ROZLYTREK

Small Molecule Antineoplastic Receptor Tyrosine Kinase ROS1 Inhibitors
Small Molecule Antineoplastic Tropomyosin Receptor Kinase (TRK) Inhibitors

Emetic Risk
Minimal/Low
Administer prn antiemetics as necessary.

Oral Administration

Administer with or without food.
Avoid grapefruit juice and other grapefruit products during administration and treatment.
If a dose is missed, make it up unless the next dose is due within 12 hours. Do not administer 2 doses at the same time.
If a patient vomits immediately after taking a dose, readminister the dose.

Oral Solid Formulations

Capsules
For patients who can swallow whole capsules and whose doses are multiples of 100 mg.
Do not open, crush, chew or dissolve the capsule contents.

Other Oral Formulations

Pellets
For patients who have difficulty or are unable to swallow capsules but can swallow soft food and whose doses are multiples of 50 mg.
Do not attempt to use partial quantities of a 50-mg pellet packet to prepare a dose.
Do not use the pellet formulation for enteral tube administration as the pellets may clog the tube.
Provide patients with the Instructions for Use for detailed instructions on home preparation and administration of entrectinib pellets.
Preparation:
Sprinkle pellets on 1 or more spoonfuls of soft food (e.g., applesauce, yogurt, or pudding).
Oral Administration:
Take within 20 minutes of preparation.
Do not crush or chew the pellets to avoid a bitter taste.
Drink water after taking the pellets to ensure the drug has been completely swallowed.

Extemporaneous Compounding-Oral

Capsules for Suspension
For patients who have difficulty or are unable to swallow capsules or who require enteral administration (e.g., nasogastric or gastric tube).
For dose increments of 10 mg, only use capsules prepared as a suspension.
Do not use pellets for preparation of the suspension.
Preparation:
Use only room temperature drinking water or milk to create the suspension. Use 100 mg or 200 mg capsules, as appropriate.
Prepare doses of 100 mg or less by carefully pouring the contents of 1 x 100-mg capsule into 5 mL of liquid.
Prepare doses of 110 mg to 200 mg by carefully pouring the contents of 1 x 200-mg capsule into 10 mL of liquid.
Prepare a 300-mg dose by carefully pouring the contents of 1 x 200-mg capsule and 1 x 100-mg capsule into 15 mL of liquid.
Prepare a 400-mg dose by carefully pouring the contents of 2 x 200-mg capsules into 20 mL of liquid.
Prepare a 600-mg dose by carefully pouring the contents of 3 x 200-mg capsule into 30 mL of liquid.
Allow the resulting 20 mg/1 mL suspension to sit for 15 minutes.
Measure the appropriate dose and administer immediately after preparation.
Storage After Preparation:
Discard any unused suspension if not used within 2 hours of preparation.
Oral Administration:
Administer orally.
Instruct patients to drink water after taking the oral suspension to ensure the full dose has been swallowed.
Enteral Tube Administration:
Administer via gastric or nasogastric tube.
For doses of 3 mL or more, use an enteral tube that is 8 FR or higher.
Divide volumes larger than 3 mL into at least 2 aliquots; divide volumes of 30 mL into at least 3 (10-mL) aliquots.
Flush the tube after administration of each full dose/aliquot with a volume of water or milk equal to the full dose/aliquot volume.

