XERMELO 250mg tablets medication leaflet

Xermelo 250 mg film-coated tablets

Each film-coated tablet contains telotristat etiprate equivalent to 250 mg telotristat ethyl.

Each tablet contains 168 mg of lactose.

For the full list of excipients, see section 6.1.

Film-coated tablet.

White to off-white film-coated oval tablets (approximately 17 mm long by 7.5 mm wide) with ‘T-E’debossed on one side and ‘250’ debossed on the other side.

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

The recommended dose is 250 mg three times daily (tid).

Available data suggest that clinical response is usually achieved within 12 weeks of treatment.

It is recommended to reassess the benefit of continued therapy in a patient not responding within thistime period.

Based on the high inter-subject variability observed, accumulation in a subset of patients withcarcinoid syndrome cannot be excluded. Therefore, intake of higher doses is not recommended (seesection 5.2).

In the event of a missed dose, patients should take their subsequent dose at the next scheduled timepoint. Patients should not take a double dose to make up for a missed dose.

Special population

No specific dose recommendations are available for elderly patients (see section 5.2).

No change in dose is required in patients with mild, moderate or severe renal impairment; who are notrequiring dialysis (see section 5.2). As a precautionary measure, it is recommended that patients withsevere renal impairment will be monitored for signs of reduced tolerability.

The use of Xermelo is not recommended in patients with end-stage renal disease requiring dialysis(eGFR < 15 mL/min requiring dialysis) because efficacy and safety of Xermelo in these patients havenot been established.

In patients with mild hepatic impairment (Child Pugh score A), it may be necessary to reduce the doseto 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 Pughscore C) (see section 5.2).

There is no relevant use of telotristat in the paediatric population in the indication of carcinoidsyndrome.

Oral use

Xermelo should be taken with food (see sections 5.1 and 5.2).

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

Elevations in hepatic enzymes were observed in clinical studies (see section 4.8). Laboratorymonitoring of hepatic enzymes prior to and during telotristat therapy is recommended as clinicallyindicated. In patients with hepatic impairment, continuous monitoring for adverse reactions andworsening of liver function is recommended.

Patients who develop symptoms suggestive of hepatic dysfunction should have liver enzymes testedand telotristat should be discontinued if liver injury is suspected. Therapy with telotristat should not beresumed unless the liver injury can be explained by another cause.

Telotristat reduces bowel movement (BM) frequency. Constipation was reported in patients using ahigher dose (500 mg). Patients should be monitored for signs and symptoms of constipation. Ifconstipation develops, the use of telotristat and other concomitant therapies affecting bowel motilityshould be re-evaluated.

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

Xermelo contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactasedeficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially“sodium-free”.

Concomitant administration of short-acting octreotide with Xermelo significantly decreased thesystemic 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 iftreatment with short-acting octreotide is needed in combination with Xermelo.

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 withno evidence of safety concerns.

Telotristat induced CYP2B6 in vitro (see section 5.2). Concomitant use of Xermelo may decrease theefficacy 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 CYP3A4substrates (e.g. midazolam, everolimus, sunitinib, simvastatin, ethinyloestradiol, amlodipine,cyclosporine…) by decreasing their systemic exposure (see section 5.2). Monitoring for suboptimalefficacy is recommended.

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 isunavoidable, monitor for suboptimal efficacy and adverse reactions.

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

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

It is unknown whether telotristat ethyl and its metabolite are excreted in human breast milk. A risk tonewborns/infants cannot be excluded. Xermelo should not be used during breast-feeding.

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

Xermelo has minor influence on the ability to drive and use machines. Fatigue may occur followingadministration of telotristat, patients with fatigue should be advised to refrain from driving or usingmachines until symptoms have subsided. (see section 4.8).

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 mildor moderate intensity. The most frequently reported adverse reaction leading to discontinuation oftelotristat was abdominal pain in 7.1% of patients (5/70).

