VITRAKVI

Small Molecule Antineoplastic Tropomyosin Receptor Kinase (TRK) Inhibitors

Emetic Risk
Minimal/Low
Administer prn antiemetics as necessary.

Oral Administration

The oral capsule and oral solution of larotrectinib may be used interchangeably.
Do not make up a missed dose within 6 hours of the next scheduled dose.
Avoid administration with grapefruit or grapefruit juice.
If vomiting occurs after taking a dose, take the next dose at the scheduled time.[63780]

Oral Solid Formulations

Do not chew or crush the larotrectinib capsules. Swallow capsules whole with water.[63780]

Oral Liquid Formulations

Read and become familiar with the manufacturer's complete "Instructions for Use" prior to preparing or administering the larotrectinib oral solution.
Write the date of opening the bottle on the bottle.
Each bottle of larotrectinib should be dispensed with 5 measured oral syringes (either 1 mL or 5 mL). Each syringe may be used over a 7-day period only.
A bottle adaptor should be utilized with the oral syringes per the manufacturer's "Instructions for Use".
Once the correct dosage is withdrawn per the manufacturer's "Instructions for Use", place the tip of the oral syringe into the patient's mouth against the side of the cheek and slowly squirt the oral solution into the mouth and allow the patient to swallow.
Keep the patient in an upright position for a few minutes right after giving the dose.
If the patient spits up the dose or if you are not sure the entire dose was given, do not give another dose and wait until the next scheduled dose.
Follow the manufacturer's "Instructions for Use" for cleaning the oral syringe.
Replace the oral syringe after 7 days, or if any of the conditions below apply to to the syringe:
there is any damage to the barrel, plunger, or tip
the dosage marking is no longer clearly recognizable
it becomes difficult to move the plunger
Storage: Store under refrigeration between 36 degrees F and 46 degrees F (2 degrees C and 8 degrees C). Do not freeze. Discard any unused larotrectinib oral solution remaining after 90 days of first opening the bottle.[63780]

Severe

hyperkalemia / Delayed / 15.0-36.0
neutropenia / Delayed / 14.0-14.0
anemia / Delayed / 10.0-10.0
bone fractures / Delayed / 7.0-9.0
lymphopenia / Delayed / 6.0-6.0
musculoskeletal pain / Early / 3.9-3.9
weight gain / Delayed / 3.6-3.6
elevated hepatic enzymes / Delayed / 2.5-3.1
dyspnea / Early / 3.0-3.0
hypocalcemia / Delayed / 2.6-2.6
fatigue / Early / 2.5-2.5
delirium / Early / 2.2-2.2
abdominal pain / Early / 2.2-2.2
leukopenia / Delayed / 1.9-1.9
hypoalbuminemia / Delayed / 1.9-1.9
fever / Early / 1.8-1.8
anorexia / Delayed / 1.4-1.4
diarrhea / Early / 1.4-1.4
infection / Delayed / 0-1.4
dizziness / Early / 1.1-1.1
edema / Delayed / 0.7-0.7
nausea / Early / 0.7-0.7
vomiting / Early / 0.7-0.7
weakness / Early / 0.7-0.7
headache / Early / 0.4-0.4
constipation / Delayed / 0.4-0.4
cough / Delayed / 0.4-0.4
rash / Early / 0.4-0.4
hepatotoxicity / Delayed / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known

Moderate

impaired cognition / Early / 11.0-11.0
depression / Delayed / 3.9-3.9
memory impairment / Delayed / 3.6-3.6
confusion / Early / 2.9-2.9
dehydration / Delayed / 1.0-1.0
amnesia / Delayed / Incidence not known
euphoria / Early / Incidence not known
hallucinations / Early / Incidence not known
aphasia / Delayed / Incidence not known
peripheral edema / Delayed / Incidence not known
cystitis / Delayed / Incidence not known
bone pain / Delayed / Incidence not known
bullous rash / Early / Incidence not known
palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known

Mild

nasal congestion / Early / 11.0-11.0
insomnia / Early / 7.0-7.0
anxiety / Delayed / 5.0-5.0
agitation / Early / 2.9-2.9
irritability / Delayed / 2.9-2.9
vertigo / Early / Incidence not known
asthenia / Delayed / Incidence not known
rhinitis / Early / Incidence not known
pharyngitis / Delayed / Incidence not known
maculopapular rash / Early / Incidence not known
acneiform rash / Delayed / Incidence not known

