XERMELO Film-coated tablet Ref.[9179] Active ingredients: Telotristat

Hepatic enzymes elevations

Elevations in hepatic enzymes were observed in clinical studies (see section 4.8). 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.

Constipation

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.

Depressive disorders

Depression, depressed mood and decreased interest have been reported in clinical trials and from post-marketing in some patients treated with telotristat (see section 4.8). Patients should be advised to report any symptoms of depression, depressed mood and decreased interest to their physicians.

Lactose intolerance

Xermelo contains anhydrous lactose as an excipient. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Effect of other medicinal products on Xermelo

Short acting octreotide

Concomitant administration of short-acting octreotide with Xermelo significantly decreased the systemic exposure of telotristat ethyl and telotristat, the active metabolite (see section 5.2). Short-acting octreotide should be administered at least 30 minutes after administration of Xermelo if treatment with short-acting octreotide is needed in combination with Xermelo.

Carboxylesterase (CES) inhibitors

Loperamide caused a <30% decrease in the formation of telotristat (active metabolite) in vitro (see section 5.2). In phase 3 clinical trials, telotristat was routinely combined with loperamide with no evidence of safety concerns.

Effect of Xermelo on other medicinal products

CYP2B6 substrates

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.

CYP3A4 substrates

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 (see section 5.2). Monitoring for suboptimal efficacy is recommended.

Women of childbearing potential

Women of childbearing potential should be advised to use adequate contraception during treatment with telotristat.

Pregnancy

There are no data from the use of telotristat in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Xermelo is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

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.

Fertility

No studies on the effect of telotristat on human fertility have been conducted. Telotristat had no effect on fertility in animal studies (see section 5.3).

Telotristat has minor influence on the ability to drive and use machines. Fatigue may occur following administration of telotristat (see section 4.8).

Summary of the safety profile

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).

Tabulated list of adverse reactions

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 in Table 1. 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.

Table 1. Adverse reactions reported in patients treated with Xermelo:

Metabolism and nutrition disorders

Common: Decreased appetite

Psychiatric disorders

Common: Depression, depressed mood

Nervous system disorders

Common: Headache

Gastrointestinal disorders

Very common: Abdominal pain^a, nausea

Common: Abdominal distension, Constipation,

Uncommon: Flatulence Faecaloma^c, intestinal obstruction

Hepatobiliary disorders

Very common: Gamma-glutamyltransferase increasedb

Common: Alanine aminotransferase increased (ALT), Aspartate aminotransferase increased (AST), Blood alkaline phosphatase increased (ALP)

General disorders and administration site conditions

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 500mg tid (twice the recommended dose).

Description of selected adverse reactions

Hepatic enzymes elevations

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. For clinical management of elevated hepatic enzymes, see section 4.4.

Gastrointestinal disorders

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).

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 in Appendix V.

Not applicable.