gher dose (500 mg) in the overall safety population (239 patients).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed below:
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
Ireland
HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail: medsafety@hpra.ie
4.9 Overdose
Symptoms
There is limited clinical experience with telotristat overdose in humans. Gastrointestinal disorders including nausea, diarrhoea, abdominal pain and vomiting have been reported in healthy subjects taking a single dose of 1,500 mg in a phase 1 study.
Management of overdose
Treatment of an overdose should include general symptomatic management.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: {not yet assigned} ATC code: {not yet assigned}.
Mechanism of action
Both the prodrug (telotristat ethyl) and its active metabolite (telotristat) are inhibitors of L-tryptophan hydroxylases (TPH1 and TPH2, the rate limiting steps in serotonin biosynthesis). Serotonin plays a critical role in regulating several major physiological processes, including secretion, motility, inflammation, and sensation of the gastrointestinal tract, and is over-secreted in patients with carcinoid syndrome. Through inhibition of peripheral TPH1, telotristat reduces the production of serotonin, thus alleviating symptoms associated with carcinoid syndrome.
Pharmacodynamic effects
In Phase 1 studies, dosing with telotristat ethyl in healthy subjects (dose range: 100 mg once daily to 500 mg tid) produced statistically significant reductions from baseline in whole blood serotonin and 24-hour urinary 5-hydroxyindoleacetic acid (u5-HIAA) compared with placebo.
In patients with carcinoid syndrome, telotristat resulted in reductions in u5-HIAA (refer to Table 3 for TELESTAR and information provided for TELECAST). Statistically significant reductions in u5-HIAA were seen for telotristat ethyl 250 mg tid compared with placebo in both Phase 3 studies.
Clinical efficacy and safety
The efficacy and safety of telotristat for the treatment of carcinoid syndrome in patients with metastatic neuroendocrine tumours who were receiving SSA therapy was established in a 12-week double-blind, placebo-controlled, randomised, multicentre phase 3 trial in adult patients, which included a 36-week extension during which all patients were treated with open-label telotristat (TELESTAR Study).
A total of 135 patients were eva luated for efficacy. The mean age was 64 years (range 37 to 88 years), 52% were male and 90% were white. All patients had well-differentiated metastatic neuroendocrine tumours and carcinoid syndrome. They were on SSA therapy and had ≥4 daily BM.
The study included a 12-week double-blind treatment (DBT) period, in which patients initially received placebo (n=45), telotristat ethyl 250 mg (n=45) or a higher dose (telotristat ethyl 500 mg; n=45) tid. During the study, patients were allowed to use rescue medication (short-acting SSA therapy) and anti-diarrhoeals for symptomatic relief but were required to be on sta |