Adverse reactions reported in a pooled safety dataset of 70 patients with carcinoid syndrome receivingtelotristat ethyl 250 mg tid in combination with SSA therapy in placebo-controlled clinical studies arelisted in Table 1. Adverse reactions are listed by MedDRA body system organ class and by frequencyusing 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 (cannotbe estimated from the available data). Within each frequency grouping, adverse reactions are presentedin order of decreasing seriousness

Table 1 - Adverse reactions reported in patients treated with Xermelo

System organ class Very common Common Uncommon

Metabolism and Decreased appetitenutrition disorders

Psychiatric disorders Depression, depressedmood

Nervous system Headachedisorders

Gastrointestinal Abdominal paina, Abdominal distension, Faecalomac, intestinaldisorders nausea constipation, obstructionflatulence

Hepatobiliary Gamma- Alanine aminotransferasedisorders glutamyltransferase increased (ALT),increasedb aspartate aminotransferaseincreased (AST),blood alkaline phosphataseincreased (ALP)

General disorders Fatigue Oedema peripheral,and administration pyrexiasite conditionsa Abdominal pain (including upper and lower abdominal pain)b Gamma-glutamyl transferase increased (including preferred terms of gamma-glutamyl transferaseincreased, gamma-glutamyl transferase, and liver function test abnormal/hepatic enzyme increasedfor which gamma-glutamyl transferase was increased).c Faecaloma has only been observed in a clinical study at a dose of 500 mg tid (twice therecommended dose).

Elevations in ALT > 3 × upper limit of normal (ULN) or ALP > 2 ULN have been reported in patientsreceiving therapy with telotristat, most cases being reported at a higher dose (500 mg). These have notbeen associated with concomitant elevations in total serum bilirubin. The increases were largelyreversible on dose interruption or reduction, or recovered whilst maintaining treatment at the samedose. For clinical management of elevated hepatic enzymes, see section 4.4.

The most frequently reported adverse event in patients receiving telotristat ethyl 250 mg tid wasabdominal pain (25.7%; 18/70) versus placebo (19.7%; 14/71). Abdominal distension was reported in7.1% 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 andplacebo 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 ahigher dose (500 mg) in the overall safety population (239 patients).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is limited clinical experience with telotristat overdose in humans. Gastrointestinal disordersincluding nausea, diarrhoea, abdominal pain, constipation and vomiting have been reported in healthysubjects taking a single dose of 1 500 mg in a phase 1 study.

Treatment of an overdose should include general symptomatic management.

Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tractand metabolism products, ATC code: A16AX15

Both the prodrug (telotristat ethyl) and its active metabolite (telotristat) are inhibitors of L-tryptophanhydroxylases (TPH1 and TPH2, the rate limiting steps in serotonin biosynthesis). Serotonin plays acritical role in regulating several major physiological processes, including secretion, motility,inflammation, and sensation of the gastrointestinal tract, and is over-secreted in patients with carcinoidsyndrome. Through inhibition of peripheral TPH1, telotristat reduces the production of serotonin, thusalleviating symptoms associated with carcinoid syndrome.

In phase 1 studies, dosing with telotristat ethyl in healthy subjects (dose range: 100 mg once daily to500 mg tid) produced statistically significant reductions from baseline in whole blood serotonin and24-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 inu5-HIAA were seen for telotristat ethyl 250 mg tid compared with placebo in both phase 3 studies.

The efficacy and safety of telotristat for the treatment of carcinoid syndrome in patients withmetastatic neuroendocrine tumours who were receiving SSA therapy was established in a 12-weekdouble-blind, placebo-controlled, randomised, multicentre phase 3 trial in adult patients, whichincluded a 36-week extension during which all patients were treated with open-label telotristat(TELESTAR study).

A total of 135 patients were evaluated 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 neuroendocrinetumours 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 initiallyreceived 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 medicinal product (short-acting SSAtherapy) and anti-diarrhoeals for symptomatic relief but were required to be on stable-dose long-acting

SSA therapy for the duration of the DBT period. Xermelo was taken within 15 minutes before, orwithin 1 hour after food.

