Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Xermelo: 250 mg
Pharmacology
Mechanism of Action
Telotristat ethyl is a small molecule inhibitor of tryptophan hydroxylase (TPH). TPH converts tryptophan to 5-hydroxytryptophan and ultimately to serotonin, and is the rate-limiting enzyme in serotonin synthesis (Kulke 2017). Decreased production of peripheral serotonin by telotristat ethyl results in a reduction in the frequency of carcinoid syndrome diarrhea.
Pharmacokinetics/Pharmacodynamics
Distribution
The high molecular weight and acidic moieties of telotristat ethyl inhibit the compound from crossing the blood brain barrier (Kulke 2017).
Metabolism
Telotristat ethyl is hydrolyzed via carboxylesterases to the metabolite telotristat (active); telotristat is further metabolized.
Excretion
Feces (~93%); urine (<1%)
Time to Peak
Telotristat ethyl: 0.5 to 2 hours; Telotristat: 1 to 3 hours
Half-Life Elimination
Telotristat ethyl: ~0.6 hours; Telotristat: ~5 hours
Protein Binding
>99%
Use: Labeled Indications
Carcinoid syndrome diarrhea: Treatment of carcinoid syndrome diarrhea (in combination with somatostatin analog therapy) in adults with symptoms inadequately controlled by somatostatin analog therapy
Contraindications
There are no contraindications listed within the manufacturer's labeling.
Dosage and Administration
Dosing: Adult
Carcinoid syndrome diarrhea: Oral: 250 mg 3 times daily
Missed dose: If a dose is missed, administer the next dose at the regularly scheduled time; do not take 2 doses at the same time.
Dosing: Geriatric
Refer to adult dosing.
Dosing: Adjustment for Toxicity
Gastrointestinal toxicity: Discontinue for severe constipation or for development of severe, persistent or worsening abdominal pain
Administration
Administer with food. If used in combination with short-acting octreotide, administer octreotide at least 30 minutes after telotristat ethyl. Rescue octreotide (short-acting) and antidiarrheals were allowed and unrestricted in a clinical study (Kulke 2017).
Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Drug Interactions
CloZAPine: CYP3A4 Inducers (Weak) may decrease the serum concentration of CloZAPine. Monitor therapy
NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Monitor therapy
Octreotide: May decrease the serum concentration of Telotristat Ethyl. Management: Administer short-acting octreotide at least 30 minutes after administration of telotristat ethyl and monitor for decreased telotristat ethyl efficacy. Consider therapy modification
Ubrogepant: CYP3A4 Inducers (Weak) may decrease the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a weak CYP3A4 inducer. Consider therapy modification
Adverse Reactions
>10%:
Central nervous system: Headache (11%)
Gastrointestinal: Nausea (13%)
1% to 10%:
Cardiovascular: Peripheral edema (7%)
Central nervous system: Depression (9%)
Endocrine & metabolic: Increased gamma-glutamyl transferase (9%)
Gastrointestinal: Decreased appetite (7%), flatulence (7%), abdominal pain (≥5%), constipation (≥5%)
Hepatic: Increased serum alkaline phosphatase (<5%), increased serum ALT (<5%), increased serum AST (<5%)
Miscellaneous: Fever (7%)
Warnings/Precautions
Concerns related to adverse effects:
- Gastrointestinal toxicity: Constipation has been reported in clinical trials. Although rarely serious, some events resulted in hospitalization, intestinal perforation or bowel obstruction (these events occurred at a dose higher than the recommended dose). Patients with advanced carcinoid tumors may be at risk for altered gastrointestinal tract wall integrity; monitor closely for constipation and/or severe, persistent, or worsening abdominal pain. Discontinue for severe constipation and/or the development of severe persistent or worsening abdominal pain.
Monitoring Parameters
Monitor for symptoms of constipation and/or severe, persistent, or worsening abdominal pain
Pregnancy
Pregnancy Considerations
Adverse events were observed in some animal reproduction studies.