VITRAKVI, VITRAKVI Solution

Rx

Tissue agnostic kinase inhibitor
Used for the treatment of adult and pediatric patients 28 days and older with solid tumors that have a neurotrophic receptor tyrosine kinase gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment
Severe adverse events include neurotoxicity and hepatotoxicity

For the treatment of neurotrophic receptor tyrosine kinase-positive solid tumors.
NOTE: Larotrectinib has been designated an orphan drug by the FDA for the treatment of solid tumors with NTRK-fusion proteins.
For the treatment of metastatic or surgically unresectable neurotrophic receptor tyrosine kinase (NTRK) gene fusion-positive solid tumors with no known acquired resistance mutation, in patients with no satisfactory alternative treatments or who have progressed following treatment.
NOTE: Patients should be selected based on the presence of an NTRK gene fusion in tumor specimens. Information on FDA-approved tests is available at www.fda.gov/CompanionDiagnostics.
Oral dosage Adults

100 mg orally twice daily. Continue therapy until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, dose reduction, or permanent discontinuation may be necessary in patients who develop toxicity.[63780] In pooled results from 3 phase 1 or 2 trials (n = 55), the overall response rate assessed by independent review (primary endpoint) was 75% in patients with NTRK fusion-positive cancers who received larotrectinib (complete response, 25%). The median duration of response was 32.9 months; 63% of patients had an observed duration of response of at least 12 months and 49% had an observed duration of response of at least 24 months. In this analysis, the median patient age was 45 years (range, 4 months to 76 years); 82% (n = 45) of patients received a median of 2 prior systemic regimens and 35% (n = 19) received 3 or more systemic regimens. The most common tumor types were salivary gland tumor (22%), soft-tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid tumor (9%).[63791]

Infants, Children, and Adolescents with a BSA of 1 m2 or greater

100 mg orally twice daily. Continue therapy until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, dose reduction, or permanent discontinuation may be necessary in patients who develop toxicity.[63780] In pooled results from 3 phase 1 or 2 trials (n = 55), the overall response rate assessed by independent review (primary endpoint) was 75% in patients with NTRK fusion-positive cancers who received larotrectinib (complete response, 25%). The median duration of response was 32.9 months; 63% of patients had an observed duration of response of at least 12 months and 49% had an observed duration of response of at least 24 months. In this analysis, the median patient age was 45 years (range, 4 months to 76 years); 82% (n = 45) of patients received a median of 2 prior systemic regimens and 35% (n = 19) received 3 or more systemic regimens. The most common tumor types were salivary gland tumor (22%), soft-tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid tumor (9%).[63791]

Infants, Children, and Adolescents with a BSA less than 1 m2

100 mg/m2 orally twice daily. Continue therapy until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, dose reduction, or permanent discontinuation may be necessary in patients who develop toxicity.[63780] In pooled results from 3 phase 1 or 2 trials (n = 55), the overall response rate assessed by independent review (primary endpoint) was 75% in patients with NTRK fusion-positive cancers who received larotrectinib (complete response, 25%). The median duration of response was 32.9 months; 63% of patients had an observed duration of response of at least 12 months and 49% had an observed duration of response of at least 24 months. In this analysis, the median patient age was 45 years (range, 4 months to 76 years); 82% (n = 45) of patients received a median of 2 prior systemic regimens and 35% (n = 19) received 3 or more systemic regimens. The most common tumor types were salivary gland tumor (22%), soft-tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid tumor (9%).[63791]

Hepatic Impairment

A larotrectinib dosage adjustment is not necessary in patients with baseline mild hepatic impairment (Child-Pugh class A). Reduce the initial larotrectinib dose by 50% in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment.[63780]

Renal Impairment

A larotrectinib dosage adjustment is not necessary in patients with baseline renal impairment.[63780]

Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with larotrectinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Larotrectinib is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with larotrectinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of larotrectinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Larotrectinib is a weak inhibitor of CYP3A4.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like larotrectinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If larotrectinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Major) Avoid coadministration of adagrasib with larotrectinib due to the risk of increased larotrectinib exposure which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of larotrectinib by 50%. After adagrasib has been discontinued for 3 to 5 elimination half-lives, resume the larotrectinib dose taken prior to initiating adagrasib. Larotrectinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the larotrectinib AUC by 4.3-fold.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If larotrectinib is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Alprazolam: (Major) Avoid coadministration of alprazolam and larotrectinib due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with larotrectinib, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and larotrectinib is a weak CYP3A4 inhibitor. Coadministration with another weak CYP3A4 inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
Amiodarone: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with amiodarone is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of larotrectinib with clarithromycin due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If clarithromycin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of clarithromycin. Larotrectinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Apalutamide: (Major) Avoid coadministration of larotrectinib with apalutamide due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If apalutamide is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of apalutamide. Larotrectinib is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
Aprepitant, Fosaprepitant: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with aprepitant/fosaprepitant is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and aprepitant/fosaprepitant is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Aripiprazole: (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of larotrectinib. Patients receiving both a CYP2D6 inhibitor plus larotrectinib may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP3A and CYP2D6 substrate; larotrectinib is a weak CYP3A inhibitor.
Artemether; Lumefantrine: (Moderate) Administering artemether with larotrectinib may result in elevated artemether plasma concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation. Artemether is a substrate of CYP3A; larotrectinib is a weak CYP3A inhibitor. (Moderate) Administering lumefantrine with larotrectinib may result in elevated lumefantrine plasma concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation. Lumefantrine is a substrate of CYP3A; larotrectinib is a weak CYP3A inhibitor.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with larotrectinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of larotrectinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Larotrectinib is a weak inhibitor of CYP3A4.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like larotrectinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If larotrectinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Major) Avoid coadministration of larotrectinib with atazanavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If atazanavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of atazanavir. Larotrectinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Atazanavir; Cobicistat: (Major) Avoid coadministration of larotrectinib with atazanavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If atazanavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of atazanavir. Larotrectinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study. (Major) Avoid coadministration of larotrectinib with cobicistat due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If cobicistat is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of cobicistat. Larotrectinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Berotralstat: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with berotralstat is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Bexarotene: (Major) Avoid concurrent use of larotrectinib and bexarotene due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If bexarotene is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of bexarotene. Larotrectinib is a CYP3A substrate and bexarotene is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease larotrectinib exposure by 72%.
Bosentan: (Major) Avoid concurrent use of larotrectinib and bosentan due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If bosentan is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of bosentan. Larotrectinib is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease larotrectinib exposure by 72%.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with larotrectinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of larotrectinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Larotrectinib is a weak inhibitor of CYP3A4.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with larotrectinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of larotrectinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Larotrectinib is a weak inhibitor of CYP3A4.
Carbamazepine: (Major) Avoid coadministration of larotrectinib with carbamazepine due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If carbamazepine is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of carbamazepine. Larotrectinib is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with larotrectinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of larotrectinib, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Cenobamate: (Major) Avoid concurrent use of larotrectinib and cenobamate due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If cenobamate is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of cenobamate. Larotrectinib is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease larotrectinib exposure by 72%.
Ceritinib: (Major) Avoid coadministration of larotrectinib with ceritinib due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If ceritinib is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of ceritinib. Larotrectinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Chloramphenicol: (Major) Avoid coadministration of larotrectinib with chloramphenicol due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If chloramphenicol is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of chloramphenicol. Larotrectinib is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with larotrectinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of larotrectinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Larotrectinib is a weak inhibitor of CYP3A4.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with larotrectinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Larotrectinib is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Ciprofloxacin: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with ciprofloxacin is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and ciprofloxacin is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Clarithromycin: (Major) Avoid coadministration of larotrectinib with clarithromycin due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If clarithromycin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of clarithromycin. Larotrectinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with larotrectinib and monitor for adverse reactions. If larotrectinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A. Larotrectinib is a weak CYP3A inhibitor.
