Consumer medicine information

Xermelo

Telotristat ethyl

BRAND INFORMATION

Brand name

Xermelo

Active ingredient

Telotristat ethyl

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Xermelo.

What is in this leaflet

This leaflet answers some common questions about XERMELO. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking XERMELO against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What XERMELO is used for

This medicine contains the active substance telotristat ethyl.

XERMELO is used in adults for the treatment of a condition called 'carcinoid syndrome'. This is when a tumour, called a 'neuroendocrine tumour', releases a hormone called serotonin into your bloodstream.

When the tumour releases too much serotonin into your bloodstream you can get symptoms such as:

  • diarrhoea and stomach (abdominal) pain
  • flushing of your skin, particularly the face
  • low blood pressure
  • rash
  • weight loss.

The symptoms are not the same for everyone.

XERMELO works by reducing the amount of serotonin made by the tumour. It will reduce your diarrhoea.

Your doctor will prescribe XERMELO:

  • when your tumour has spread to different parts of your body
  • and if your diarrhoea is not well controlled with injections of other medicines called 'somatostatin analogues' (lanreotide or octreotide). You should keep having injections of these other medicines when taking XERMELO.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription.

Before you take XERMELO

When you must not take it

Do not take XERMELO if you have an allergy to:

  • telotristat ethyl
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take this medicine if you are pregnant. It is not known how XERMELO may affect the baby.

Do not breast-feed if you are taking this medicine. It is unknown if the active ingredient in XERMELO passes into breast milk and there is a possibility that your baby may be affected.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • if you have liver problems. This is because this medicine is not recommended for use in patients with severe liver problems. Your doctor may decide to decrease your daily dose of XERMELO in cases where your liver problems are considered mild or moderate. Your doctor will also monitor your liver.
  • if you have end-stage kidney disease or are on dialysis. This is because this medicine has not been tested in patients with end-stage kidney disease requiring dialysis.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Do not take XERMELO if you are pregnant or might become pregnant. It is not known how XERMELO may affect the baby.

  • Women should use effective methods of contraception while taking this medicine.
  • Do not breast-feed if you are taking XERMELO, as this medicine may be passed on to your baby.

If you are pregnant or breast-feeding, think you might be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

If you have not told your doctor about any of the above, tell them before you start taking XERMELO.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and XERMELO may interfere with each other. Tell your doctor or pharmacist if you are taking, have taken or are planning to take any of the following:

  • medicines for diarrhoea. XERMELO and these medicines reduce the number of your bowel movements and taken together, they can cause severe constipation. Your doctor may need to change the dose of your medicines.
  • medicines used to treat epilepsy, such as valproic acid, carbamazepine and topiramate.
  • medicines used to treat your neuroendocrine tumour, such as sunitinib or everolimus.
  • medicines to treat depression, such as sertraline.
  • medicine to treat smoking cessation, such as bupropion.
  • medicines used to avoid transplant rejection, such as ciclosporin.
  • medicines used to lower cholesterol levels, such as simvastatin and atorvastatin.
  • oral contraceptives, such as ethinyloestradiol.
  • medicines used to treat high blood pressure, such as amlodipine, nifedipine, felodipine, verapamil and diltiazem.
  • medicines used to treat some types of cancers, such as irinotecan, capecitabine and flutamide.
  • medicines used to reduce the chance of a blood clot forming, such as prasugrel
  • octreotide. If you need treatment with octreotide subcutaneous injection, you should have your injection at least 30 minutes after taking XERMELO.

If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking Xermelo. These medicines may be affected by XERMELO or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take XERMELO

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions in this leaflet, ask your doctor or pharmacist for help.

How much to take

The recommended dose is one tablet three times a day. If needed, your doctor may tell you to take a different dose.

If your symptoms do not improve, talk to your doctor.

How to take it

Swallow the tablets with food or a meal.

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

Take your medicine with food

How long to take it

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

Continue taking your medicine until you finish the pack.

Stop using this medicine when the redness and itching have gone.

