Xermelo: Uses, Dosage & Side Effects

What Is Xermelo and What Is It Used For?

Xermelo contains the active substance telotristat ethyl, a first-in-class tryptophan hydroxylase (TPH) inhibitor. It was developed specifically to address a significant unmet medical need: the management of persistent diarrhea in patients with carcinoid syndrome whose symptoms are not adequately controlled by somatostatin analogue (SSA) therapy alone. Approved by the European Medicines Agency (EMA) in 2017 and the U.S. Food and Drug Administration (FDA) in 2017, Xermelo represents a targeted pharmacological approach to reducing peripheral serotonin overproduction.

Carcinoid syndrome is a clinical condition that arises when neuroendocrine tumors (NETs), most commonly arising in the gastrointestinal tract or lungs, secrete excessive amounts of bioactive substances into the systemic circulation. The most prominent of these substances is serotonin (5-hydroxytryptamine, or 5-HT). When neuroendocrine tumors metastasize to the liver, the liver can no longer effectively metabolize the serotonin before it reaches the systemic circulation, leading to the characteristic symptoms of carcinoid syndrome. These symptoms include watery diarrhea (often more than 4–6 bowel movements per day), episodic flushing of the face and upper body, wheezing, and in some cases right-sided heart valve disease (carcinoid heart disease).

The diarrhea associated with carcinoid syndrome can be profoundly debilitating. Patients may experience 10 or more bowel movements per day, leading to dehydration, electrolyte imbalances, malnutrition, and a significant reduction in quality of life. The standard first-line treatment for carcinoid syndrome is somatostatin analogues (SSAs) such as octreotide long-acting release (LAR) or lanreotide, which reduce hormone secretion from the tumors and partially control symptoms. However, a substantial proportion of patients—estimated at 20–40%—continue to experience inadequately controlled diarrhea despite optimized SSA therapy.

Xermelo addresses this problem through a novel mechanism. After oral administration, telotristat ethyl is rapidly hydrolyzed by carboxylesterases in the gut to its active metabolite, telotristat (also known as LP-778902). Telotristat is a potent inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in the biosynthesis of serotonin. Tryptophan hydroxylase catalyzes the conversion of the amino acid L-tryptophan to 5-hydroxytryptophan, which is then decarboxylated to serotonin. By blocking this enzymatic step peripherally (outside the brain), Xermelo reduces the production of serotonin by neuroendocrine tumor cells without significantly affecting serotonin levels in the central nervous system.

The clinical efficacy of Xermelo was demonstrated in the pivotal TELESTAR phase III randomized controlled trial, which enrolled patients with carcinoid syndrome who were experiencing at least four bowel movements per day despite stable SSA therapy. Patients treated with Xermelo 250 mg three times daily showed a statistically significant and clinically meaningful reduction in the average number of daily bowel movements compared with placebo (a reduction of approximately 1.7 bowel movements per day versus 0.9 for placebo). The reduction in urinary 5-hydroxyindoleacetic acid (5-HIAA), the primary serotonin metabolite, confirmed the pharmacological mechanism of action. The benefit was sustained in the open-label extension study (TELESTAR extension), where patients continued to show durable improvement over 84 weeks of treatment.

What Should You Know Before Taking Xermelo?

Contraindications

There is one absolute contraindication to the use of Xermelo:

• Hypersensitivity: Do not take Xermelo if you are allergic to telotristat ethyl or any of the other ingredients in the tablet (lactose, hydroxypropylcellulose, croscarmellose sodium, magnesium stearate, colloidal anhydrous silica, poly(vinyl alcohol), titanium dioxide, macrogol 3350, or talc).

Warnings and Precautions

Before and during treatment with Xermelo, discuss the following with your doctor:

• Liver problems: Xermelo is not recommended for patients with severe liver impairment. If you have mild or moderate liver problems, your doctor may decide to reduce your daily dose and will monitor your liver function more closely. Elevated liver enzymes, including gamma-glutamyltransferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), have been observed during treatment.
• End-stage kidney disease or dialysis: Xermelo has not been studied in patients with end-stage renal disease requiring dialysis. If you have severe kidney problems, discuss the risks and benefits with your doctor before starting treatment.
• Depression and mood changes: Some patients treated with Xermelo have experienced depression, depressed mood, and decreased interest in usual activities. Tell your doctor if you feel persistently sad, lose interest in activities you normally enjoy, or experience other changes in mood. Your doctor will evaluate whether continued treatment is appropriate.
• Constipation: Because Xermelo reduces the number of bowel movements, it can contribute to constipation, particularly when used alongside other anti-diarrheal medications. Report signs of significant constipation to your doctor, as severe constipation can lead to complications such as fecal impaction or bowel obstruction.

Your doctor will perform blood tests before you start Xermelo and periodically during treatment to monitor your liver function and assess your overall response to the medication.

Pregnancy and Breastfeeding

Xermelo should not be taken during pregnancy or if you are planning to become pregnant. The effects of telotristat ethyl on the developing fetus are not fully known, and preclinical data are limited. Women of childbearing potential should use effective contraception during treatment with Xermelo.

Breastfeeding is not recommended during treatment with Xermelo. It is not known whether telotristat ethyl or its active metabolite telotristat is excreted in human breast milk. Because of the potential risk to the nursing infant, a decision must be made whether to discontinue breastfeeding or discontinue the drug, taking into account the importance of the medication to the mother.

Driving and Operating Machinery

Xermelo may have a minor effect on your ability to drive or operate machinery. Fatigue has been reported as a common side effect. If you feel unusually tired after taking Xermelo, do not drive or use tools or machines until you feel well enough to do so safely.