Table 2: BM response (TELESTAR study)

Telotristat ethyl

Parameter Placebo250 mg tid

Number of patients 45 45

BMs/day at baseline

Baseline mean (SD) 5.2 (1.35) 6.1 (2.07)

Primary endpoint: Number of patients 45 45change from baseline

Change averagedin BMs/day averagedover 12 weeks: mean ˗0.6 (0.83) ˗1.4 (1.37)over 12 weeks(SD)

Least square mean

- -- -0.6difference

ANCOVAa 97.5% CL for

- -- -1.16, -0.06differencep value --- 0.01

Percentage of Number of patients 45 45patients with durablecresponseb Responder, n (%) 9 (20.0) 20 (44.4)

Telotristat ethyl

Parameter Placebo250 mg tid

BM = bowel movement; CL=confidence limit; tid=three times daily; SD=standard deviation.

a. Analysis of covariance including treatment group and urinary 5-HIAA stratification atrandomisation as fixed effects, and the baseline number of BM as a fixed covariate.

b. Defined as the proportion of responders with ≥ 30% reduction in daily number of BMs for≥ 50% of time over the DBT period.

c. p =0.01

When the full effect of telotristat is observed (during the last 6 weeks of the DBT period) theproportion of responders with at least 30% BM reduction was 51% (23/45) in the 250 mg group versus22% (10/45) in the placebo group (post-hoc analysis).

In the 12-week DBT period of the study, average weekly reductions in BM frequency on telotristatwere observed as early as 3 weeks, with the greatest reductions occurring during the last 6 weeks ofthe DBT period, compared with placebo (refer to Figure 1).

Figure 1 - Mean change from baseline in BMs by study week during the DBT period, intent-to-treat population

Study week

Note: This figure plots the arithmetic mean and 95% confidence limits (CL) (based on normalapproximation) of the change from baseline in the number of daily bowel movements (counts/day)averaged at each week.

The proportions of patients reporting reductions from baseline in daily BM frequency (averaged over12 weeks) were:

- Patients with a mean reduction of at least 1 BM per day: 66.7% (telotristat ethyl 250 mg) and31.1% (placebo);

- Patients with a mean reduction of at least 1.5 BM per day: 46.7% (telotristat ethyl 250 mg) and20.0% (placebo);

- Patients with a mean reduction of at least 2 BM per day: 33.3% (telotristat ethyl 250 mg) and4.4% (placebo).

Table 3: u5-HIAA excretion at baseline and week 12 (TELESTAR study)

Telotristat ethyl

Parameter Placebo250 mg tidu5-HIAA excretion Number of patients 44 42(mg/24 hours) atbaseline Baseline meana (SD) 81.0 (161.01) 92.6 (114.90)

Number of patients 28 32

Percent change from

Percent change at weekbaseline in u5-HIAA 14.4 (57.80) -42.3 (41.96)12: Mean (SD)excretion (mg/24hours) at week 12 Estimate of treatment -53.4 c

- --difference (95% CL)b (-69.32, -38.79)

CL=confidence limit; tid=three times daily; SD=standard deviation; u5-HIAA = urinary5-hydroxyindoleacetic acid.

a. Baseline data based on all patients with data at baseline.

b. Statistical tests used a blocked 2-sample Wilcoxon Rank Sum statistic (van Elteren test)stratified by the u5-HIAA stratification at randomisation. CLs were based on the Hodges-

Lehmann estimator of the median paired difference.

c. p < 0.001

There was no significant difference between treatment groups for the endpoints of flushing andabdominal pain.

A post-hoc analysis showed that the average number of daily short-acting SSA injections used forrescue therapy over the 12-week DBT period was 0.3 and 0.7 in the telotristat ethyl 250 mg andplacebo groups, respectively.

A pre-specified patient exit interview substudy was conducted to assess relevance and clinicalmeaningfulness of symptom improvements in 35 patients. Questions were asked to blindedparticipants to further characterise the degree of change experienced during the trial. There were12 patients who were “very satisfied”, and all of them were on telotristat. The proportions of patientswho were “very satisfied” were 0/9 (0%) on placebo, 5/9 (56%) on telotristat ethyl 250 mg tid and7/15 (47%) on a higher dose of telotristat ethyl.