If you forget to take it

If you forget a dose, take your next dose when it is due, skipping the missed dose.

Do not take a double dose to make up for the dose that you missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice if you think that you or anyone else may have taken too much XERMELO. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include feeling or being sick, diarrhoea or stomach pain.

While you are taking XERMELO

Things you must do

You should keep having injections of somatostatin analogues (lanreotide or octreotide) when taking XERMELO.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking XERMELO.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may carry out blood tests before you start taking this medicine and while you are taking it. This is to check that your liver is working normally.

Things you must not do

Do not take XERMELO to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how XERMELO affects you. This medicine may cause fatigue in some people. If you have this symptom, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking XERMELO.

This medicine helps most people with carcinoid syndrome, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Tell your doctor or pharmacist if you notice any of the following:

Very common side effects:

  • Stomach (abdominal) pain
  • Feeling tired or weak (fatigue)
  • Feeling sick (nausea)

Common side effects:

  • Wind
  • Fever
  • Headache
  • Constipation
  • Swollen stomach
  • Decreased appetite
  • Swelling (build-up of fluid in the body)
  • Depression. You may experience decreased self-esteem, lack of motivation, sadness or low mood

Uncommon side effects:

  • Impacted stools (faecaloma), constipation, watery diarrhoea
  • Pale skin (anaemia)
  • Vomiting, weight loss
  • Back pain or stomach pains particularly after eating or a reduction in passing water (urination)

Tell your doctor immediately if you experience any of the following side effects:

  • Breathing problems, rapid heartbeat
  • Fever
  • Incontinence (uncontrollable urination)
  • Confusion, dizziness or agitation.

Tell your doctor or pharmacist as soon as possible if you notice any of the following:

  • feeling or being sick, abnormally dark urine, yellow skin or eyes, pain in the upper right belly.

These may be signs that your liver is not working properly. This might also be shown by changes in your blood test results, such as an increase of liver enzymes.

These are serious side effects that may require medical attention. Liver disorders are common.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After taking XERMELO

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack, they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 30°C.

Do not store XERMELO or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

XERMELO tablets are white to off-white, film-coated and oval shaped. Each tablet is approximately 17 mm long by 7.5 mm wide with 'T-E' debossed on one side and '250' debossed on the other. The tablets are packaged in a PVC/PCTFE/PVC/Aluminium blister. The blisters are packaged in a carton of 90 tablets.

Ingredients

Each XERMELO tablet contains 250 mg of telotristat ethyl (free base) equivalent to 327.9 mg telotristat etiprate as the active ingredient. The inactive ingredients of XERMELO tablets include:

  • colloidal anhydrous silica
  • croscarmellose sodium
  • hyprolose
  • lactose
  • magnesium stearate
  • polyvinyl alcohol
  • titanium dioxide (E171)
  • macrogol 3350
  • purified talc (E553b).

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

XERMELO is sponsored in Australia by:

Ipsen Pty Ltd
Level 2, Building 4
Brandon Office Park
540 Springvale Road
Glen Waverley Victoria 3150
Telephone: 1800 317 033

This leaflet was prepared in June 2021

Australian Registration Number:

AUST R 291734

Published by MIMS November 2021

BRAND INFORMATION

Brand name

Xermelo

Active ingredient

Telotristat ethyl

Schedule

S4

 

1 Name of Medicine

Telotristat ethyl (as telotristat etiprate).

2 Qualitative and Quantitative Composition

Each Xermelo tablet contains 250 mg of telotristat ethyl (free base) equivalent to 327.9 mg telotristat etiprate as the active ingredient.

Excipients with known effect.

Sugars as lactose. Each tablet contains 167.91 mg of lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Xermelo tablets are white to off-white film-coated oval tablets with 'T-E' debossed on one side and '250' debossed on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of Administration

The recommended dose is 250 mg three times daily.
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 this time period.
Based on the high inter-subject variability observed, accumulation in a subset of patients with carcinoid syndrome cannot be excluded. Therefore, intake of higher doses is not recommended (see Section 5.2 Pharmacokinetic Properties).

