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  • CLASSES

    Tryptophan Hydroxylase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Tryptophan hydroxylase inhibitor
    Indicated for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy alone
    Most common adverse reactions include nausea, headache, increased GGT, depression, flatulence, decreased appetite, peripheral edema, and pyrexia; constipation has also been reported, with rare GI obstruction or perforation

    COMMON BRAND NAMES

    Xermelo

    HOW SUPPLIED

    Xermelo Oral Tab: 250mg

    DOSAGE & INDICATIONS

    For the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in patients inadequately controlled by SSA therapy.
    Oral dosage
    Adults

    250 mg orally three times daily. If taking with short-acting octreotide, administer telotristat ethyl at least 30 minutes before short-acting octreotide. In a multicenter, double-blind clinical trial, patients with well-differentiated metastatic neuroendocrine tumor and carcinoid syndrome diarrhea despite stable SSA therapy for at least 3 months were randomized to treatment with telotristat ethyl (n = 45) or placebo (n = 45). Baseline SSA therapy was continued along with rescue medications (i.e., short-acting octreotide) and antidiarrheal therapy (i.e., loperamide). Treatment with telotristat ethyl resulted in a mean change of -1.4 +/- 1.4 daily bowel movements from baseline, while placebo resulted in -0.6 +/- 0.8 daily bowel movements from baseline (p < 0.001); other symptoms such as abdominal pain or flushing were not improved. Increasing the dose of telotristat ethyl to 500 mg three times daily increased the incidence of adverse reactions without increasing benefit, and is not recommended.

    MAXIMUM DOSAGE

    Adults

    250 mg orally three times daily.

    Geriatric

    250 mg orally three times daily.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild hepatic impairment (Child-Pugh Class A): No dosage adjustment is necessary; however, additional monitoring for telotristat-related adverse reactions (e.g., constipation) is recommended.
    Moderate to severe hepatic impairment (Child-Pugh Class B or C): Treatment with telotristat ethyl is not recommended.

    Renal Impairment

    Mild, moderate, or severe renal impairment (excluding dialysis): No dosage adjustment is necessary.
    End-stage renal disease (ESRD) requiring dialysis (eGFR less than 15 mL/min/1.73 m2): Information is not available.

    ADMINISTRATION

    Oral Administration

    Administer telotristat ethyl orally with food.
    If a dose is missed, take the next dose at the regular time; do not double the dose to make up for a missed dose.

    STORAGE

    Xermelo:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Abdominal pain, constipation, GI obstruction, GI perforation

    Constipation, GI obstruction, and GI perforation have been reported with telotristat ethyl therapy. Monitor patients for constipation and abdominal pain, as patients with metastatic carcinoid tumors may have impaired gut integrity. Discontinue telotristat ethyl in patients with severe constipation or with severe, persistent, or worsening abdominal pain. In a 12-week placebo-controlled trial in which patients with 4 or more daily bowel movements were treated with a higher than recommended dose of telotristat ethyl (n = 45), 2 patients reported constipation; one patient required hospitalization. During the 36-week extension period of this trial (n = 115), 10 patients receiving higher than the recommended dose developed constipation, including one patient with GI perforation and one with GI obstruction. The incidence was higher in a separate 12-week placebo-controlled trial in which patients had less than 4 daily bowel movements and were treated with the recommended dose of telotristat ethyl (4 of 25 patients).

    Pregnancy

    Although there are not adequately controlled human studies in pregnancy, no effects on embryo-fetal development were observed with the administration of oral telotristat ethyl to rats during organogenesis at exposures up to approximately 9 times the exposure at the recommended human dose. In a pre-/postnatal development study that administered telotristat ethyl during organogenesis through lactation, an increased incidence of mortality in rat offspring was observed during postnatal days 0 to 4 at maternal exposures approximately 5 times that achieved with the recommended human dose; however, no developmental abnormalities or effects on growth, learning and memory, or reproductive performance were observed in surviving offspring. When administered to pregnant rabbits during organogenesis, maternal toxicity and postimplantation loss occurred at exposures approximately 15 times what is achieved with the recommended human dose, and reduced fetal weight at approximately 33 times the exposure at the recommended human dose.

