Telotristat Ethyl — Drug Monograph

Brand names: Xermelo

Drug class: Other

Mechanism of Action

Oral prodrug that is hydrolyzed by carboxylesterases to telotristat, a potent inhibitor of tryptophan hydroxylase (TPH1 and TPH2) — the rate-limiting enzyme in serotonin biosynthesis. By inhibiting TPH in enterochromaffin-like cells and NETs, telotristat reduces peripheral serotonin production. In carcinoid syndrome, tumor-derived serotonin excess causes the hallmark diarrhea and flushing; telotristat directly addresses the root biochemical cause rather than providing symptomatic relief. Because telotristat has limited CNS penetration, central serotonin synthesis (important for mood and…

FDA Indications

• Carcinoid syndrome diarrhea in adults inadequately controlled by somatostatin analogue (SSA) therapy — FDA approved February 2017 (based on TELESTAR Phase 3 trial)

Common Side Effects

• Nausea
• Flatulence
• Constipation
• Headache
• Fatigue
• Elevated GGT
• Abdominal pain
• Decreased appetite
• Peripheral edema
• Depressed mood (mild)

Clinical Pearl

The TELESTAR trial enrolled patients with ≥4 bowel movements per day on stable SSA therapy — a population with significant unmet need. Telotristat reduced mean daily BMs by ~1.7/day vs. placebo, with ~38% of patients achieving a ≥30% reduction sustained over 12 weeks. Importantly, constipation is the most clinically troublesome adverse effect — counsel patients to maintain hydration, dietary fiber, and immediately report ≥3 consecutive days without a bowel movement. CYP3A4 induction by…

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