Missed doses.

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

Special populations.

Elderly patients (65 years of age and above).

No dosage adjustments are required in elderly patients (see Section 5.2 Pharmacokinetic Properties).

Patients with renal impairment.

No change in dosage is required in patients with mild, moderate or severe renal impairment; who are not requiring dialysis (see Section 5.2 Pharmacokinetic Properties).
The efficacy and safety of Xermelo in patients with end-stage renal disease who require dialysis (eGFR < 15 mL/min/1.73 m2) has not been established.
The use of Xermelo is not recommended in patients with end-stage renal disease requiring dialysis (see Section 5.2 Pharmacokinetic Properties).

Patients with hepatic impairment.

In patients with mild hepatic impairment (Child Pugh class 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 class 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 class C) (see Section 5.2 Pharmacokinetic Properties).

Paediatric population.

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

Method of administration.

Oral use.
Xermelo should be taken with food (see Section 5.2 Pharmacokinetic Properties).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Hepatic enzymes elevations.

Elevations in hepatic enzymes were observed in clinical studies (see Section 4.8 Adverse Effects (Undesirable Effects)). 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 Adverse Effects (Undesirable Effects)). Patients should be advised to report any symptoms of depression, depressed mood and decreased interest to their physicians.

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration.

Use in the elderly.

No dosage adjustments are required in elderly patients (see Section 5.2 Pharmacokinetic Properties).

Paediatric use.

The safety and efficacy of telotristat in children and adolescents aged < 18 years have not yet been established. No data are available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 Pharmacokinetic Properties). 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.
A study examining the effect of short-acting octreotide (3 doses of 200 microgram given 8 hours apart) on the single dose pharmacokinetics of Xermelo in normal healthy volunteers showed an 83% and 81% decrease in Cmax and AUC of telotristat ethyl and telotristat, respectively. Reduced exposures were not observed in a 12 week double-blind, placebo-controlled, randomised, multicentre clinical trial in adult patients with carcinoid syndrome on long-acting SSA therapy.

Carboxylesterase 2 (CES2) inhibitors.

The IC50 of the inhibition of loperamide on the metabolism of telotristat ethyl by CES2 was 5.2 microM. In phase 3 clinical trials, telotristat was routinely combined with loperamide with no evidence of a change in exposure of telotristat or safety concerns.

Effect of Xermelo on other medicinal products.

CYP2B6 substrates.

Telotristat induced CYP2B6 in vitro (see Section 5.2 Pharmacokinetic Properties). 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.
In vitro telotristat (active metabolite) caused a concentration dependent increase in CYP2B6 mRNA levels (> 2-fold increase and > 20% of the positive control, with a maximum observed effect similar to the positive control), suggesting possible CYP2B6 induction.

CYP3A4 substrates.

Concomitant use of Xermelo may decrease the efficacy of medicinal products that are CYP3A4 substrates (e.g. midazolam, everolimus, sunitinib, simvastatin, atorvastatin, ethinylestradiol, amlodipine, nifedipine, felodipine, verapamil, diltiazem, ciclosporin, carbamazepine, topiramate, valproic acid) by decreasing their systemic exposure (see Section 5.2 Pharmacokinetic Properties). Monitoring for suboptimal efficacy is recommended.
Telotristat ethyl and its active metabolite were not shown to be inducers of CYP3A4 at systemically relevant 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 solubility in vitro. In vitro telotristat ethyl inhibited CYP3A4, suggesting a potential interaction with CYP3A4 substrates.
In an in vivo clinical drug-drug interaction (DDI) study with midazolam (a sensitive CYP3A4 substrate), following administration of multiple doses of telotristat ethyl, the systemic exposure to concomitant midazolam was significantly decreased. When 3 mg midazolam was co-administered orally after 5-day treatment with telotristat ethyl 500 mg three times daily (twice the recommended dosage), the mean Cmax, and AUC0-inf for midazolam were decreased by 25%, and 48%, respectively, compared to administration of midazolam alone. The mean Cmax, and AUC0-inf for the active metabolite, 1'-hydroxymidazolam, were also decreased by 34%, and 48%, respectively.