    Breast-feeding

    Use telotristat ethyl with caution in women who are breast-feeding, due to the absence of available data in human or animal milk. Monitor the breast-fed infant for symptoms of constipation; the effects of local gastrointestinal and systemic exposure to telotristat ethyl on breast-fed infants are unknown. Consider the risks and benefits of treatment with telotristat ethyl and breast-feeding.

    ADVERSE REACTIONS

    Severe

    GI obstruction / Delayed / 0-1.0
    GI perforation / Delayed / 0-1.0

    Moderate

    constipation / Delayed / 4.4-16.0
    elevated hepatic enzymes / Delayed / 0-9.0
    depression / Delayed / 9.0-9.0
    peripheral edema / Delayed / 7.0-7.0

    Mild

    nausea / Early / 13.0-13.0
    headache / Early / 11.0-11.0
    flatulence / Early / 7.0-7.0
    anorexia / Delayed / 7.0-7.0
    fever / Early / 7.0-7.0
    abdominal pain / Early / 5.0

    DRUG INTERACTIONS

    Acetaminophen; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with telotristat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If telotristat is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Telotristat is a weak CYP3A4 inducer. Concomitant use with telotristat can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Acetaminophen; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of hydrocodone as needed. If telotristat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with telotristat ethyl is necessary; consider increasing the dose of oxycodone as needed. If telotristat ethyl is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and telotristat ethyl is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Alfentanil: (Moderate) Consider an increased dose of alfentanil and monitor for evidence of opioid withdrawal if coadministration with telotristat is necessary. If telotristat is discontinued, consider reducing the alfentanil dosage and monitor for evidence of respiratory depression. Coadministration of a weak CYP3A4 inducer like telotristat with alfentanil, a CYP3A4 substrate, may decrease exposure to alfentanil resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to alfentanil. Alfentanil plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with telotristat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If telotristat is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Telotristat is a weak CYP3A4 inducer. Concomitant use with telotristat can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with telotristat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If telotristat is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Telotristat is a weak CYP3A4 inducer. Concomitant use with telotristat can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with telotristat ethyl is necessary; consider increasing the dose of oxycodone as needed. If telotristat ethyl is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and telotristat ethyl is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Avanafil: (Major) Coadministration of avanafil with telotristat is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
    Benzhydrocodone; Acetaminophen: (Moderate) Monitor for reduced efficacy of benzhydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of benzhydrocodone as needed. If telotristat is discontinued, consider a dose reduction of benzhydrocodone and frequently monitor for signs of respiratory depression and sedation. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of hydrocodone as needed. If telotristat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of hydrocodone as needed. If telotristat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Buprenorphine: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with telotristat is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If telotristat is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and telotristat is a CYP3A4 inducer.
    Buprenorphine; Naloxone: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with telotristat is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If telotristat is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and telotristat is a CYP3A4 inducer.
    Buspirone: (Moderate) Use caution if coadministration of telotristat ethyl and buspirone is necessary, as the systemic exposure of buspirone may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of buspirone; consider increasing the dose of buspirone if necessary. Buspirone is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with telotristat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If telotristat is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Telotristat is a weak CYP3A4 inducer. Concomitant use with telotristat can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Carbamazepine: (Moderate) Monitor carbamazepine concentrations closely during coadministration of telotristat; carbamazepine dose adjustments may be needed. Concomitant use may decrease carbamazepine concentrations. Carbamazepine is a CYP3A4 substrate and telotristat is a CYP3A4 inducer.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of hydrocodone as needed. If telotristat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of hydrocodone as needed. If telotristat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Cariprazine: (Major) Coadministration of cariprazine with telotristat is not recommended as the net effect of CYP3A4 induction on cariprazine and its metabolites is unclear. Cariprazine is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Coadministration of cariprazine with CYP3A4 inducers has not been evaluated.
    Chlorpheniramine; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with telotristat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If telotristat is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Telotristat is a weak CYP3A4 inducer. Concomitant use with telotristat can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of hydrocodone as needed. If telotristat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Chlorpheniramine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of hydrocodone as needed. If telotristat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of hydrocodone as needed. If telotristat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of hydrocodone as needed. If telotristat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Clozapine: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with telotristat. Consideration should be given to increasing the clozapine dose if necessary. When telotristat is discontinued, reduce the clozapine dose based on clinical response. Telotristat is a weak inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
    Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with telotristat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If telotristat is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Telotristat is a weak CYP3A4 inducer. Concomitant use with telotristat can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Codeine; Guaifenesin: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with telotristat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If telotristat is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Telotristat is a weak CYP3A4 inducer. Concomitant use with telotristat can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with telotristat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If telotristat is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Telotristat is a weak CYP3A4 inducer. Concomitant use with telotristat can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Codeine; Phenylephrine; Promethazine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with telotristat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If telotristat is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Telotristat is a weak CYP3A4 inducer. Concomitant use with telotristat can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Codeine; Promethazine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with telotristat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If telotristat is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Telotristat is a weak CYP3A4 inducer. Concomitant use with telotristat can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Cyclosporine: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with telotristat is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; telotristat is a weak CYP3A4 inducer.
    Diazepam: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with telotristat is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A4 and CYP2B6 substrate. Telotristat is a weak CYP3A4 inducer and based on in vitro studies, Potential induction of CYP2B6 in vivo by telotristat cannot be ruled out.
