Chemical formula: C₂₇H₂₆ClF₃N₆O₃ Molecular mass: 546.94 g/mol
Telotristat interacts in the following cases:
No change in dosage is required in patients with mild, moderate or severe renal impairment; who are not requiring dialysis. As a precautionary measure, it is recommended that patients with severe renal impairment will be monitored for signs of reduced tolerability.
The use of telotristat is not recommended in patients with end-stage renal disease requiring dialysis (eGFR <15 mL/min requiring dialysis) because efficacy and safety of telotristat in these patients has not been established.
In patients with mild hepatic impairment (Child Pugh score A), it may be necessary to reduce the dose to 250 mg twice daily according to tolerability.
In patients with moderate hepatic impairment (Child Pugh score B), it may be necessary to reduce the dose to 250 mg once daily according to tolerability.
The use of telotristat is not recommended in patients with severe hepatic impairment (Child Pugh score C) as no data are available.
Telotristat induced CYP2B6 in vitro (see section 5.2). Concomitant use of Xermelo may decrease the efficacy of medicinal products that are CYP2B6 substrates (e.g. valproic acid, bupropion, sertraline) by decreasing their systemic exposure. Monitoring for suboptimal efficacy is recommended.
Concomitant use of Xermelo may decrease the efficacy of medicinal products that are CYP3A4 substrates (e.g. midazolam, everolimus, sunitinib, simvastatin, ethinyloestradiol, amlodipine, cyclosporine) by decreasing their systemic exposure. Monitoring for suboptimal efficacy is recommended.
Loperamide caused a <30% decrease in the formation of telotristat (active metabolite) in vitro. In phase 3 clinical trials, telotristat was routinely combined with loperamide with no evidence of safety concerns.
Concomitant administration of short-acting octreotide with telotristat significantly decreased the systemic exposure of telotristat ethyl and telotristat, the active metabolite. Short-acting octreotide should be administered at least 30 minutes after administration of telotristat if treatment with short-acting octreotide is needed in combination with telotristat.
Elevations in hepatic enzymes were observed in clinical studies.
Laboratory monitoring of hepatic enzymes prior to and during telotristat therapy is recommended as clinically indicated. In patients with hepatic impairment, continuous monitoring for adverse events and worsening of liver function is recommended.
Patients who develop symptoms suggestive of hepatic dysfunction should have liver enzymes tested and telotristat should be discontinued if liver injury is suspected. Therapy with telotristat should not be resumed unless the liver injury can be explained by another cause.
Depression, depressed mood and decreased interest have been reported in clinical trials and from post-marketing in some patients treated with telotristat. Patients should be advised to report any symptoms of depression, depressed mood and decreased interest to their physicians.
Telotristat reduces bowel movement (BM) frequency. Constipation was reported in patients using a higher dose (500 mg). Patients should be monitored for signs and symptoms of constipation. If constipation develops, the use of telotristat and other concomitant therapies affecting bowel motility should be re-evaluated.
There are no data from the use of telotristat in pregnant women. Animal studies have shown reproductive toxicity. Telotristat is not recommended during pregnancy and in women of childbearing potential not using contraception.
It is unknown whether telotristat ethyl and its metabolite are excreted in human breast milk. A risk to newborns/infants cannot be excluded. Patients should not breast-feed during telotristat treatment.
No studies on the effect of telotristat on human fertility have been conducted. Telotristat had no effect on fertility in animal studies.
Telotristat has minor influence on the ability to drive and use machines. Fatigue may occur following administration of telotristat.
The most commonly reported adverse reactions in patients treated with telotristat were abdominal pain (26%), gamma-glutamyl transferase increased (11%) and fatigue (10%). They were generally of mild or moderate intensity. The most frequently reported adverse reaction leading to discontinuation of telotristat was abdominal pain in 7.1% of patients (5/70).
Adverse reactions reported in a pooled safety dataset of 70 patients with carcinoid syndrome receiving telotristat ethyl 250 mg tid in combination with SSA therapy in placebo-controlled clinical trials are listed below. Adverse reactions are listed by MedDRA body system organ class and by frequency using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Adverse reactions reported in patients treated with telotristat:
Common: Decreased appetite
Common: Depression, depressed mood
Common: Headache
Very common: Abdominal paina, nausea
Common: Abdominal distension, Constipation,
Uncommon: Flatulence Faecalomac, intestinal obstruction
Very common: Gamma-glutamyltransferase increasedb
Common: Alanine aminotransferase increased (ALT), Aspartate aminotransferase increased (AST), Blood alkaline phosphatase increased (ALP)
Very common: Fatigue
Common: Oedema peripheral, Pyrexia
a Abdominal pain (including upper and lower abdominal pain)
b Gamma-glutamyl transferase increased (including preferred terms of gamma-glutamyl transferase increased, gamma-glutamyl transferase, and liver function test abnormal/hepatic enzyme increased for which gamma-glutamyl transferase was increased).
c Faecaloma has only been observed in a clinical study at a dosage of 500 mg tid (twice the recommended dose).
Elevations in ALT >3 × upper limit of normal (ULN) or ALP >2 ULN have been reported in patients receiving therapy with telotristat, most cases being reported at a higher dose (500 mg). These have not been associated with concomitant elevations in total serum bilirubin. The increases were largely reversible on dose interruption or reduction, or recovered whilst maintaining treatment at the same dose.
The most frequently reported adverse event in patients receiving telotristat ethyl 250 mg tid was abdominal pain (25.7%; 18/70) versus placebo (19.7%; 14/71). Abdominal distension was reported in 7.1% of patients (5/70) receiving telotristat ethyl 250 mg tid, versus 4.2% in the placebo group (3/71). Flatulence was seen in 5.7% of patients (4/70) and 1.4% (1/71) in the telotristat ethyl 250 mg and placebo groups, respectively. Most events were mild or moderate and did not limit study treatment. Constipation was reported in 5.7% of patients (4/70) in the telotristat ethyl 250 mg group and in 4.2% of patients (3/71) in the placebo group. Serious constipation was observed in 3 patients treated with a higher dose (500 mg) in the overall safety population (239 patients).
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