Overall, 18 patients (13.2%) prematurely discontinued from the study during the DBT period,7 patients in the placebo group, 3 in the telotristat ethyl 250 mg group and 8 in the higher dose group.

At the conclusion of the 12-week DBT period, 115 patients (85.2%) entered the 36-week open-labelextension period, where all patients were titrated to receive a higher dose of telotristat ethyl (500 mg)tid.

In a phase 3 study of similar design (TELECAST), a total of 76 patients were evaluated for efficacy.

The mean age was 63 years (range 35 to 84 years), 55% were male and 97% were white.

All patients had well-differentiated metastatic neuroendocrine tumour with carcinoid syndrome. Mostpatients (92.1%) had fewer than 4 BM per day and all except 9 were treated by SSA therapy.

The primary endpoint was the percent change from baseline in u5-HIAA at week 12. The meanu5-HIAA excretion at baseline was 69.1 mg/24 hours in the 250 mg group (n = 17) and84.8 mg/24 hours in the placebo group (n = 22). The percent change from baseline in u5-HIAAexcretion at week 12 was +97.7% in the placebo group versus -33.2% in the 250 mg group.

The mean number of daily BM at baseline was 2.2 and 2.5 respectively in the placebo (n =25) and250 mg group (n = 25). The change from baseline in daily BM averaged over 12 weeks was + 0.1 and

- 0.5 in the placebo and 250 mg groups respectively. Telotristat ethyl 250 mg showed that stoolconsistency, as measured by Bristol Stool Form Scale, was improved compared with placebo. Therewere 40% patients (10/25) with durable response (as defined in Table 2) in the telotristat ethyl 250 mggroup, versus 0% in the placebo group (0/26) (p = 0.001).

The long-term safety and tolerability of telotristat was evaluated in a nonpivotal (nonrandomised),phase 3, multicentre, open-label, long-term extension study. Patients having participated in any

Xermelo phase 2 or phase 3 carcinoid syndrome study were eligible to enter the study at the same doselevel and regimen as identified in their original study, for at least 84 weeks of treatment. No newsignificant safety signals were identified.

The secondary objective of this study was to evaluate changes in patients’ quality of life (QOL)through week 84. QOL was generally stable over the course of the study.

The European Medicines Agency has waived the obligation to submit the results of studies with

Xermelo in all subsets of the paediatric population in the treatment of carcinoid syndrome (seesection 4.2 for information on paediatric use).

The pharmacokinetics of telotristat ethyl and its active metabolite have been characterised in healthyvolunteers and patients with carcinoid syndrome.

After oral administration to healthy volunteers, telotristat ethyl was rapidly absorbed, and almostcompletely converted to its active metabolite. Peak plasma levels of telotristat ethyl were achieved in0.53 to 2.00 hours and those of the active metabolite in 1.50 to 3.00 hours after oral administration.

Following administration of a single 500 mg dose of telotristat ethyl (twice the recommended dose)under fasted conditions in healthy subjects, the mean Cmax and AUC0-inf were 4.4 ng/mL and6.23 ng*hr/mL, respectively for telotristat ethyl. The mean Cmax and AUC0-inf were 610 ng/mL and2 320 ng*hr/mL, respectively for telotristat.

In patients with carcinoid syndrome on long-acting SSA therapy, there was also a rapid conversion oftelotristat ethyl to its active metabolite. A high variability (% CV range of 18% to 99%) in telotristatethyl and its active metabolite parameters was observed within the overall PK. The mean PKparameters for telotristat ethyl and the active metabolite appeared unchanged between week 24 andweek 48, suggesting the achievement of steady-state conditions at or prior to week 24.

In a food effect study administration of telotristat ethyl 500 mg with a high-fat meal resulted in higherexposure to the parent compound (Cmax, AUC0-tlast, and AUC0-∞ being 112%, 272%, and 264% higher,respectively compared with the fasted state) and its active metabolite (Cmax, AUC0-tlast, and AUC0-∞,47%, 32%, and 33% higher, respectively compared with the fasted state).