Other CYPs.

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

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). If co-administration is unavoidable, monitor for suboptimal efficacy and safety events.
In vitro, telotristat ethyl inhibited CES2 with an IC50 approximately of 0.56 microM.

P-glycoprotein (P-gp) and multi-drug resistance associated protein 2 (MRP-2).

Telotristat ethyl and telotristat are not substrates of the transporters P-gp and MRP-2.
Telotristat ethyl is an inhibitor of P-gp (IC50 2 microM) and it may increase the absorption of co-administered drugs that are substrates of this transporter.

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 dose of telotristat ethyl 500 mg administered tid (twice the recommended dose) for 5 days. Based on the small increase observed, clinically meaningful interactions with P-gp and MRP-2 substrates are unlikely.

Breast cancer resistance protein (BCRP).

In vitro telotristat ethyl inhibited BCRP (IC50 = 20 microM), but its active metabolite telotristat did not show any significant inhibition of BCRP activity (IC50 > 30 microM). The potential for in vivo drug interaction via inhibition of BCRP is considered low.

Other transporters.

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No studies on the effect of telotristat on human fertility have been conducted. Telotristat had no effect on fertility in rats at oral doses up to 500 mg/kg/day of telotristat etiprate (up to 2.5 times the clinical exposure to the active metabolite based on AUC).
(Category B3)
There are no data from the use of telotristat in pregnant women. Animal studies have shown reproductive toxicity (described below). Xermelo is not recommended during pregnancy and in women of childbearing potential not using contraception.
Women of childbearing potential should be advised to use adequate contraception during treatment with telotristat.
Telotristat was not teratogenic in rats or rabbits.
Telotristat etiprate administered orally to pregnant rats during organogenesis at up to 750 mg/kg/day (6 times the clinical exposure to the active metabolite based on AUC) did not affect embryofoetal development.
In rabbits, maternal toxicity and post-implantation losses were observed at ≥ 250 mg/kg/day telotristat etiprate (> 10 times the clinical exposure to the active metabolite based on AUC) and reduced foetal weights at 500 mg/kg/day telotristat etiprate (21 times the clinical exposure to the active metabolite based on AUC).
 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.
Telotristat etiprate administered to rats at 500 mg/kg/day during from gestation day 6 to lactation day 20 resulted in increased pup mortalities during postnatal days 0 to 4 (no effects at 200 mg/kg/day, exposure similar to the clinical exposure based on AUC), without effect on functional or behavioural development.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

Summary of 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 three times daily 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.

Description of selected adverse reactions.

Hepatic enzymes elevations.

Elevations in ALT > 3 x 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 Special Warnings and Precautions for Use.

Gastrointestinal disorders.

The most frequently reported adverse event in patients receiving telotristat 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).

Long-term safety study.

In a long-term open-label, extension study (TELEPATH) a total of 124 patients were enrolled with 22 patients receiving telotristat etiprate 250 mg tid and 102 receiving 500 mg tid. The mean duration of exposure was approximately 103 weeks. No new adverse effects were identified from this study.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

Symptoms.

There is limited clinical experience with telotristat overdose in humans. Gastro-intestinal 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: Other alimentary tract and metabolism products: Various alimentary tract and metabolism products.
ATC code: A16AX15.

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 gastro-intestinal 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 three times daily) 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 as shown in Table 3 and Table 4. Statistically significant reductions in u5-HIAA were seen for telotristat ethyl 250 mg three times daily compared with placebo in both Phase 3 studies.

Clinical trials.