Severe

neutropenia / Delayed / 2.0-27.0
bone fractures / Delayed / 5.0-25.0
weight gain / Delayed / 7.0-18.0
lymphopenia / Delayed / 1.0-12.0
hyperuricemia / Delayed / 1.7-10.0
anemia / Delayed / 9.0-9.0
hypoalbuminemia / Delayed / 2.9-9.0
hyperbilirubinemia / Delayed / 8.0-8.0
hypercalcemia / Delayed / 8.0-8.0
elevated hepatic enzymes / Delayed / 0-7.0
hypophosphatemia / Delayed / 7.0-7.0
dyspnea / Early / 3.0-6.0
infection / Delayed / 0-6.0
hyperamylasemia / Delayed / 5.4-5.4
hydrocephalus / Delayed / 0-5.0
fatigue / Early / 2.6-5.0
renal failure (unspecified) / Delayed / 2.1-5.0
hypermagnesemia / Delayed / 5.0-5.0
hypoxia / Early / 3.4-4.0
pulmonary embolism / Delayed / 3.9-3.9
hyperglycemia / Delayed / 3.8-3.8
QT prolongation / Rapid / 0.6-3.1
pleural effusion / Delayed / 0-3.1
gait disturbance / Delayed / 0-3.0
hypotension / Rapid / 2.8-2.8
headache / Early / 0.3-2.6
abdominal pain / Early / 0.6-2.6
syncope / Early / 0-2.5
heart failure / Delayed / 2.3-2.3
dizziness / Early / 0-2.2
visual impairment / Early / 0-2.0
diarrhea / Early / 0-2.0
hypocalcemia / Delayed / 1.8-1.8
hyperkalemia / Delayed / 1.5-1.5
anorexia / Delayed / 0.3-1.3
constipation / Delayed / 0.6-1.3
cough / Delayed / 0.3-1.3
fever / Early / 0.8-1.3
edema / Delayed / 1.1-1.1
peripheral neuropathy / Delayed / 1.1-1.1
dehydration / Delayed / 1.1-1.1
myalgia / Early / 0-1.1
back pain / Delayed / 0-1.0
hypernatremia / Delayed / 0.9-0.9
ataxia / Delayed / 0-0.8
rash / Early / 0-0.8
vomiting / Early / 0-0.8
myasthenia / Delayed / 0-0.8
arthralgia / Delayed / 0-0.6
myocarditis / Delayed / 0.3-0.3
dysesthesia / Delayed / 0.3-0.3
nausea / Early / 0-0.3
dysgeusia / Early / 0-0.3
GI perforation / Delayed / 0-0.3
hepatotoxicity / Delayed / Incidence not known
corneal erosion / Delayed / Incidence not known
retinal hemorrhage / Delayed / Incidence not known
tumor lysis syndrome (TLS) / Delayed / Incidence not known

Moderate

hypoglycemia / Early / 26.0-26.0
photophobia / Early / 0-20.0
urinary incontinence / Early / 0-20.0
confusion / Early / 2.0-11.0
dysphagia / Delayed / 0-10.0
blurred vision / Early / 0-9.0
memory impairment / Delayed / 3.7-3.7
depression / Delayed / 2.8-2.8
amnesia / Delayed / 2.5-2.5
aphasia / Delayed / 2.3-2.3
hallucinations / Early / 1.1-1.1
photopsia / Delayed / 0-1.1
cataracts / Delayed / 0-1.1
peripheral edema / Delayed / Incidence not known
fluid retention / Delayed / Incidence not known
euphoria / Early / Incidence not known
neuropathic pain / Delayed / Incidence not known
palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
hyperesthesia / Delayed / Incidence not known
orthostatic hypotension / Delayed / Incidence not known

Mild

paresthesias / Delayed / 6.0-20.0
pruritus / Rapid / 0-20.0
ocular pain / Early / 0-20.0
nasal congestion / Early / 0-20.0
insomnia / Early / 7.0-7.0
drowsiness / Early / 7.0-7.0
anxiety / Delayed / 4.8-4.8
diplopia / Early / 0-3.1
agitation / Early / 2.0-2.0
emotional lability / Early / Incidence not known
irritability / Delayed / Incidence not known
vertigo / Early / Incidence not known
hypoesthesia / Delayed / Incidence not known
maculopapular rash / Early / Incidence not known
asthenia / Delayed / Incidence not known
musculoskeletal pain / Early / Incidence not known

Rozlytrek

Rx

Tyrosine kinase inhibitor with activity against multiple targets
Used for ROS1-positive non-small cell lung cancer (NSCLC) and for solid tumors with a neurotrophic tyrosine receptor kinase (NTRK) gene fusion
May cause QT prolongation, cognitive impairment, mood disorders, dizziness, and sleep disturbances; use with caution in patients at risk for these conditions