Both telotristat ethyl and its active metabolite are > 99% bound to human plasma proteins.

After oral administration, telotristat ethyl undergoes hydrolysis via carboxylesterases to its active andmajor metabolite. The only metabolite of telotristat (active metabolite) representing consistently> 10% of total plasma drug-related material was its oxidative decarboxylated deaminated metabolite,

LP-951757. Systemic exposure to LP-951757 was about 35% of the systemic exposure to telotristat(active metabolite) in the mass balance study. LP-951757 was pharmacologically inactive at TPH1 invitro.

In vitro telotristat (active metabolite) caused a concentration dependent increase in CYP2B6 mRNAlevels (> 2-fold increase and > 20% of the positive control, with a maximum observed effect similar tothe positive control), suggesting possible CYP2B6 induction (see section 4.5).

Telotristat ethyl and its active metabolite were not shown to be inducers of CYP3A4 at systemicallyrelevant concentrations, based on in vitro findings. The potential of telotristat ethyl as an inducer of

CYP3A4 was not assessed at concentrations expectable at the intestinal level, due to its low solubilityin vitro.

In vitro telotristat ethyl engages in an allosteric interaction with CYP3A4 resulting at the same time ina reduced conversion of midazolam to 1’-OH-MDZ, and increased conversion to 4-OH-MDZ.

In an in vivo clinical drug-drug interaction (DDI) study with midazolam (a sensitive CYP3A4substrate), following administration of multiple doses of telotristat ethyl, the systemic exposure toconcomitant midazolam was significantly decreased (see section 4.5). When 3 mg midazolam wascoadministered orally after 5-day treatment with telotristat ethyl 500 mg tid (twice the recommendeddose), the mean Cmax, and AUC0-inf for midazolam were decreased by 25%, and 48%, respectively,compared with administration of midazolam alone. The mean Cmax, and AUC0-inf for the activemetabolite, 1’-hydroxymidazolam, were also decreased by 34%, and 48%, respectively.

Based on in vitro findings, no clinically-relevant interaction is expected with other cytochromes P450.

The IC50 of the inhibition of loperamide on the metabolism of telotristat ethyl by CES2 was 5.2 µM(see section 4.5).

In vitro, telotristat ethyl inhibited CES2 with an IC50 approximately of 0.56 μM.

In vitro telotristat ethyl inhibited P-gp, but its active metabolite did not at the clinically relevantconcentrations.

Telotristat ethyl inhibited MRP2-mediated transport (98% inhibition).

In a specific clinical DDI study, the Cmax and AUC of fexofenadine (a P-gp and MRP-2 substrate)increased by 16% when a single 180 mg dose of fexofenadine was co-administered orally with a doseof telotristat ethyl 500 mg administered tid (twice the recommended dose) for 5 days. Based on thesmall increase observed, clinically meaningful interactions with P-gp and MRP-2 substrates areunlikely.

In vitro telotristat ethyl inhibited BCRP (IC50 = 20 µM), but its active metabolite telotristat did notshow any significant inhibition of BCRP activity (IC50 > 30 µM). The potential for in vivo druginteraction via inhibition of BCRP is considered low.

Based on in vitro findings, no clinically-relevant interaction is expected with other transporters.

A study examining the effect of short-acting octreotide (3 doses of 200◦micrograms injectedsubcutaneously 8◦hours apart) on the single dose pharmacokinetics of telotristat ethyl 500◦mg innormal healthy volunteers showed an 86% and 81% decrease in geometric mean Cmax and AUC0-tlast oftelotristat ethyl (see section 4.5). Reduced exposures were not observed in a 12◦week double-blind,placebo-controlled, randomised, multicentre clinical study in adult patients with carcinoid syndromeon long-acting SSA therapy

Concomitant use of telotristat etiprate (Xermelo, the hippurate salt of telotristat ethyl) with acid-reducers (omeprazole and famotidine) showed that the AUC of telotristat ethyl was increased 2-3 fold,while the AUC of the active metabolite (telotristat) was not changed. Since telotristat ethyl is rapidlyconverted to its active metabolite, which is > 25 × more active than telotristat ethyl, no doseadjustments are required when using Xermelo with acid reducers.

