not fully understood. (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

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

Drugs Affected by Transportation Systems

Clinically important pharmacokinetic interactions 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 the bile salt export pump are unlikely (BSEP). (See “Specific Medications” under “Interactions.”)

Medications that affect stomach acid

Solubility of telotristat ethyl depends on pH. Possible pharmacokinetic interaction with drugs that increase gastric pH. (See “Specific Medications” under “Interactions.”)

Specific medications

Pharmacokinetics of telotristat

absorption

Bioavailability

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

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

After multiple doses of 500 mg telotristat ethyl three times daily, there was negligible accumulation of both telotristat ethyl and telotristat at steady state.

The plasma concentrations of telotristat ethyl and telotristat decrease in a biphasic manner.

Eat

Administration of 500 mg telotristat ethyl with a high-fat meal increased the peak concentrations of telotristat ethyl and telotristat by 112 and 47%, respectively, and increased the 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 above ULN): Pharmacokinetics not affected.

Moderate or severe hepatic impairment (total bilirubin concentration > 1.5 times ULN at 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), the pharmacokinetics are similar to those in patients with normal renal function. Not studied in patients with end-stage renal disease requiring dialysis.

Age (18-83 years), gender and body weight (40-115 kg) have no clinically relevant effects on the pharmacokinetics of telotristat.

distribution

extent

It is not known whether it passes into breast milk.

Plasma protein binding

Telotristat ethyl and telotristat: >99%.

Elimination

metabolism

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

Elimination route

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

Half-life

Telotristat Ethyl: Approximately 0.6 hours.

Telotristat: Approximately 5 hours.

stability

storage

Orally

Tablets

25°C (can 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 gastrointestinal tract.

• Serotonin plays a role in mediating secretion, motility, inflammation, and sensation of the gastrointestinal 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 the frequency of diarrhea in carcinoid syndrome.

• Telotristat is 29-fold more potent than telotristat ethyl in inhibiting tryptophan hydroxylase in vitro.

Advice for patients

• There is a risk of constipation, which can be serious. Advise patients to discontinue telotristat ethyl and contact their healthcare provider 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, it is important to administer short-acting octreotide acetate ≥ 30 minutes after telotristat ethyl administration.

• If a dose is missed or vomited, it is important to give the next dose at the regular time; An additional dose should not be given to make up for a missed dose.

• It is important to inform physicians about any existing or planned concomitant therapies, including prescription and over-the-counter medications, as well as any comorbidities.

• It is important to inform patients of other important precautionary information. (See Precautions.)

Preparations

Excipients in commercial drug preparations may have clinically significant effects in some individuals; Details can be found on the respective product labeling.

For information about shortages of one or more of these drugs, visit the ASHP Drug Shortages Resource Center.

The distribution of telotristat ethyl is limited. (See Restricted Distribution under Dosage and Administration.)

Telotristat Etiprate

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

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