Telotristat

Brand names: Xermelo
Drug class: Antineoplastic Agents

Usage of Telotristat

Carcinoid Syndrome Diarrhea

Used (in combination with somatostatin analog therapy) for treatment of carcinoid syndrome diarrhea inadequately controlled by somatostatin analog therapy alone (designated an orphan drug by FDA for the treatment of carcinoid syndrome in patients with neuroendocrine tumors).

Carcinoid syndrome, a condition associated with serotonin overproduction, is characterized by flushing, diarrhea, wheezing, occasionally congestive heart failure, and various other manifestations. Although somatostatin analogs (e.g., octreotide, lanreotide) are standard treatment for carcinoid syndrome and are effective initially in most patients, some patients may not respond adequately or may develop recurrent symptoms, including diarrhea, despite therapy.

In clinical studies, Telotristat ethyl reduced the frequency of daily bowel movements in patients with carcinoid syndrome diarrhea. Reductions in other symptoms of carcinoid syndrome (e.g., abdominal pain, flushing) not observed.

Relate drugs

How to use Telotristat

General

  • Use in combination with a somatostatin analog (e.g., octreotide). (See Carcinoid Syndrome Diarrhea under Uses.)
  • In the pivotal efficacy study, rescue therapy with short-acting octreotide and antidiarrheals (e.g., loperamide) was allowed and unrestricted.
  • When used in combination with short-acting octreotide acetate, administer octreotide ≥30 minutes following administration of telotristat etiprate. (See Specific Drugs under Interactions.)

    • Restricted Distribution

  • Available only through specialty pharmacies. Consult the Xermelo website for specific information ([Web]).

    • Administration

    Oral Administration

    Administer orally 3 times daily with food. (See Food under Pharmacokinetics.)

    Dosage

    Available as telotristat etiprate (the hippurate salt of telotristat ethyl); dosage expressed in terms of telotristat ethyl (the free base).

    Adults

    Carcinoid Syndrome Diarrhea Oral

    250 mg 3 times daily; use in combination with a somatostatin analog.

    Higher dosages (e.g., 500 mg 3 times daily) have been studied in some patients, but increase the risk of adverse effects (e.g., severe constipation) without providing additional therapeutic benefit.

    Therapy Interruption for Toxicity GI Effects Oral

    If severe constipation or severe persistent or worsening abdominal pain occurs, discontinue therapy.

    Prescribing Limits

    Adults

    Carcinoid Syndrome Diarrhea Oral

    Dosages >250 mg 3 times daily not recommended.

    Special Populations

    Hepatic Impairment

    No specific dosage recommendations at this time. (See Hepatic Impairment under Cautions.)

    Renal Impairment

    No specific dosage recommendations at this time. (See Renal Impairment under Cautions.)

    Geriatric Patients

    No specific dosage recommendations at this time. (See Geriatric Use under Cautions.)

    Warnings

    Contraindications

  • Manufacturer states none known.

    • Warnings/Precautions

    Constipation

    Reduces bowel movement frequency; constipation reported. Severe constipation resulting in GI obstruction or perforation reported in patients receiving a higher than recommended dosage (500 mg 3 times daily).

    Because the integrity of the GI tract wall may be impaired in patients with metastatic carcinoid tumors, monitor patients for development of constipation and/or severe persistent or worsening abdominal pain. If such manifestations occur, discontinue therapy.

    Specific Populations

    Pregnancy

    Adequate data in pregnant women not available.

    Embryotoxicity (i.e., post-implantation loss, decreased fetal weight), maternal toxicity (i.e., mortality, impaired weight gain), and an increase in pup mortality on postnatal days 0–4 observed in animals at dosages tested.

    Lactation

    Not known whether telotristat ethyl distributes into human milk. Effects of the drug on nursing infants and on milk production also not known. In addition, effects of local GI and systemic exposure to the drug in breast-fed infants are unknown.