Following a single 500 mg oral dose of 14C-telotristat ethyl, approximately 93% of the dose wasrecovered. The majority was eliminated in the faeces.

Telotristat ethyl and telotristat have a low renal elimination following oral administration (less than1% of the dose recovered from the urine).

Following a single oral 250 mg dose of telotristat ethyl to heathy volunteers, urine concentrations oftelotristat ethyl were close to or below the limit of quantification (< 0.1 ng/mL). The renal clearance oftelotristat was 0.126 L/h.

The apparent half-life of telotristat ethyl in normal healthy volunteers following a single 500 mg oraldose 14C-telotristat ethyl was approximately 0.6 hour and that of its active metabolite was 5 hours.

Following administration of 500 mg tid, the apparent terminal half-life was approximately 11 hours.

In patients treated at 250 mg tid, a slight accumulation of telotristat levels was observed with a medianaccumulation ratio based on AUC0-4h of 1.55 [minimum, 0.25; maximum, 5.00; n = 11; week 12], witha high inter-subject variability (%CV = 72%). In patients treated at 500 mg tid (twice therecommended dose), a median accumulation ratio based on AUC0-4h of 1.095 (minimum, 0.274;maximum, 11.46; n = 16; week 24) was observed, with a high inter-subject variability(%CV = 141.8%).

Based on the high inter-subject variability observed, accumulation in a subset of patients with CScannot be excluded.

The influence of age on the pharmacokinetics of telotristat ethyl and its active metabolite has not beenconclusively evaluated. No specific study has been performed in the elderly population.

A study was conducted to investigate the impact of renal impairment on the pharmacokinetics of asingle dose of telotristat ethyl 250 mg. Eight subjects with severe to moderate renal impairment notrequiring dialysis [eGFR ≤ 33 mL/min at screening and ≤40 mL/min at the day prior to dosing] andeight healthy to mildly impaired subjects [eGFR ≥ 88 mL/min at screening and ≥ 83 mL/min at theday prior to dosing] were included in this study.

In the subjects with severe to moderate renal impairment, an increase (1.3-fold) in peak exposure

Cmax of telotristat ethyl and an increase (< 1.52-fold) in plasma exposure (AUC) and Cmax of itsactive metabolite telotristat was observed compared to healthy to mildly impaired subjects.

Variability of the main plasma telotristat PK parameters was higher in subjects with severe tomoderate renal impairment, with CV% ranging from 53.3% for Cmax to 77.3% for AUC as comparedto 45.4% for Cmax and 39.7% for AUC in healthy to mildly impaired subjects, respectively.

Administration of a single dose of 250 mg was well tolerated in subjects with severe to moderate renalimpairment.

Overall, severe to moderate renal impairment did not result in a clinically meaningful change in the

PK profile or safety of telotristat ethyl and its metabolite telotristat. Therefore, dose adjustment doesnot appear necessary in patients with mild, moderate or severe renal impairment; who are not requiringdialysis. Given the high variability observed, it is recommended as a precautionary measure thatpatients with severe renal impairment will be monitored for signs of reduced tolerability.

The efficacy and safety in patients with end-stage renal disease who require dialysis(eGFR < 15 mL/min/1.73 m² requiring dialysis) has not been established.

A hepatic impairment study was conducted in subjects with mild and moderate hepatic impairmentand in healthy subjects. At a single dose of 500 mg, exposures to the parent compound and its activemetabolite (based on AUC0-last) were higher in patients with mild hepatic impairment (2.3- and2.4-fold, respectively) and in patients with moderate hepatic impairment (3.2- and 3.5-fold,respectively) compared with healthy subjects. Administration of a single dose of 500 mg was welltolerated. A reduction in dose may be necessary in patients with mild or moderate hepatic impairment(respectively Child Pugh score A and B) based on tolerability (see section 4.2).