Cobicistat: (Major) Avoid coadministration of larotrectinib with cobicistat due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If cobicistat is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of cobicistat. Larotrectinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Codeine: (Moderate) Concomitant use of codeine with larotrectinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of larotrectinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Larotrectinib is a weak inhibitor of CYP3A4.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with larotrectinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of larotrectinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Larotrectinib is a weak inhibitor of CYP3A4.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with larotrectinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of larotrectinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Larotrectinib is a weak inhibitor of CYP3A4.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with larotrectinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of larotrectinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Larotrectinib is a weak inhibitor of CYP3A4.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with larotrectinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of larotrectinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Larotrectinib is a weak inhibitor of CYP3A4.
Colchicine: (Moderate) Monitor for an increase in colchicine-related adverse reactions including neuromuscular toxicity and other serious toxicities if coadministration with larotrectinib is necessary, especially in patients with renal or hepatic impairment. Larotrectinib is a weak inhibitor of CYP3A while colchicine is a CYP3A4 substrate with a narrow therapeutic index.
Conivaptan: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with conivaptan is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Crizotinib: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with crizotinib is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Cyclosporine: (Moderate) Monitor for increase in adverse reactions from both drugs if concomitant use of larotrectinib and cyclosporine is necessary. Closely monitor cyclosporine whole blood trough concentrations as appropriate and adjust the dose as needed. Concomitant use may increase the exposure of both drugs. Larotrectinib is a CYP3A substrate and weak CYP3A inhibitor; cyclosporine is a CYP3A substrate and moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Dabrafenib: (Major) Avoid concurrent use of larotrectinib and dabrafenib due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If dabrafenib is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of dabrafenib. Larotrectinib is a CYP3A substrate and dabrafenib is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease larotrectinib exposure by 72%.
Danazol: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with danazol is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and danazol is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Darunavir: (Major) Avoid coadministration of larotrectinib with darunavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If darunavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of darunavir. Larotrectinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Darunavir; Cobicistat: (Major) Avoid coadministration of larotrectinib with cobicistat due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If cobicistat is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of cobicistat. Larotrectinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study. (Major) Avoid coadministration of larotrectinib with darunavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If darunavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of darunavir. Larotrectinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of larotrectinib with cobicistat due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If cobicistat is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of cobicistat. Larotrectinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study. (Major) Avoid coadministration of larotrectinib with darunavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If darunavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of darunavir. Larotrectinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Delavirdine: (Major) Avoid coadministration of larotrectinib with delavirdine due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If delavirdine is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of delavirdine. Larotrectinib is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Diltiazem: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with diltiazem is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Disopyramide: (Moderate) Caution is warranted during coadministration of disopyramide and larotrectinib due to the potential for elevated disopyramide plasma concentrations and associated adverse events including QT prolongation. Disopyramide is a CYP3A4 substrate; larotrectinib is a weak CYP3A4 inhibitor.
Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with larotrectinib is necessary. Larotrectinib is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
Doxorubicin Liposomal: (Major) Avoid coadministration of larotrectinib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Larotrectinib is a weak CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of larotrectinib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Larotrectinib is a weak CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
Dronedarone: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with dronedarone is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and dronedarone is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Duvelisib: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with duvelisib is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and duvelisib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Efavirenz: (Major) Avoid concurrent use of larotrectinib and efavirenz due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If efavirenz is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of efavirenz. Larotrectinib is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Coadministration with efavirenz is predicted to decrease larotrectinib exposure by 72%.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent use of larotrectinib and efavirenz due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If efavirenz is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of efavirenz. Larotrectinib is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Coadministration with efavirenz is predicted to decrease larotrectinib exposure by 72%.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent use of larotrectinib and efavirenz due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If efavirenz is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of efavirenz. Larotrectinib is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Coadministration with efavirenz is predicted to decrease larotrectinib exposure by 72%.
Elagolix: (Major) Avoid concurrent use of larotrectinib and elagolix due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If elagolix is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of elagolix. Larotrectinib is a CYP3A substrate and elagolix is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease larotrectinib exposure by 72%.
Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid concurrent use of larotrectinib and elagolix due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If elagolix is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of elagolix. Larotrectinib is a CYP3A substrate and elagolix is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease larotrectinib exposure by 72%.
Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of larotrectinib and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Larotrectinib ia a weak CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration of eliglustat with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of larotrectinib with cobicistat due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If cobicistat is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of cobicistat. Larotrectinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of larotrectinib with cobicistat due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If cobicistat is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of cobicistat. Larotrectinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Enzalutamide: (Major) Avoid coadministration of larotrectinib with enzalutamide due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If enzalutamide is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of enzalutamide. Larotrectinib is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