    Consider benefits of breast-feeding to the infant along with the women's clinical need for the drug and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition. Monitor breast-fed infants for symptoms of constipation. (See Constipation under Cautions.)

    Pediatric Use

    Safety and efficacy not established.

    Geriatric Use

    No overall differences in safety and efficacy observed in patients ≥65 years of age compared with younger adults, but increased sensitivity cannot be ruled out. (See Special Populations under Pharmacokinetics.)

    Hepatic Impairment

    Mild hepatic impairment does not alter pharmacokinetics of telotristat. Not studied in patients with moderate or severe hepatic impairment. (See Special Populations under Pharmacokinetics.)

    Renal Impairment

    Mild to moderate renal impairment (Clcr 20–89 mL/minute) does not substantially alter pharmacokinetics.

    Not studied in patients with end-stage renal disease requiring dialysis.

    Common Adverse Effects

    Nausea, headache, increased γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP) concentrations, depression, peripheral edema, flatulence, decreased appetite, pyrexia, abdominal pain, constipation.

    What other drugs will affect Telotristat

    Metabolized by carboxylesterases to telotristat. Telotristat further metabolized by decarboxylation and deamination, including to a major inactive metabolite; however, drug interaction potential of this metabolite unknown.

    Neither telotristat ethyl nor telotristat is a substrate of CYP isoenzymes in vitro. Telotristat ethyl and telotristat not adequately studied in vitro to indicate whether the drug or its active metabolite inhibit CYP isoenzymes 2B6, 2C8, or 2C9 or induce CYP isoenzymes 1A2 or 2B6. Effects on CYP3A4 not fully established. (See Drugs Metabolized by Hepatic Microsomal Enzymes under Interactions.)

    In vitro, telotristat ethyl inhibits P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). In vitro, telotristat is not an inhibitor of P-gp and BCRP, but is a substrate of P-gp at clinically relevant concentrations.

    Drugs Metabolized by Hepatic Microsomal Enzymes

    Substrates of CYP3A4: Possible pharmacokinetic interaction (decreased systemic exposure of CYP3A4 substrate and suboptimal efficacy). Monitor for signs of reduced efficacy of the CYP3A4 substrate, particularly drugs with a narrow therapeutic index, and consider increasing dosage of CYP3A4 substrate, if necessary. (See Specific Drugs under Interactions.)

    Drugs Affected by Transport Systems

    Clinically important pharmacokinetic interactions unlikely with substrates of P-gp, BCRP, organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT) 1, OAT3, organic anion transport protein (OATP) 1B1, OATP1B3, or bile salt export pump (BSEP). (See Specific Drugs under Interactions.)

    Drugs Affecting Gastric Acidity

    Solubility of telotristat ethyl Dependent on pH. Possible pharmacokinetic interaction with drugs that increase gastric pH. (See Specific Drugs under Interactions.)

    Specific Drugs

    Drug

    Interaction

    Comments

    Fexofenadine

    Telotristat ethyl did not alter AUC and peak concentrations of fexofenadine in healthy individuals

    Midazolam

    Telotristat ethyl decreased AUC and peak concentrations of midazolam (a CYP3A4 substrate) by 48 and 25%, respectively; AUC and peak concentrations of midazolam's active metabolite decreased by 48 and 34%, respectively

    Monitor for signs of reduced efficacy of CYP3A4 substrate; consider dosage increase of CYP3A4 substrate, if necessary

    Octreotide acetate

    Short-acting octreotide acetate decreased AUC and peak concentrations of telotristat ethyl by 81 and 86%, respectively; AUC and peak concentrations of telotristat decreased by 68 and 79%, respectively

    Administer short-acting octreotide acetate ≥30 minutes following administration of telotristat ethyl

    Proton-pump inhibitors (e.g., omeprazole)

    Not studied; possible pharmacokinetic interaction

    In principal efficacy study, 42% of patients received concomitant therapy with telotristat ethyl and drugs affecting gastric acidity

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