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 in the TELESTAR Study (overall mean age of 63.6 years [range 37-88 years], 52% male, 90% white) were randomized 1:1:1 to receive treatment with placebo or Xermelo (250 mg or 500 mg three times daily) and were evaluated for efficacy. All patients had well-differentiated metastatic neuroendocrine tumours and carcinoid syndrome. They were on SSA therapy and had ≥ 4 daily bowel movements (BM).
The study included a 12-week double-blind treatment (DBT) period, in which patients initially received placebo (n=45), or Xermelo 250 mg (n=45) three times daily for one week, or a higher dose (telotristat ethyl 500 mg; n=45) tid (the 500 mg results are not presented as 500 mg tid is not a recommended dose). 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 stable-dose long-acting SSA therapy for the duration of the DBT period. Xermelo was taken within 15 minutes before, or within 1 hour after food.
The primary efficacy endpoint was the reduction in the mean number of daily BM averaged over the 12-week double-blind treatment period. Secondary endpoints included changes from baseline in u5-HIAA at Week 12, daily number of flushing episodes averaged over the 12-week double-blind treatment period and abdominal pain averaged over the 12-week double-blind treatment period. Other endpoints included the proportion of patients with durable response, defined as the proportion of responders with ≥ 30% reduction in daily number of BMs for ≥ 50% of time over the double blind treatment period and the change from Baseline in BM frequency averaged at each study week.
The efficacy of Xermelo was demonstrated through significantly greater reductions in BM frequency averaged over 12 weeks in both doses compared with placebo (p < 0.001). Statistically significant differences were also seen in reductions in BM frequency at Week 12, in percentage of patients with durable response, and in reductions in u5-HIAA excretion over 24 hours at Week 12 (Table 2 and Table 3).
When the full effect of telotristat is observed (during the last 6 weeks of the DBT period) the proportion of responders with at least 30% BM reduction was 51% (23/45) in the 250 mg group versus 22% (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 telotristat were observed as early as 3 weeks, with the greatest reductions occurring during the last 6 weeks of the DBT period, compared with placebo (see Figure 1).
The proportions of patients reporting reductions from baseline in daily BM frequency (averaged over 12 weeks) were:
- Patients with a mean reduction of at least 1 BM per day: 66.7% (telotristat ethyl 250 mg) and 31.1% (placebo);
- Patients with a mean reduction of at least 1.5 BM per day: 46.7% (telotristat ethyl 250 mg) and 20.0% (placebo);
- Patients with a mean reduction of at least 2 BM per day: 33.3% (telotristat ethyl 250 mg) and 4.4% (placebo).
There was no significant difference between treatment groups for the endpoints of flushing and abdominal pain.
A post-hoc analysis showed that the average number of daily short-acting SSA injections used for rescue therapy over the 12-week DBT period was 0.3 and 0.7 in the telotristat ethyl 250 mg and placebo groups, respectively.
A pre-specified patient exit interview substudy was conducted to assess relevance and clinical meaningfulness of symptom improvements in 35 patients. Questions were asked to blinded participants to further characterise the degree of change experienced during the trial. There were 12 patients who were "very satisfied", and all of them were on Xermelo. The proportions of patients who were "very satisfied" were 0/9 (0%) on placebo, 5/9 (56%) on Xermelo 250 mg three times daily, and 7/15 (47%) on a higher dose of Xermelo.
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-label extension period, where all patients were titrated to receive a higher dose of Xermelo three times daily. Patients then entered an extension study (TELEPATH) to evaluate long-term safety of telotristat.
In a phase 3 study of similar design (TELECAST), a total of 76 patients were evaluated for efficacy. The mean age 63 years (range 35-84 years), 55% male and 97% white. All patients had well-differentiated metastatic neuroendocrine tumour with carcinoid syndrome. Most patients (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 mean u5-HIAA excretion at baseline was 69.1 mg/24 hours in the 250 mg group (n=17) and 84.8 mg/24 hours in the placebo group (n=22). The percent change from baseline in u5-HIAA excretion at week 12 was +97.7% in the placebo group versus -33.2% in the 250 mg group (Table 4).
The mean number of daily BM at baseline was 2.2 and 2.5 respectively in the placebo (n=25) and 250 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 stool consistency, as measured by Bristol Stool Form Scale, was improved compared with placebo (Table 5). There were 40% patients (10/25) with durable response (as defined in Table 2) in the telotristat ethyl 250 mg group, versus 0% in the placebo group (0/26) (p=0.001).