Erythromycin: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with erythromycin is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and erythromycin is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Eslicarbazepine: (Major) Avoid concurrent use of larotrectinib and eslicarbazepine due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If eslicarbazepine is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of eslicarbazepine. Larotrectinib is a CYP3A substrate and eslicarbazepine is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease larotrectinib exposure by 72%.
Etravirine: (Major) Avoid concurrent use of larotrectinib and etravirine due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If etravirine is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of etravirine. Larotrectinib is a CYP3A substrate and etravirine is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease larotrectinib exposure by 72%.
Fedratinib: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with fedratinib is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Felodipine: (Moderate) Concurrent use of felodipine and larotrectinib should be approached with caution with conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and larotrectinib is a weak CYP3A4 inhibitor. Concurrent use of another weak CYP3A4 inhibitor increased felodipine AUC and Cmax by approximately 50%.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If larotrectinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or larotrectinib; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and larotrectinib is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including larotrectinib, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the potential outcomes of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
Fluconazole: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with fluconazole is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Coadministration with fluconazole is predicted to increase larotrectinib exposure by 2.7-fold.
Fluvoxamine: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with fluvoxamine is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Fosamprenavir: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with fosamprenavir is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and fosamprenavir is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Fosphenytoin: (Major) Avoid coadministration of larotrectinib with fosphenytoin due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If fosphenytoin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of fosphenytoin. Larotrectinib is a CYP3A4 substrate; fosphenytoin is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
Grapefruit juice: (Major) Advise patients to avoid grapefruit or grapefruit juice while taking larotrectinib. Coadministration may increase larotrectinib exposure resulting in treatment-related adverse effects. Larotrectinib is a CYP3A4 substrate; grapefruit is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like larotrectinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If larotrectinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Idelalisib: (Major) Avoid coadministration of larotrectinib with idelalisib due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If idelalisib is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of idelalisib. Larotrectinib is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Imatinib: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with imatinib is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and imatinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Indinavir: (Major) Avoid coadministration of larotrectinib with indinavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If indinavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of indinavir. Larotrectinib is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Isavuconazonium: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with isavuconazonium is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and isavuconazonium is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of larotrectinib with rifampin due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If rifampin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of rifampin. Larotrectinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the larotrectinib AUC by 81% in a drug interaction study.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of larotrectinib with rifampin due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If rifampin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of rifampin. Larotrectinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the larotrectinib AUC by 81% in a drug interaction study.
Itraconazole: (Major) Avoid coadministration of larotrectinib with Itraconazole due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If itraconazole is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of itraconazole. Larotrectinib is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of larotrectinib is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and larotrectinib a weak CYP3A inhibitor.
Ketoconazole: (Major) Avoid coadministration of ketoconazole with larotrectinib due to the risk of increased larotrectinib exposure which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of larotrectinib by 50%. After ketoconazole has been discontinued for 3 to 5 elimination half-lives, resume the larotrectinib dose taken prior to initiating ketoconazole. Larotrectinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the larotrectinib AUC by 4.3-fold.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of larotrectinib with clarithromycin due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If clarithromycin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of clarithromycin. Larotrectinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Lefamulin: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with lefamulin is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and lefamulin is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Lemborexant: (Major) Limit the dose of lemborexant to a maximum of 5 mg PO once daily if coadministered with larotrectinib as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; larotrectinib is a weak CYP3A4 inhibitor. Coadministration of lemborexant with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
Lenacapavir: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with lenacapavir is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Letermovir: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with letermovir is necessary. Avoid concomitant use in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. If concomitant use of combination letermovir plus cyclosporine is necessary, reduce the dose of larotrectinib by 50%. After combination letermovir plus cyclosporine has been discontinued for 3 to 5 elimination half-lives, resume the larotrectinib dose taken prior to initiating letermovir plus cyclosporine. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate. Letermovir is a moderate CYP3A inhibitor; however, when given with cyclosporine, the combined effect on CYP3A substrates may be similar to a strong CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold. Coadministration with a strong CYP3A inhibitor increased larotrectinib exposure by 4.3-fold.
Levoketoconazole: (Major) Avoid coadministration of ketoconazole with larotrectinib due to the risk of increased larotrectinib exposure which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of larotrectinib by 50%. After ketoconazole has been discontinued for 3 to 5 elimination half-lives, resume the larotrectinib dose take

