Allopathy
Prescription Required
DCGI (Drugs Controller General of India)
Schedule H
Telotristat ethyl is a Tryptophan Hydroxylase Inhibitor belonging to an antidiarrheal drug.
Telotristat ethyl is a tryptophan hydroxylase inhibitor that is used to treat carcinoid syndrome diarrhea.
After a single oral dose of Telotristat ethyl to healthy subjects, Telotristat ethyl was absorbed and metabolized to its active metabolite, telotristat. Peak plasma concentrations of Telotristat ethyl were achieved within 0.5 to 2 hours and those of Telotristat within 1 to 3 hours. Both Telotristat ethyl and Telotristat are greater than 99% bound to human plasma proteins. After oral administration, Telotristat ethyl undergoes hydrolysis via carboxylesterases to telotristat, its active metabolite. Telotristat is further metabolized.
Following a single 500 mg oral dose of 14C-Telotristat ethyl, 93.2% of the dose was recovered over 240 hours: 92.8% was recovered in the feces, with less than 0.4% being recovered in the urine.
Telotristat ethyl shows side effects like Nausea, headache, depression, swelling of your hands, feet, or legs, gas, decreased appetite, and fever.
Telotristat ethyl is available in the form of an Oral Tablet.
Telotristat ethyl is available in India, the US, the UK, Canada, France, Italy, Russia, Spain, China, Japan, and Australia.
Telotristat ethyl belongs to the gut specific antidiarrheal drug acts as a Tryptophan Hydroxylase Inhibitor.
Telotristat, the active metabolite of telotristat ethyl, is an inhibitor of tryptophan hydroxylase, which mediates the rate-limiting step in serotonin biosynthesis. The in vitro inhibitory potency of telotristat towards tryptophan hydroxylase is 29 times higher than that of telotristat ethyl. Serotonin plays a role in mediating secretion, motility, inflammation, and sensation of the gastrointestinal tract, and is over-produced in patients with carcinoid syndrome. Through inhibition of tryptophan hydroxylase, telotristat and telotristat ethyl reduce the production of peripheral serotonin, and the frequency of carcinoid syndrome diarrhea.
The onset and duration of action of Telotristat ethyl is not clinically established.
The Tmax of Telotristat ethyl is approximately 0.5-2 hours.
Telotristat ethyl is available in the form of Oral Tablet.
Telotristat ethyl tablet is taken orally, usually three times a day.
Telotristat is in a class of medications called antidiarrheal agents. It works by blocking the formation of a certain natural substance in the body that is released by the carcinoid tumors and causes diarrhea.
Telotristat ethyl is a Tryptophan Hydroxylase Inhibitor belonging to antidiarrheal drug.
Telotristat ethyl is a small molecule inhibitor of tryptophan hydroxylase (TPH). TPH converts tryptophan to 5-hydroxytryptophan and ultimately to serotonin and is the rate-limiting enzyme in serotonin synthesis. Decreased production of peripheral serotonin by telotristat ethyl results in a reduction in the frequency of carcinoid syndrome diarrhea.
Telotristat ethyl is approved for use in the following clinical indications
- Carcinoid syndrome diarrhea
Telotristat ethyl is a tryptophan hydroxylase inhibitor that is used to treat carcinoid syndrome diarrhea.
- Carcinoid syndrome diarrhea
Oral: 250 mg 3 times daily.
Telotristat ethyl is available in various strengths as 250mg.
Telotristat ethyl is available in the form of Oral Tablet.
- Dosage Adjustment in Kidney Patient
Mild to severe impairment: No dosage adjustment necessary.
End-stage renal disease requiring dialysis: There are no dosage adjustments provided.
- Dosage Adjustment in Hepatic impairment Patient
Mild impairment (Child-Pugh class A): No dosage adjustment necessary; additional monitoring for adverse reactions recommended.
Moderate to severe hepatic impairment (Child-Pugh class B and C): Use not recommended.
Telotristat ethyl is contraindicated in patients with Hypersensitivity to Telotristat ethyl and any of its ingredients
- Constipation
Telotristat ethyl reduces bowel movement frequency. 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 Telotristat ethyl reported constipation. In one patient the constipation was serious, resulting in hospitalization. During the 36-week extension period with higher than the recommended dosage, 10 of 115 patients reported constipation: one developed intestinal perforation and one developed obstruction. 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 Telotristat ethyl reported constipation. 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 Telotristat ethyl. Discontinue Telotristat ethyl if severe constipation or severe persistent or worsening abdominal pain develops.
Breast Feeding Warning
There are no data on the presence of Telotristat ethyl in human or animal milk, the effects on the breastfed infant, or the effects on milk production. The effects of local gastrointestinal and systemic exposure to Telotristat ethyl on breastfed infants are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Telotristat ethyl and any potential adverse effects on the breastfed infant from Telotristat ethyl or from the underlying maternal condition.
Pregnancy Warning
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Common
● Nausea, Headache, Increased GGT, Depression, Peripheral edema, Flatulence Decreased appetite, Pyrexia, Abdominal pain, Constipation, Increased alkaline phosphatase, Increased ALT, and AST.
Rare
● Intestinal obstruction, Angioedema, Pruritus, rash.
- CYP3A4 Substrates
Concomitant use of Telotristat ethyl may decrease the efficacy of drugs that are CYP3A4 substrates (e.g., midazolam) by decreasing their systemic exposure. Monitor for suboptimal efficacy and consider increasing the dose for concomitant CYP3A4 substrates, if necessary.