5.2 Pharmacokinetic Properties

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

Absorption.

After oral administration of Xermelo to healthy volunteers, telotristat ethyl was rapidly absorbed, and almost completely converted to its active metabolite. Peak plasma levels of telotristat ethyl were achieved in 0.53 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 nanogram/mL and 6.23 nanogram.hr/mL, respectively for telotristat ethyl. The mean Cmax and AUC0-inf were 610 nanogram/mL and 2320 nanogram.hr/mL, respectively for telotristat.
In patients with carcinoid syndrome on long-acting SSA therapy, there was also a rapid conversion of telotristat ethyl to its active metabolite. A high variability (% CV range of 18% to 99%) in telotristat ethyl and its active metabolite parameters was observed within the overall PK. The mean PK parameters for telotristat ethyl and the active metabolite appeared unchanged between week 24 and week 48, suggesting the achievement of steady-state conditions at, or prior to, week 24.

Food effect.

In a food effect study administration of telotristat ethyl 500 mg with a high-fat meal resulted in higher exposure 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).

Distribution.

Both telotristat ethyl and its active metabolite are > 99% bound to human plasma proteins. From the population modelling, the apparent total volume of distribution for the active metabolite in patients with carcinoid syndrome was estimated at 348.7 L.

Metabolism.

After oral administration, telotristat ethyl undergoes hydrolysis via carboxylesterases to its active and major 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 in the mass balance study.
LP-951757 was pharmacologically inactive at TPH1 in vitro.

Excretion.

Following a single 500 mg oral dose of 14C-telotristat ethyl, approximately 93% of the dose was recovered. The majority was eliminated in the faeces, with less than 1% in the urine.
Following a single oral 250 mg dose of telotristat ethyl to heathy volunteers, urine concentrations of telotristat ethyl were close to or below the limit of quantification (< 0.1 nanogram/mL). The renal clearance of telotristat was 0.126 L/h, confirming that renal elimination is not a significant route of elimination for telotristat ethyl or the active metabolite (telotristat).
The apparent half-life of telotristat ethyl in normal healthy volunteers following a single 500 mg oral dose 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.

Linearity/non-linearity.

In patients treated at 250 mg three times daily, a slight accumulation of telotristat levels was observed with a median accumulation ratio based on AUC0-4h of 1.55 [minimum, 0.25; maximum, 5.00; n=11; week 12], with a high inter-subject variability (% CV = 72%). In patients treated at 500 mg tid (twice the recommended 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 CS cannot be excluded.

Pharmacokinetic/pharmacodynamic relationship(s).

Acid reducers.

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 rapidly converted to its active metabolite, which is > 25 times more active than telotristat ethyl, no dose adjustments are required when using Xermelo with acid reducers.

Pharmacokinetics in special patient populations.

Elderly.

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

Renal impairment.

A study was conducted at a single dose of 250 mg telotristat ethyl in eight subjects with severe renal impairment and eight healthy subjects. All renally impaired subjects had severely decreased renal function (eGFR < 30 mL/min/1.73 m2 not requiring dialysis).
An increase in Cmax of telotristat ethyl (1.3-fold) was observed in subjects with severe renal impairment compared with healthy subjects.
An increase (< 1.52 fold) in plasma exposure (AUC) and Cmax of the active metabolite (telotristat) was observed in subjects with severe renal impairment.
As the Cmax increase in telotristat ethyl and the total and unbound exposure increase (Cmax and AUC) in its active metabolite (telotristat) was less than 2-fold in subjects with severe renal impairment compared to healthy subjects, there is no expected clinical significance of the increase in exposure in subjects with severe renal impairment.
Overall, severe renal impairment, does not result in a clinically meaningful change in the PK profile of telotristat ethyl or its active metabolite (telotristat). A single oral dose of 250 mg telotristat ethyl was well tolerated in subjects with severe renal impairment and therefore it is not necessary to alter the dose in patients with mild, moderate or severe renal impairment; who are not requiring dialysis.
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.