n prior to initiating ketoconazole. Larotrectinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the larotrectinib AUC by 4.3-fold.
Lomitapide: (Major) Decrease the dose of lomitapide by one-half not to exceed 30 mg/day PO if coadministration with larotrectinib is necessary. Concomitant use may significantly increase the serum concentration of lomitapide. Larotrectinib is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
Lonafarnib: (Major) Avoid coadministration of lonafarnib and larotrectinib; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce the dose of larotrectinib by 50% and reduce to or continue lonafarnib at a dosage of 115 mg/m2; closely monitor patients for adverse reactions from both drugs. After lonafarnib has been discontinued for 3 to 5 elimination half-lives, resume the larotrectinib dose taken prior to initiating lonafarnib. Resume previous lonafarnib dosage 14 days after discontinuing larotrectinib. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; larotrectinib is a CYP3A4 substrate and weak CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the larotrectinib AUC by 4.3-fold.
Lopinavir; Ritonavir: (Major) Avoid coadministration of larotrectinib with ritonavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If ritonavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of ritonavir. Larotrectinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Lorlatinib: (Major) Avoid concurrent use of larotrectinib and lorlatinib due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If lorlatinib is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of lorlatinib. Larotrectinib is a CYP3A substrate and lorlatinib is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease larotrectinib exposure by 72%.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of larotrectinib with lumacaftor; ivacaftor due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If lumacaftor; ivacaftor is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of lumacaftor; ivacaftor. Larotrectinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of larotrectinib with lumacaftor; ivacaftor due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If lumacaftor; ivacaftor is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of lumacaftor; ivacaftor. Larotrectinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
Mavacamten: (Major) Avoid concurrent use of larotrectinib and mavacamten due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If mavacamten is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of mavacamten. Larotrectinib is a CYP3A substrate and mavacamten is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease larotrectinib exposure by 72%.
Methadone: (Moderate) Concomitant use of methadone with larotrectinib may increase methadone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of methadone until stable drug effects are achieved. Discontinuation of larotrectinib could decrease methadone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to methadone. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Methadone is a substrate for CYP3A4. Larotrectinib is a weak inhibitor of CYP3A4.
Midazolam: (Moderate) Monitor for more intense and prolonged sedation due to increased midazolam exposure if coadministration with larotrectinib is necessary. Midazolam is a CYP3A4 substrate; larotrectinib is a weak CYP3A4 inhibitor. In a drug interaction study, coadministration with larotrectinib increased the both the midazolam AUC and Cmax by 1.7-fold. The AUC and Cmax of 1-hydroxymidazolam, the main metabolite of midazolam, were both increased 1.4-fold.
Mifepristone: (Major) Avoid coadministration of larotrectinib with chronic mifepristone use due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If mifepristone is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of mifepristone. Larotrectinib is a CYP3A4 substrate; mifepristone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
Mitotane: (Major) Avoid coadministration of larotrectinib with mitotane due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If mitotane is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of mitotane. Larotrectinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
Nafcillin: (Major) Avoid concurrent use of larotrectinib and nafcillin due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If nafcillin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of nafcillin. Larotrectinib is a CYP3A substrate and nafcillin is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease larotrectinib exposure by 72%.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of larotrectinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and larotrectinib is a weak CYP3A inhibitor.
Nefazodone: (Major) Avoid coadministration of larotrectinib with nefazodone due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If nefazodone is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of nefazodone. Larotrectinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Nelfinavir: (Major) Avoid coadministration of larotrectinib with nelfinavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If nelfinavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of nelfinavir. Larotrectinib is a CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with netupitant is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Nilotinib: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with nilotinib is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Nimodipine: (Moderate) Monitor blood pressure and watch for an increase in nimodipine-related adverse reactions if coadministration with larotrectinib is necessary; consider reducing the dose of nimodipine if needed. Nimodipine is a CYP3A4 substrate and larotrectinib is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of nimodipine.
Nirmatrelvir; Ritonavir: (Major) Avoid coadministration of larotrectinib with ritonavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If ritonavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of ritonavir. Larotrectinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with larotrectinib due to increased plasma concentrations of nisoldipine. Nisoldipine is a CYP3A4 substrate and larotrectinib is a weak CYP3A4 inhibitor.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid concurrent use of larotrectinib and rifabutin due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If rifabutin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of rifabutin. Larotrectinib is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease larotrectinib exposure by 72%.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like larotrectinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If larotrectinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Pexidartinib: (Major) Avoid concurrent use of larotrectinib and pexidartinib due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If pexidartinib is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of pexidartinib. Larotrectinib is a CYP3A substrate and pexidartinib is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease larotrectinib exposure by 72%.
Phenobarbital: (Major) Avoid coadministration of larotrectinib with phenobarbital due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If phenobarbital is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of phenobarbital. Larotrectinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of larotrectinib with phenobarbital due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If phenobarbital is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of phenobarbital. Larotrectinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