A further hepatic impairment study was conducted in subjects with severe hepatic impairment and inhealthy subjects. At a single dose of 250 mg, exposure to the parent compound (AUCt and Cmax) wasincreased 317.0% and 529.5%, respectively, and to the active metabolite (AUCt, AUCinf, and Cmax)497%, 500%, and 217%, respectively, for subjects with severe hepatic impairment compared tosubjects with normal hepatic function. In addition, the half-life of the active metabolite was increased,i.e. the mean half life was 16.0 hours in subjects with severe hepatic impairment compared to5.47 hours in healthy subjects. Based on these findings, the use of telotristat etiprate is notrecommended in patients with severe hepatic impairment (Child Pugh score C) (see section 4.2).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeat dose toxicity, genotoxicity, carcinogenic potential.

In rats decrease in brain serotonin (5-HT) was observed at doses ≥ 1 000 mg/kg/day of telotristatetiprate per os. Brain 5-HIAA levels were unchanged at all doses of telotristat ethyl examined. This isapproximately 14 times the human exposure (AUC total) at the maximum recommended human dose(MRHD) of 750 mg/day for the active metabolite LP-778902.

In a 26-week repeat-dose toxicity study in rats a No-Observed Adverse Effect Level (NOAEL) of50 mg/kg/day was determined. This is approximately 0.4 times the human exposure (AUC total) at

MRHD of 750 mg/day for the active metabolite LP-778902. At doses of 200 and 500 mg/kg/daydegeneration/necrosis in the nonglandular and/or glandular portions of the stomach and/or increasedprotein droplets in the glandular portions were observed. The microscopic changes in thegastrointestinal tract reversed with a 4-week recovery period. Relevance of these gastrointestinalfindings to humans is unknown.

In dogs decreases in brain 5-HT and 5-HIAA levels were observed at dose of 200 mg/kg/day and30 mg/kg/day of telotristat etiprate per os, respectively. This is approximately 21 times the humanexposure (AUC total) at MRHD of 750 mg/day for the active metabolite LP-778902. No decrease inbrain 5-HT and 5-HIAA levels were observed after intravenous application of active metabolite. Theclinical significance of the decrease in brain 5-HIAA with or without a concomitant decrease in brain5-HT is unknown.

In a 39-week repeat-dose toxicity study in dogs NOAEL of 300 mg/kg/day was determined. Clinicalsigns were limited to increase in frequency of liquid faeces at all doses. This is approximately 20 timesthe human exposure (AUC total) at MRHD of 750 mg/day for the active metabolite LP-778902.

The carcinogenic potential of telotristat etiprate was studied in transgenic mice (26 weeks) and rats(104 weeks). These studies confirmed that telotristat did not increase the incidence of tumours in bothspecies and sexes, at doses corresponding to an exposure of approximately 10- to 15-fold and 2- to4.5-fold the human exposure to the active metabolite at the MRHD in mice and rats, respectively.

In rats, there were no adverse effects on male and female fertility. Prenatal development in rats andrabbits was affected by increased prenatal lethality (increased early and late resorptions), while noadverse effects were noted on postnatal development in rats. The NOAEL forparental/maternal/prenatal and postnatal toxicity is 500 mg/kg/day in rats corresponding to 3 to 4 timesthe estimated human exposure (AUC0-24) of the active metabolite LP-778902 at the MRHD. In rabbitsthe NOAEL for maternal and prenatal toxicity is 125 mg/kg/d corresponding to 1.5 to 4 times theestimated human exposure (AUC0-24) of the active metabolite LP-778902 at the MRHD.

Hydroxypropylcellulose

Croscarmellose sodium

Magnesium stearate

Colloidal anhydrous silica

Poly(vinyl alcohol) (E1203)

Titanium dioxide (E171)

Macrogol 3350 (E1521)

Talc (E553b)

Not applicable.

5 years

This medicinal product does not require any special storage conditions.

PVC/PCTFE/PVC/Al blister

The blisters are packaged in a carton.

Pack sizes of 90 and 180 film-coated tablets. Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

SERB SAS40 Avenue George V75008 Paris

France

EU/1/17/1224/001

EU/1/17/1224/002

Date of first authorisation: 18 September 2017

Date of latest renewal: 14 June 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.