For the treatment of non-small cell lung cancer (NSCLC). For the treatment of metastatic ROS1-positive non-small cell lung cancer (NSCLC).
NOTE: The FDA has designated entrectinib as an orphan drug for the treatment of ROS1-positive non-small cell lung cancer (NSCLC)
NOTE: Select patients for treatment based on the presence of ROS1 rearrangement(s) in tumor specimens; plasma specimens may be used if tumor specimens are not available. Information on FDA-approved tests for the detection of ROS1 rearrangements in NSCLC is available at www.fda.gov/CompanionDiagnostics. Oral dosage Adults

600 mg PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with various doses and schedules of entrectinib (90% received entrectinib 600 mg once daily) resulted in an overall response rate of 74% (complete response, 15%) in a pooled subgroup of patients with ROS1-positive metastatic NSCLC (n = 92) enrolled in one of three multicenter, single-arm, open-label trials (ALKA, STARTRK-1, and STARTRK-2). Seventy-five percent of patients had a response duration of 9 months or more, while the duration of response lasted for 12 months or more in 57% of patients and for 18 months or more in 38% of patients. Responses to intracranial lesions were observed in 7 of 10 patients with measurable CNS metastases at baseline and had not received radiation therapy within 2 months prior to study entry.

For the treatment of neurotrophic receptor tyrosine kinase-positive solid tumors.
NOTE: The FDA has designated entrectinib as an orphan drug for the treatment of neurotrophic tyrosine kinase fusion-positive solid tumors.
For the treatment of metastatic neurotrophic receptor tyrosine kinase-positive solid tumors that have either progressed following treatment or have no satisfactory alternative therapy, where surgical resection will likely result in severe morbidity.
NOTE: Select patients for treatment based on the presence of a neurotrophic tyrosine kinase (NTRK) gene fusion in tumor specimens; plasma specimens may be used if tumor specimens are not available. Information on FDA-approved tests for the detection of NTRK gene fusions in solid tumors is available at www.fda.gov/CompanionDiagnostics.[64567]
Oral dosage Adults

600 mg PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with entrectinib resulted in an overall response rate (ORR) of 59% (complete response, 13%) in a pooled subgroup of adult patients with unresectable or metastatic solid tumors with an NTRK gene fusion (n = 54) enrolled in one of three multicenter, single-arm, open-label clinical trials (ALKA, STARTRK-1, and STARTRK-2); patients were required to have progressed after systemic therapy for their disease, if available, or would have required surgery causing significant morbidity for locally advanced disease. Seventy-two percent of patients had a response duration of 6 months or more, while 66% had a duration of response of 9 months or more, and 56% had a duration of response of 12 months or more. Response rates by tumor type were salivary tumors with an ORR of 86% (n = 7), breast cancer with an ORR of 83% (n = 6), non-small cell lung cancer with an ORR of 60% (n = 10), thyroid cancer with an ORR of 60% (n = 5), sarcoma with an ORR of 46% (n = 13), and colorectal cancer with an ORR of 25% (n = 4).[64567]

Children and Adolescents, with a BSA of 1.51 m2 or higher

600 mg PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The use of entrectinib in pediatric patients older than 1 month of age is supported by evidence from well-controlled studies of entrectinib in adult and pediatric patients with support of additional population pharmacokinetic data in the pediatric population.

Children and Adolescents, with BSA 1.11 m2 to 1.5 m2

400 mg PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The use of entrectinib in pediatric patients older than 1 month of age is supported by evidence from well-controlled studies of entrectinib in adult and pediatric patients with support of additional population pharmacokinetic data in the pediatric population.

Children and Adolescents, with BSA 0.81 m2 to 1.1 m2

300 mg PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The use of entrectinib in pediatric patients older than 1 month of age is supported by evidence from well-controlled studies of entrectinib in adult and pediatric patients with support of additional population pharmacokinetic data in the pediatric population.

Infants and Children older than 6 months, with BSA 0.51 m2 to 0.8 m2

200 mg PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The use of entrectinib in pediatric patients older than 1 month of age is supported by evidence from well-controlled studies of entrectinib in adult and pediatric patients with support of additional population pharmacokinetic data in the pediatric population.

Infants and Children older than 6 months, with BSA less than or equal to 0.5 m2

300 mg/m2 PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The use of entrectinib in pediatric patients older than 1 month of age is supported by evidence from well-controlled studies of entrectinib in adult and pediatric patients with support of additional population pharmacokinetic data in the pediatric population.