    Dihydroergotamine: (Moderate) Use caution if coadministration of telotristat ethyl and dihydroergotamine is necessary, as the systemic exposure of dihydroergotamine may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of dihydroergotamine; consider increasing the dose of dihydroergotamine if necessary. Dihydroergotamine is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of hydrocodone as needed. If telotristat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Doravirine: (Minor) Concurrent administration of doravirine and telotristat may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; telotristat is a weak CYP3A4 inducer.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Minor) Concurrent administration of doravirine and telotristat may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; telotristat is a weak CYP3A4 inducer.
    Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of telotristat ethyl is necessary. If telotristat ethyl is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like telotristat ethyl with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
    Guaifenesin; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of hydrocodone as needed. If telotristat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of hydrocodone as needed. If telotristat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Homatropine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of hydrocodone as needed. If telotristat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of hydrocodone as needed. If telotristat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone; Ibuprofen: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of hydrocodone as needed. If telotristat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone; Phenylephrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of hydrocodone as needed. If telotristat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of hydrocodone as needed. If telotristat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of hydrocodone as needed. If telotristat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of hydrocodone as needed. If telotristat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with telotristat ethyl is necessary; consider increasing the dose of oxycodone as needed. If telotristat ethyl is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and telotristat ethyl is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Isradipine: (Moderate) Monitor for decreased efficacy of isradipine if coadministration with telotristat is necessary. Concomitant use may decrease isradipine exposure. Isradipine is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer.
    Lumateperone: (Major) Avoid coadministration of lumateperone and telotristat as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; telotristat is a weak CYP3A4 inducer.
    Mefloquine: (Moderate) Use mefloquine with caution if coadministration with telotristat is necessary as concurrent use may decrease mefloquine exposure and efficacy. Mefloquine is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer.
    Methadone: (Moderate) Monitor for reduced efficacy of methadone and signs of opioid withdrawal if coadministration with telotristat is necessary; these effects may be more pronounced with telotristat as it can induce multiple CYP enzymes. Consider increasing the dose of methadone as needed. If telotristat is discontinued, consider a dose reduction of methadone and frequently monitor for signs of respiratory depression and sedation. Methadone is a substrate of CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6. Telotristat is a weak CYP3A4 inducer and based on in vitro studies, potential induction of CYP2B6 in vivo by telotristat cannot be ruled out. Concomitant use can decrease methadone exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with telotristat is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer.
    Nimodipine: (Moderate) Monitor for decreased efficacy of nimodipine if coadministration with telotristat is necessary as concomitant use may decrease plasma concentrations of nimodipine. Nimodipine is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with telotristat as concurrent use may decrease nisoldipine exposure and efficacy. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and telotristat is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
    Octreotide: (Moderate) Administer short-acting octreotide at least 30 minutes after the administration of telotristat ethyl if concomitant use is necessary. Telotristat ethyl is indicated for use in combination with somatostatin analogs, including octreotide, and patients in clinical trials received rescue treatment with short-acting octreotide and antidiarrheal medications (i.e., loperamide). However, systemic exposures of telotristat ethyl and its active metabolite were significantly decreased by short-acting octreotide in a pharmacokinetic study. When a single telotristat ethyl 500-mg PO dose (twice the recommended dose) was administered with a short-acting octreotide 200-mcg subcutaneous dose, the mean telotristat ethyl Cmax decreased by 86% and the mean telotristat ethyl AUC(0-last) decreased by 81% in healthy volunteers. Additionally, the mean Cmax and AUC(0-last) values for the active metabolite, telotristat, were decreased by 79%, and 68%, respectively.
    Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with telotristat ethyl is necessary; consider increasing the dose of oxycodone as needed. If telotristat ethyl is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and telotristat ethyl is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Paclitaxel: (Moderate) Monitor for decreased efficacy of paclitaxel if coadministration with telotristat is necessary due to the risk of decreased plasma concentrations of paclitaxel. Paclitaxel is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer.
    Praziquantel: (Moderate) Monitor for reduced response to praziquantel if coadministered with telotristat. Concomitant use may produce therapeutically ineffective concentrations of praziquantel. In vitro and drug interactions studies suggest that the CYP3A4 isoenzyme is the major enzyme involved in praziquantel metabolism. Telotristat is a weak CYP3A4 inducer.
    Segesterone Acetate; Ethinyl Estradiol: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 28 days after discontinuation of telotristat. Telotristat is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
    Sildenafil: (Moderate) Monitor for decreased efficacy of sildenafil if coadministration with telotristat is necessary as concurrent use may decrease sildenafil exposure. Sildenafil is a sensitive CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Population pharmacokinetic analysis indicates an approximately 3-fold increase in sildenafil clearance with concomitant use of weak CYP3A4 inducers.
    Sirolimus: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of telotristat; a sirolimus dose adjustment may be necessary. Sirolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; telotristat is a weak CYP3A4 inducer.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if telotristat ethyl must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with telotristat ethyl is necessary; consider increasing the dose of sufentanil injection as needed. If telotristat ethyl is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs or respiratory depression and sedation. Sufentanil is a CYP3A4 substrate and telotristat ethyl is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with telotristat is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; telotristat is a weak CYP3A4 inducer.
    Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of tramadol as needed. If telotristat is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Tramadol; Acetaminophen: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with telotristat is necessary; consider increasing the dose of tramadol as needed. If telotristat is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Ubrogepant: (Major) Increase the initial and second dose of ubrogepant to 100 mg if coadministered with telotristat as concurrent use may decrease ubrogepant exposure and reduce its efficacy. Ubrogepant is a CYP3A4 substrate; telotristat is a weak CYP3A4 inducer.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with telotristat is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Telotristat is a weak CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.