Phenytoin: (Major) Avoid coadministration of larotrectinib with phenytoin due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If phenytoin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of phenytoin. Larotrectinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
Posaconazole: (Major) Avoid coadministration of larotrectinib with posaconazole due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If posaconazole is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of posaconazole. Larotrectinib is a CYP3A4 substrate; posaconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Primidone: (Major) Avoid coadministration of larotrectinib with primidone due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If primidone is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of primidone. Larotrectinib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
Probenecid; Colchicine: (Moderate) Monitor for an increase in colchicine-related adverse reactions including neuromuscular toxicity and other serious toxicities if coadministration with larotrectinib is necessary, especially in patients with renal or hepatic impairment. Larotrectinib is a weak inhibitor of CYP3A while colchicine is a CYP3A4 substrate with a narrow therapeutic index.
Ribociclib: (Major) Avoid coadministration of larotrectinib with ribociclib due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If ribociclib is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of ribociclib. Larotrectinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Ribociclib; Letrozole: (Major) Avoid coadministration of larotrectinib with ribociclib due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If ribociclib is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of ribociclib. Larotrectinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Rifabutin: (Major) Avoid concurrent use of larotrectinib and rifabutin due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If rifabutin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of rifabutin. Larotrectinib is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease larotrectinib exposure by 72%.
Rifampin: (Major) Avoid coadministration of larotrectinib with rifampin due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If rifampin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of rifampin. Larotrectinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the larotrectinib AUC by 81% in a drug interaction study.
Rifapentine: (Major) Avoid coadministration of rifapentine with larotrectinib due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is unavoidable, double the dose of larotrectinib. After rifapentine has been discontinued for 3 to 5 elimination half-lives, resume the larotrectinib dose taken prior to initiating rifapentine. Larotrectinib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the larotrectinib AUC by 81%.
Ritlecitinib: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with ritlecitinib is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Ritonavir: (Major) Avoid coadministration of larotrectinib with ritonavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If ritonavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of ritonavir. Larotrectinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Saquinavir: (Major) Avoid coadministration of larotrectinib with saquinavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If saquinavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of saquinavir. Larotrectinib is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of larotrectinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and larotrectinib is a weak CYP3A inhibitor.
Sotorasib: (Major) Avoid concurrent use of larotrectinib and sotorasib due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If sotorasib is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of sotorasib. Larotrectinib is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease larotrectinib exposure by 72%.
St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of larotrectinib with St. John's wort due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If St. John's wort is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of St. John's wort. Larotrectinib is a CYP3A4 substrate; St. John's wort is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
Sufentanil: (Moderate) Consider a reduced dose of sufentanil with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the sufentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a sensitive CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like larotrectinib can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If larotrectinib is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Tacrolimus: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with larotrectinib. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Larotrectinib is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
Tipranavir: (Major) Avoid coadministration of larotrectinib with tipranavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If tipranavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of tipranavir. Larotrectinib is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with larotrectinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of larotrectinib, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with larotrectinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of larotrectinib, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Trandolapril; Verapamil: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with verapamil is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with larotrectinib and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and larotrectinib is a weak CYP3A inhibitor.
Tucatinib: (Major) Avoid coadministration of larotrectinib with tucatinib due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If tucatinib is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of tucatinib. Larotrectinib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with larotrectinib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; larotrectinib is a weak CYP3A4 inhibitor.
Verapamil: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with verapamil is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with larotrectinib is necessary. Vinorelbine is a CYP3A4 substrate and larotrectinib is a weak CYP3A4 inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of larotrectinib with clarithromycin due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If clarithromycin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of clarithromycin. Larotrectinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Voriconazole: (Major) Avoid coadministration of larotrectinib with voriconazole due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If voriconazole is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of voriconazole. Larotrectinib is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Voxelotor: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with voxelotor is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with larotrectinib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Larotrectinib is a weak CYP3A4 inhibitor 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.