Important Information About Ingredients

Xermelo tablets contain lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. Each tablet also contains less than 1 mmol sodium (23 mg), meaning it is essentially sodium-free.

Use in Children and Adolescents

Xermelo is not recommended for use in patients under 18 years of age. The safety and efficacy of telotristat ethyl have not been established in the pediatric population, and carcinoid syndrome is exceedingly rare in children.

How Does Xermelo Interact with Other Drugs?

Telotristat ethyl and its active metabolite telotristat can affect the way other medications work, and other medications can influence the effectiveness or side effect profile of Xermelo. The active metabolite telotristat is a substrate of CYP3A4 and can inhibit or induce certain CYP enzymes at clinically relevant concentrations. It is essential to inform your doctor about all prescription and non-prescription medications, herbal supplements, and vitamins you are taking.

Major Interactions

Other Notable Interactions

In clinical practice, patients with carcinoid syndrome are often taking multiple medications concurrently, including SSAs, anti-diarrheal agents, pancreatic enzyme supplements, and targeted anticancer therapies (such as everolimus or sunitinib). The potential for pharmacokinetic interactions means that careful monitoring and dose adjustments may be required when initiating or changing concomitant medications.

What Is the Correct Dosage of Xermelo?

Always take Xermelo exactly as your doctor or pharmacist has told you. The tablets should be swallowed whole with water, taken with a meal or a snack, and at approximately evenly spaced intervals throughout the day (for example, morning, midday, and evening). Taking Xermelo with food is important for optimal absorption.

Adults

Patients with Liver Problems

Children and Adolescents

Xermelo is not recommended for patients under 18 years of age. Carcinoid syndrome is extremely rare in the pediatric population, and the safety and efficacy of telotristat ethyl have not been studied in children or adolescents.

Elderly Patients

No dose adjustment is required for elderly patients based on age alone. However, elderly patients may be more likely to have reduced hepatic or renal function, and your doctor will consider these factors when determining the appropriate dose and monitoring schedule.

Missed Dose

If you forget to take a dose of Xermelo, skip the missed dose and take the next dose at the usual scheduled time. Do not take a double dose to make up for a forgotten dose. If you are unsure about when to take your next dose, contact your doctor or pharmacist for guidance.

Overdose

If you take more Xermelo than you should, you may experience nausea, vomiting, diarrhea, or abdominal pain. Contact your doctor or go to the nearest emergency department immediately. Bring the medicine packaging with you so that the healthcare team can identify what you have taken. There is no specific antidote for telotristat ethyl overdose; treatment is supportive and symptomatic.

What Are the Side Effects of Xermelo?

Like all medicines, Xermelo can cause side effects, although not everybody gets them. The majority of side effects observed in clinical trials were mild to moderate in severity. Your healthcare team will monitor you regularly and help manage any side effects that arise.

Signs Requiring Immediate Medical Attention

Side Effects by Frequency

Because Xermelo reduces the frequency of bowel movements by lowering serotonin production, patients should be aware that constipation is a pharmacological extension of the drug’s intended effect. This is particularly relevant for patients who are also taking other anti-diarrheal medications. If you notice a significant reduction in bowel movements or develop abdominal discomfort suggestive of constipation, inform your healthcare provider so that adjustments can be made to your treatment regimen.

Liver enzyme elevations, particularly of gamma-glutamyltransferase (GGT), were among the most commonly observed laboratory abnormalities in clinical trials. In the TELESTAR trial, elevations of GGT occurred more frequently in the Xermelo group compared with placebo. Elevations of ALT, AST, and alkaline phosphatase were also observed. Most elevations were grade 1–2 and did not require treatment discontinuation, but regular monitoring is essential to detect clinically significant hepatotoxicity early.

Depression and depressed mood were reported in clinical trials and post-marketing experience. The mechanism by which Xermelo might influence mood is not entirely clear, but reduced peripheral serotonin availability could theoretically have indirect neuropsychiatric effects. Patients with a history of depression or mood disorders should be monitored carefully, and any new or worsening psychiatric symptoms should be discussed with the treating physician.

How Should You Store Xermelo?

Xermelo does not require any special storage conditions. Store the tablets in the original packaging (blister pack) to protect them from light and moisture. Keep the medicine out of the sight and reach of children at all times.

Do not use Xermelo after the expiry date printed on the carton and blister after “EXP.” The expiry date refers to the last day of the stated month. Once expired, return unused tablets to your pharmacist for proper disposal.

Do not dispose of medications via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. These measures help to protect the environment and prevent accidental ingestion by others.

What Does Xermelo Contain?

Active Ingredient

Each film-coated tablet contains telotristat etiprate, equivalent to 250 mg of telotristat ethyl. Telotristat ethyl is a prodrug that is converted in the body to the pharmacologically active metabolite telotristat (LP-778902), a tryptophan hydroxylase inhibitor.

Inactive Ingredients

The other ingredients in Xermelo tablets are:

• Tablet core: Lactose, hydroxypropylcellulose, croscarmellose sodium, magnesium stearate, and colloidal anhydrous silica
• Film coating: Poly(vinyl alcohol) (E1203), titanium dioxide (E171), macrogol 3350 (E1521), and talc (E553b)

Appearance and Pack Sizes

Xermelo tablets are white to off-white, oval, film-coated tablets approximately 17 mm long and 7.5 mm wide. Each tablet is embossed with “T-E” on one side and “250” on the other side. The tablets are packaged in PVC/PCTFE/PVC/Al blisters within an outer carton. Xermelo is available in packs of 90 tablets and 180 tablets. Not all pack sizes may be marketed in all countries.