- Short-Acting Octreotide
Concurrent administration of short-acting octreotide with Telotristat ethyl significantly decreased the systemic exposure of Telotristat ethyl and telotristat, the active metabolite. If treatment with short-acting octreotide is needed in combination with Telotristat ethyl, administer short-acting octreotide at least 30 minutes after administration of Telotristat ethyl.
The common side effects of Telotristat ethyl include the following
Common side effects
● Nausea, headache, depression, swelling of your hands, feet, or legs, gas, decreased appetite, fever.
Rare side effects
● Constipation, abdominal pain, rash or itching, swelling around the lips or eyes, difficulty breathing.
- Pregnancy
Pregnancy Category B
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
- Nursing Mothers
There are no data on the presence of Telotristat ethyl in human or animal milk, the effects on the breastfed infant, or the effects on milk production. The effects of local gastrointestinal and systemic exposure to Telotristat ethyl on breastfed infants are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Telotristat ethyl and any potential adverse effects on the breastfed infant from Telotristat ethyl or from the underlying maternal condition.
- Pediatric Use
The safety and effectiveness of Telotristat ethyl in pediatric patients have not been established.
- Geriatric Use
Of 45 patients in a clinical trial of Telotristat ethyl, 19 (42%) patients were 65 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Pharmacodynamic
In normal mice, Telotristat ethyl etiprate (administered once daily for 4 days at doses of 15–300 mg/kg/day) was found to reduce serotonin levels throughout the gastrointestinal tract. These reductions occurred in a dose-dependent fashion with maximal effects observed with doses of Telotristat ethyl etiprate ≥150 mg/kg. No significant change in brain serotonin or 5-hydroxy indole acetic acid (5-HIAA, a serotonin metabolite) was observed. Similar findings were seen in Sprague-Dawley rats. Gastrointestinal motility studies were conducted in rats using the charcoal meal test. There was a significant dose-related delay in both gastrointestinal transit and gastric emptying, associated with a reduction in blood serotonin levels and proximal colon serotonin. A quantitative whole-body autoradiography study was conducted to assess the absorption, distribution, and excretion of radioactivity in rats following a single oral dose of Telotristat ethyl etiprate labeled with carbon 14. Rats were administered either 30 mg/kg or 100 mg/kg of the compound. The distribution of radioactivity was limited to tissues of the hepatic and renal system and the contents of the GI tract. There was no measurable radioactivity in the brain at any dose tested.
Pharmacokinetics
- Absorption
After a single oral dose of Telotristat ethyl to healthy subjects, Telotristat ethyl was absorbed and metabolized to its active metabolite, telotristat. Peak plasma concentrations of Telotristat ethyl were achieved within 0.5 to 2 hours and those of Telotristat within 1 to 3 hours. Plasma concentrations thereafter declined in a biphasic manner. Following administration of a single 500 mg dose of Telotristat ethyl (twice the recommended dosage) under fasted conditions in healthy subjects, the mean Cmax and AUC0-inf were 4.4 ng/mL and 6.23 ng•hr/mL, respectively for Telotristat ethyl. The mean Cmax and AUC0-inf were 610 ng/mL and 2320 ng• hr/mL, respectively for telotristat. Peak plasma concentrations and AUC of Telotristat ethyl and Telotristat appeared to be dose proportional following administration of a single dose of Telotristat ethyl in the range of 100 mg (0.4 times the lowest recommended dose to 1000 mg [4 times the highest recommended dose]) under fasted conditions.
- Distribution
The estimated apparent total volume of distribution for the active metabolite from the Population PK model of 428.1 L in a typical healthy fasted subject and 348.7 L in patients with carcinoid syndrome. Both Telotristat and Telotristat ethyl are greater than 99% bound to human plasma proteins.
- Metabolism and Excretion
After oral administration, Telotristat ethyl undergoes hydrolysis via carboxylesterases to telotristat, its active metabolite. Telotristat is further metabolized. Among the metabolites of telotristat, the systemic exposure to an acid metabolite of oxidative deaminated decarboxylated Telotristat ethyl was about 35% of that of telotristat.
Following a single 500 mg oral dose of 14C-Telotristat ethyl, 93.2% of the dose was recovered over 240 hours: 92.8% was recovered in the feces, with less than 0.4% being recovered in the urine.
- Kulke M, Hörsch D, Caplin M, Anthony L, Bergsland E, Oberg K, Welin S, Warner R, Bohas CL, Kunz PL, Grande E. Integrated placebo-controlled safety analysis from clinical studies of telotristat ethyl for the treatment of carcinoid syndrome. Annals of Oncology. 2016 Oct 1;27:vi138.
- Lapuerta P, Zambrowicz B, Fleming D, Wheeler D, Sands A. Telotristat etiprate, a novel inhibitor of serotonin synthesis for the treatment of carcinoid syndrome. Clinical Investigation. 2015 May;5(5):447-56.
- Pavel M, Hörsch D, Caplin M, Ramage J, Seufferlein T, Valle J, Banks P, Lapuerta P, Sands A, Zambrowicz B, Fleming D. Telotristat etiprate for carcinoid syndrome: a single-arm, multicenter trial. The Journal of Clinical Endocrinology & Metabolism. 2015 Apr 1;100(4):1511-9.
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf
- https://medlineplus.gov/druginfo/meds/a617029.html#:~:text=Telotristat is in a class,carcinoid tumors and causes diarrhea.
- https://reference.medscape.com/drug/Telotristat ethyl -telotristat-ethyl-1000118#4
- https://www.drugs.com/pregnancy/telotristat.html
- https://go.drugbank.com/drugs/DB12095
- https://www.rxlist.com/consumer_Telotristat ethyl _telotristat_ethyl/drugs-condition.htm#what_are_warnings_and_precautions_for_telotristat_ethyl