Hepatic impairment.

A hepatic impairment study was conducted in subjects with mild and moderate hepatic impairment and in healthy subjects. At a single dose of 500 mg, exposures to the parent drug and its active metabolite (based on AUC0-last) were higher in patients with mild hepatic impairment (2.3- and 2.4-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 well tolerated. A reduction in dose may be necessary in patients with mild or moderate hepatic impairment (respectively Child Pugh class A and B) based on tolerability (see Section 4.2 Dose and Method of Administration).
A further hepatic impairment study was conducted in subjects with severe hepatic impairment and in healthy subjects. At a single dose of 250 mg, exposure to the parent compound (AUCt and Cmax) was increased 317.0% and 529.5%, respectively, and to the active metabolite (AUC0-last, AUCinf, and Cmax) 497%, 500%, and 217%, respectively, for subjects with severe hepatic impairment compared to subjects 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 to 5.47 hours in healthy subjects. Based on these findings, the use of telotristat etiprate is not recommended in patients with severe hepatic impairment (Child Pugh class C) (see Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

Telotristat ethyl was negative in the in vitro Ames test, the in vitro chromosomal aberration test using Chinese hamster ovary cells, and the in vivo rat micronucleus test.

Carcinogenicity.

The carcinogenic potential of telotristat etiprate was studied in transgenic (Tg.rasH2) mice (26 weeks) and rats (85-90 weeks). Telotristat etiprate was not tumourigenic in mice at oral doses up to 300 mg/kg/day (8-12 times the clinical exposure to the active metabolite based on AUC) or rats at oral doses up to 170 mg/kg/day (1-4 times the clinical exposure to the active metabolite based on AUC).

6 Pharmaceutical Particulars

6.1 List of Excipients

The inactive ingredients of Xermelo tablets are: colloidal anhydrous silica, croscarmellose sodium, hyprolose, lactose, magnesium stearate.
The tablet film-coating contains: polyvinyl alcohol, titanium dioxide, macrogol 3350, purified talc.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Xermelo telotristat ethyl (as telotristat etiprate) 250 mg film-coated tablets are supplied in PVC/PCTFE/PVC/Aluminium blister packs packaged in cartons of 90 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Telotristat etiprate is a white to off-white solid. The solubility is a function of pH at 25°C; at pH 1 (0.1 N HCl), the solubility is greater than 71 mg/mL, at pH 3 phosphate buffer, the solubility is 0.30 mg/mL, at a pH of 5 to 9, the solubility is negligible. In organic solvents, telotristat etiprate is freely soluble in methanol, dimethyl sulfoxide and tetrahydrofuran/water (1:1), soluble in acetone, sparingly soluble in ethanol and slightly soluble in acetonitrile. It is also slightly soluble in water.

Chemical structure.

Xermelo tablets contain telotristat ethyl, as telotristat etiprate, a tryptophan hydroxylase inhibitor. Telotristat etiprate is the hippuric acid salt form of telotristat ethyl (the free base). Telotristat is the active metabolite of the prodrug, telotristat ethyl. The chemical name for telotristat etiprate is: [(1S)-1-[[4-[2-amino-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl) phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-4-yl] phenyl] methyl]-2-ethoxy-2-oxo-ethyl] ammonium; 2-benzamidoacetate (IUPAC Name).
The molecular formula of telotristat etiprate is C27H26ClF3N6O3.C9H9NO3 and its molecular mass is 754.2. The molecular formula of telotristat ethyl is C27H26ClF3N6O3 and its molecular mass is 575.0.
Telotristat etiprate has two asymmetric centres with absolute configuration as indicated in the structure above (R, S configuration).
The pKa values of telotristat ethyl are pKa1 = 3.4 (pyrimidine, measured) and pKa2 = 6.7 (amine, measured).

CAS number.

CAS numbers: 1137608-69-5 (telotristat etiprate), 1033805-22-9 (telotristat ethyl free base).

7 Medicine Schedule (Poisons Standard)

Schedule 4.

Summary Table of Changes