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Telotristat Ethyl

Pronunciation

(tel OH tri state ETH il)

Index Terms

  • LX1032
  • LX1606
  • Telotristat Etiprate
  • Xermelo

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Xermelo: 250 mg

Brand Names: U.S.

  • Xermelo

Pharmacologic Category

  • Tryptophan Hydroxylase Inhibitor

Pharmacology

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.

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.

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: Renal Impairment

CrCl >20 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling; however, population pharmacokinetic analysis suggests that CrCl 20 to 89 mL/minute does not affect telotristat pharmacokinetics.

End-stage renal disease (ESRD) requiring dialysis: There are no dosage adjustment provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

Mild impairment (total bilirubin >1 to 1.5 times ULN or AST > ULN): There are no dosage adjustments provided in the manufacturer’s labeling; however, population pharmacokinetic analysis suggests that mild hepatic impairment does not affect telotristat pharmacokinetics.

Moderate or severe impairment (total bilirubin >1.5 times ULN and any AST): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

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

HYDROcodone: CYP3A4 Inducers (Weak) may decrease the serum concentration of HYDROcodone. 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

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 Considerations

Adverse events were observed in some animal reproduction studies.

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