    PREGNANCY AND LACTATION

    Pregnancy

    Although there are not adequately controlled human studies in pregnancy, no effects on embryo-fetal development were observed with the administration of oral telotristat ethyl to rats during organogenesis at exposures up to approximately 9 times the exposure at the recommended human dose. In a pre-/postnatal development study that administered telotristat ethyl during organogenesis through lactation, an increased incidence of mortality in rat offspring was observed during postnatal days 0 to 4 at maternal exposures approximately 5 times that achieved with the recommended human dose; however, no developmental abnormalities or effects on growth, learning and memory, or reproductive performance were observed in surviving offspring. When administered to pregnant rabbits during organogenesis, maternal toxicity and postimplantation loss occurred at exposures approximately 15 times what is achieved with the recommended human dose, and reduced fetal weight at approximately 33 times the exposure at the recommended human dose.

    Use telotristat ethyl with caution in women who are breast-feeding, due to the absence of available data in human or animal milk. Monitor the breast-fed infant for symptoms of constipation; the effects of local gastrointestinal and systemic exposure to telotristat ethyl on breast-fed infants are unknown. Consider the risks and benefits of treatment with telotristat ethyl and breast-feeding.

    MECHANISM OF ACTION

    Telotristat ethyl is metabolized to telotristat, an active metabolite that is 29 times more potent in vitro than telotristat ethyl. Telotristat inhibits tryptophan hydroxylase, which mediates the rate-limiting step in the formation of serotonin. Serotonin is overproduced in patients with carcinoid syndrome and plays a role in the secretion, motility, inflammation, and sensation of the gastrointestinal tract. By inhibiting tryptophan hydroxylase, telotristat ethyl and telotristat decrease the production of peripheral serotonin, which decreases the frequency of carcinoid syndrome diarrhea.

    PHARMACOKINETICS

    Telotristat ethyl is administered orally. Both telotristat ethyl and telotristat, its active metabolite, are greater than 99% bound to human plasma proteins. In healthy subjects, the apparent half-life of telotristat ethyl and telotristat after a single dose was approximately 0.6 hours and 5 hours, respectively. The apparent total clearance at steady state (CL/Fss) in healthy subjects was 2.7 L/hr and 152 L/hr for telotristat ethyl and telotristat, respectively. Following a single radiolabeled dose, 93.2% was recovered over 240 hours: 92.8% in the feces, and less than 0.4% in the urine.
     
