Xermelo · 4.4 Special warnings and precautions for use · 1

HOS-216893 · has-adverse-reaction-information · PDF-Seite 5

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 studies 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 System organ class Very common Common Uncommon Metabolism and Decreased appetite nutrition disorders Psychiatric disorders Depression, depressed mood Nervous system Headache disorders Gastrointestinal Abdominal paina, Abdominal distension, Faecalomac, intestinal disorders nausea constipation, obstruction flatulence Hepatobiliary Gamma- Alanine aminotransferase disorders glutamyltransferase increased (ALT), increasedb aspartate aminotransferase increased (AST), blood alkaline phosphatase increased (ALP) General disorders Fatigue Oedema peripheral, and administration pyrexia site conditions a Abdominal pain (including upper and lower abdominal pain) 5 b Gamma-glutamyl transferase increased (including preferred terms of gamma-glutamyl transf

Auszug; vollständigen Abschnitt im Original lesen.

HOS-216889 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-216888 · has-indication-information · PDF-Seite 2

Xermelo is indicated for the treatment of carcinoid syndrome diarrhoea in combination with somatostatin analogue (SSA) therapy in adults inadequately controlled by SSA therapy.

HOS-216891 · has-interaction-information · PDF-Seite 4

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 2 (CES2) inhibitors The IC50 of the inhibition of loperamide on the metabolism of telotristat ethyl by CES2 was 5.2 µM (see section 5.2). In phase 3 clinical studies, 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. Carboxylesterase 2 (CES2) substrates Concomitant use of Xermelo may change the exposure of medicinal products that are CES2 substrates (e.g. prasugrel, irinotecan, capecitabine and flutamide) (see section 5.2). If co-administration is unavoidable, monitor for suboptimal efficacy and adverse reactions.

HOS-216892 · has-pregnancy-information · PDF-Seite 4

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 ethyl 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. 4 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. Xermelo should not be used during breast-feeding. 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).

HOS-216890 · has-warning-information · PDF-Seite 3

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 reactions 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 studies 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. 3 Excipients Lactose Xermelo contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Sodium This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.