XERMELO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for XERMELO (XERMELO).
Telotristat ethyl is a prodrug that is hydrolyzed to the active metabolite telotristat, an inhibitor of tryptophan hydroxylase (TPH). TPH is the rate-limiting enzyme in the peripheral conversion of tryptophan to serotonin. By inhibiting TPH, telotristat reduces serotonin production in the gut, thereby decreasing gastrointestinal motility and secretion, and reducing diarrhea associated with carcinoid syndrome.
| Metabolism | Telotristat ethyl is hydrolyzed by carboxylesterases to the active metabolite, telotristat. Further metabolism involves glucuronidation and oxidation, primarily via UGT1A1 and CYP3A4/5. |
| Excretion | Primarily excreted via feces (approximately 82% of absorbed dose) with a minor renal component (approximately 12% of absorbed dose as unchanged drug and metabolites). |
| Half-life | Terminal elimination half-life is approximately 6-10 hours in patients with carcinoid syndrome, supporting twice-daily dosing. In patients with moderate hepatic impairment, half-life may be prolonged to up to 19 hours. |
| Protein binding | Approximately 97% bound to plasma proteins, primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Apparent volume of distribution is approximately 1650 L (24 L/kg for a 70 kg individual), indicating extensive tissue distribution and binding to target receptors. |
| Bioavailability | Absolute oral bioavailability is approximately 65% (30-86% range) due to first-pass metabolism. Administration with food does not significantly alter overall exposure. |
| Onset of Action | Oral administration: Reduction in bowel movement frequency observed within 1-2 weeks of starting therapy. Time to peak plasma concentration is 2-5 hours post-dose. |
| Duration of Action | Duration of symptomatic control is sustained with twice-daily dosing. Steady-state is achieved within approximately 3-5 days. Clinical effect persists as long as regular dosing is maintained. |
| Molecular Weight | 446.53 |
250 mg orally three times daily with or without food.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (creatinine clearance ≥30 mL/min). Not recommended in severe renal impairment (creatinine clearance <30 mL/min) due to lack of data. |
| Liver impairment | No dose adjustment required for mild hepatic impairment (Child-Pugh class A). Not recommended in moderate or severe hepatic impairment (Child-Pugh class B or C) due to lack of data. |
| Pediatric use | Safety and efficacy have not been established in pediatric patients. |
| Geriatric use | No specific dose adjustments recommended based on age; consider renal and hepatic function as in adults. |
| 1st trimester | Teratogenic in animal studies; risk of fetal harm; avoid use in pregnancy unless no alternative. |
| 2nd trimester | Avoid use; no human data; based on animal data, may cause fetal harm. |
| 3rd trimester | Avoid use; potential risk of premature closure of ductus arteriosus and oligohydramnios due to NSAID component (telotristat ethyl is a pro-drug of a serotonin synthesis inhibitor, not an NSAID). Note: Xermelo (telotristat ethyl) is not an NSAID; however, caution advised in third trimester due to possible adverse effects on fetal circulation. |
Clinical note
Comprehensive clinical and safety monograph for XERMELO (XERMELO).
| Placental transfer | Not studied in humans; in animal studies, telotristat ethyl and its active metabolite cross the placenta at low levels. |
| Breastfeeding | No human data on presence in breast milk; due to potential for serious adverse reactions in breastfed infant, advise against breastfeeding during therapy and for at least 1 week after last dose. |
■ FDA Black Box Warning
None
| Serious Effects |
Hypersensitivity to telotristat ethyl or any component of the formulation
| Precautions | Should only be used in patients with carcinoid syndrome diarrhea inadequately controlled on SSA therapy, Monitor for constipation; serious constipation may lead to intestinal obstruction, especially in patients with underlying gastrointestinal obstruction or tumor, Discontinue if severe constipation develops, Risk of hepatotoxicity; monitor liver enzymes |
| Food/Dietary | Take with food to ensure adequate absorption. Avoid grapefruit and grapefruit juice as they may affect drug metabolism. No other specific food restrictions known. |
Loading safety data…
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | XERMELO (telotristat ethyl) is classified as Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. In animal studies, telotristat ethyl administered during organogenesis resulted in embryofetal toxicity (reduced fetal body weight, increased skeletal variations) at doses approximately 4 times the maximum recommended human dose (MRHD) based on AUC. In the first trimester, risk cannot be excluded; in second and third trimesters, fetal risks remain undefined due to lack of human data. |
| Fetal Monitoring | Maternal monitoring: assess renal function (serum creatinine, BUN) and hepatic function (ALT, AST, bilirubin) periodically due to potential excretion pathways. Fetal monitoring: standard prenatal care including ultrasound for growth and anatomy if exposure occurs during pregnancy. No specific fetal testing is required beyond usual obstetrical surveillance. |
| Fertility Effects | Animal studies in rats showed no adverse effects on male or female fertility with telotristat ethyl at doses up to 300 mg/kg/day (approximately 19 times MRHD based on AUC). However, clinical data on human fertility are lacking. In patients with carcinoid syndrome, underlying disease may impact fertility; treatment with XERMELO is not expected to impair fertility. |
| Clinical Pearls |
| XERMELO (telotristat ethyl) is indicated for carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy. Monitor for constipation, which may be severe; discontinue if severe constipation develops. No dose adjustment needed for mild to moderate hepatic impairment; not recommended for severe hepatic impairment. Administer with food to reduce variability in absorption. Do not use in patients with prior hypersensitivity reactions to telotristat ethyl. |
| Patient Advice | Take XERMELO exactly as prescribed, usually one 250 mg tablet three times daily with food. · Do not stop taking your somatostatin analog (e.g., octreotide) unless instructed by your doctor. · Inform your doctor immediately if you develop severe constipation, abdominal pain, or bloating. · Common side effects include mild nausea, headache, and flatulence; report persistent symptoms. · Store tablets at room temperature, away from moisture and heat. |