Larotrectinib/VITRAKVI Solution Oral Sol: 1mL, 20mg
VITRAKVI Oral Cap: 25mg, 100mg

Adults

100 mg PO twice daily.

Geriatric

100 mg PO twice daily.

Adolescents

100 mg PO twice daily.

Children

BSA 1 m2 or greater: 100 mg PO twice daily; BSA less than 1 m2: 100 mg/m2 PO twice daily.

Infants

100 mg/m2 PO twice daily.

Neonates

Safety and efficacy not established.

Larotrectinib is an inhibitor of the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC. In a broad panel of purified enzyme assays, larotrectinib inhibited these kinases with IC50 values between 5 to 11 nM. One other kinase, TNK2, was inhibited at approximately 100-fold higher concentrations. TRKA, B, and C are encoded by the genes NTRK1, NTRK2, and NTRK3. Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively-activated cell proliferation and survival in tumor cell lines. In in vitro and in vivo tumor models, larotrectinib demonstrated anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression. It had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation, G595R. Point mutations in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L.[63780]

Larotrectinib is administered orally. It is 70% bound to human plasma proteins in vitro and binding is independent of drug concentrations. The blood-to-plasma ratio is 0.9. The mean (CV%) volume of distribution (Vss) of larotrectinib is 48 (38%) L after intravenous administration in healthy subjects. Larotrectinib is metabolized predominantly by CYP3A4. After oral administration of a single radiolabeled dose to healthy subjects, unchanged larotrectinib constituted 19% and an O-linked glucuronide constituted 26% of the major circulating radioactive drug components in plasma. Additionally, 58% (5% unchanged) of the administered radioactivity was recovered in the feces and 39% (20% unchanged) was recovered in the urine. The mean (CV%) clearance (CL/F) of larotrectinib is 90 (44%) L/h and the half-life is 2.9 hours after oral administration in healthy subjects.[63780]
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-glycoprotein (P-gp)
Larotrectinib is a CYP3A4 substrate and a weak inhibitor of CYP3A4. Coadministration of a single larotrectinib dose with a strong CYP3A inhibitor increased the AUC of larotrectinib by 4.3-fold and the Cmax by 2.8-fold. Coadministration of a single larotrectinib dose with a strong CYP3A inducer decreased the AUC of larotrectinib by 81% and the Cmax by 71%; moderate CYP3A inducers are also expected to reduce larotrectinib exposure. The effects of moderate and weak CYP3A4 inhibitors and or weak CYP3A inducers on larotrectinib pharmacokinetics have not been studied.
 
Coadministration of larotrectinib with a sensitive CYP3A4 substrate, midazolam, increased both the AUC and the Cmax of midazolam by 1.7-fold. The AUC and Cmax of 1-hydroxymidazolam, the main metabolite of midazolam, were both increased 1.4-fold. Larotrectinib is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations. Larotrectinib is a substrate of P-glycoprotein (P-gp). Coadministration with a P-gp inhibitor increased the AUC of larotrectinib by 1.7-fold and the Cmax by 1.8-fold. Larotrectinib is also a substrate for the breast cancer resistance protein (BCRP), but the clinical significance is not known. Larotrectinib is not a substrate of organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, organic anion transporting polypeptide (OATP) 1B1, or OATP1B3. Larotrectinib is not an inhibitor of BCRP, P-gp, OAT1, OAT3, OCT1, OCT2, OATP1B1, OAT1B3, bile salt export pump (BSEP), multidrug and toxin extrusion (MATE) protein 1, or MATE2-K at clinically relevant concentrations.[63780]

Oral Route

The mean absolute bioavailability of larotrectinib capsules is 34%. In healthy subjects, the AUC of larotrectinib oral solution was similar to that of the capsules and the Cmax was 36% higher with the oral solution. Larotrectinib is dose proportional after single-dose studies over the dose range of 100 mg to 400 mg (1 to 4 times the recommended adult dose) and slightly greater than proportional at doses of 600 mg to 900 mg (6 to 9 times the recommended adult dose). In adult patients who received the 100 mg capsules twice daily, peak plasma concentrations (Cmax) were achieved at approximately 1 hour after dosing and steady-state was reached within 3 days. Mean steady-state larotrectinib [coefficient of variation (CV%)] for Cmax was 788 (81%) ng/mL and AUC was 4351 (97%) ng x h/mL.[63780]
 
Effects of food: The AUC of larotrectinib was similar and the Cmax was reduced by 35% after a single 100 mg capsule to healthy subjects was administered with a high-fat meal (approximately 900 calories, 56 g of fat) compared to the fasted state.[63780]

Pregnancy

Larotrectinib may cause fetal harm when administered during pregnancy, based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, its mechanism of action, and data from animal studies. Females of reproductive potential should avoid becoming pregnant while taking larotrectinib. Discuss the potential hazard to the fetus if a patient becomes pregnant while taking this drug. Although larotrectinib has not been evaluated in pregnant women, congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are associated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis. Fetal malformations (e.g., anasarca, omphalocele) occurred when pregnant rats and rabbits received a larotrectinib dose resulting in approximately 11- and 0.7-times the exposure that was observed in humans who received the recommended dose.

It is not known if larotrectinib or its active metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because there is a potential for adverse reactions in nursing infants from larotrectinib, women should discontinue breast-feeding during larotrectinib therapy and for 1 week after the last dose.[63780]