    Affected cytochrome (CYP) 450 isoenzymes and drug transporters: CYP3A4, CYP2B6
    Telotristat ethyl undergoes hydrolysis via carboxylesterases to telotristat, its active metabolite, which is 29 times more potent than the parent compound. Systemic exposure to an acid metabolite of oxidative deaminated decarboxylated telotristat was about 35% of that of telotristat. Neither telotristat ethyl nor telotristat are substrates for CYP isoenzymes in vitro. Telotristat ethyl may decrease the efficacy of drugs that are CYP3A4 substrates. Coadministration with telotristat decreased the Cmax and AUC of midazolam by 25% and 48%, respectively. The Cmax and AUC of the active metabolite of midazolam were also decreased, suggesting that telotristat ethyl may increase the glucuronidation of the active metabolite. Based on in vitro studies, potential induction of CYP2B6 in vivo by telotristat ethyl cannot be ruled out. In vitro, telotristat ethyl (but not telotristat) inhibited P-glycoprotein (P-gp); however, clinically meaningful interactions with P-gp substrates are unlikely. Telotristat ethyl (but not telotristat) also inhibited BCRP at clinically relevant concentrations in vitro, but the in vivo drug interaction potential is low.
     
    Based on in vitro studies, the potential for telotristat ethyl, telotristat, and the acid metabolite of telotristat to inhibit major CYP enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5) and to induce CYP1A2 is low at the recommended dosage. The drug interaction potential via inhibition of OCT1, OCT2, OAT1, OAT3, OATP1B1, OATP1B3, or BSEP transporters by telotristat ethyl and telotristat, and the potential for inhibition of P-gp, BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1, OATP1B3, BSEP, and MRP2 transporters by the acid metabolite of telotristat, is low at the recommended dosage.

    Oral Route

    Under fasting conditions in healthy subjects, the mean Cmax of telotristat ethyl and telotristat after a single 500 mg dose (twice the recommended dose) was 4.4 ng/mL and 610 ng/mL, respectively, reached between 0.5 to 2 hours for the parent compound and 1 to 3 hours for the metabolite. At this dose, the mean AUC was 6.23 ng x hr/mL for telotristat ethyl and 2,320 ng x hr/mL for telotristat. After administration of a single dose, peak plasma concentrations and AUC of both telotristat ethyl and telotristat were dose-proportional over a range of 100 mg to 1,000 mg; plasma concentrations decreased in a biphasic manner after achieving peak concentrations.
     
    In patients with metastatic neuroendocrine tumors and carcinoid syndrome diarrhea treated with somatostatin analog therapy, the mean Cmax of telotristat ethyl and telotristat after 500 mg three times daily with meals (twice the recommended dose) was 7 ng/mL and 900 ng/mL, respectively, reached at approximately 1 and 2 hours after administration. In these patients, the mean AUC was 22 ng x hr/mL for telotristat ethyl and 3,000 ng x hr/mL for telotristat. The pharmacokinetic parameters for both telotristat ethyl and telotristat were highly variable (coefficient of variation, CV%, 55%). Accumulation for both telotristat ethyl and telotristat was negligible at steady-state.
     
    Exposure to telotristat ethyl and telotristat is significantly increased by administration with food. Following a high-fat meal, the Cmax and AUC of telotristat ethyl increased by 112% and 264% (Cmax, 908 ng/mL; AUC, 2,980 ng x hr/mL), respectively, compared to administration under fasting conditions. The Cmax and AUC of telotristat were increased by 47% and 33% (Cmax, 908 ng/mL; AUC, 2,980 ng x hr/mL), respectively, with a high-fat meal. Coadministration with omeprazole increased the Cmax and AUC of telotristat ethyl by 68% and 185%, respectively; however, there were no significant changes (less than 9%) to the Cmax and AUC of the active metabolite, telotristat. Coadministration with famotidine increased the Cmax and AUC of telotristat ethyl by 22% and 111%, respectively; again, there were no significant changes (less than 5%) to the Cmax and AUC of the active metabolite, telotristat. These changes in exposure are not considered to be clinically meaningful.