Oral dosage Infants 6 months and younger

250 mg/m2 PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The use of entrectinib in pediatric patients older than 1 month of age is supported by evidence from well-controlled studies of entrectinib in adult and pediatric patients with support of additional population pharmacokinetic data in the pediatric population.

Hepatic Impairment

Baseline Hepatic Impairment:
Mild hepatic impairment (total bilirubin 1.5 times the upper limit of normal (ULN) or less): No dosage adjustment is recommended.
Moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN): The effect of moderate or severe hepatic impairment on the safety of entrectinib at the recommended dose is unknown. Monitor more frequently for adverse reactions.[64567]
 
Treatment-Related Hepatotoxicity:
Grade 3: Hold entrectinib. If hepatic function recovers to grade 1 or less (or baseline) within 4 weeks, resume entrectinib therapy at the same dose for the first occurrence, and at a reduced dose for recurrent grade 3 hepatotoxicity. Permanently discontinue entrectinib therapy if hepatic function does not recover to grade 1 or less (or baseline within 4 weeks) or for patients who are unable to tolerate therapy after 2 dose reductions.
Grade 4: Hold entrectinib. If hepatic function recovers to grade 1 or less (or baseline) within 4 weeks, resume entrectinib therapy at a reduced dose. Permanently discontinue entrectinib therapy if hepatic function does not recover to grade 1 or less (or baseline within 4 weeks) or for patients who are unable to tolerate therapy after 2 dose reductions.
ALT or AST greater than 3 times ULN with concurrent total bilirubin greater than 1.5 times ULN, in the absence of cholestasis or hemolysis: Permanently discontinue entrectinib therapy.[64567]

Renal Impairment

CrCl 30 to 89 mL/minute: No dosage adjustment is recommended.
CrCl less than 30 mL/minute: Entrectinib has not been studied in this patient population.

Adagrasib: (Major) Avoid concomitant use of entrectinib with adagrasib due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Alfuzosin: (Major) Avoid coadministration of entrectinib with alfuzosin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Alfuzosin may prolong the QT interval in a dose-dependent manner.
Amiodarone: (Major) Avoid concomitant use of entrectinib with amiodarone due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, amiodarone is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Amisulpride: (Major) Avoid coadministration of entrectinib with amisulpride due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs. Entrectinib has been associated with QT prolongation. Amisulpride causes dose- and concentration -dependent QT prolongation.
Amobarbital: (Major) Avoid coadministration of entrectinib with amobarbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; amobarbital is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of entrectinib with clarithromycin due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Anagrelide: (Major) Avoid coadministration of entrectinib with anagrelide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects.
Apalutamide: (Major) Avoid coadministration of entrectinib with apalutamide due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
Apomorphine: (Major) Avoid coadministration of entrectinib with apomorphine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aprepitant, Fosaprepitant: (Major) Avoid coadministration of entrectinib with aprepitant/fosaprepitant due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and aprepitant/fosaprepitant is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Aripiprazole: (Major) Concomitant use of entrectinib and aripiprazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Arsenic Trioxide: (Major) Avoid coadministration of entrectinib with arsenic trioxide due to the risk of QT prolongation. If concomitant drug use is unavoidable, frequently monitor electrocardiograms. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Entrectinib has been associated with QT prolongation.
Artemether; Lumefantrine: (Major) Avoid coadministration of entrectinib with artemether; lumefantrine due to the risk of QT prolongation. Consider ECG monitoring if entrectinib must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval. Entrectinib has been associated with QT prolongation.
Asenapine: (Major) Avoid coadministration of entrectinib with asenapine due to the risk of QT prolongation. Both entrectinib and asenapine have been associated with QT prolongation.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid coadministration of entrectinib with butalbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Atazanavir: (Major) Avoid coadministration of entrectinib with atazanavir due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Atazanavir; Cobicistat: (Major) Avoid coadministration of entrectinib with atazanavir due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold. (Major) Avoid coadministration of entrectinib with cobicistat due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Atomoxetine: (Major) Concomitant use of entrectinib with atomoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Azithromycin: (Major) Avoid coadministration of azithromycin with entrectinib due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Entrectinib has been associated with QT prolongation.
Bedaquiline: (Major) Avoid coadministration of entrectinib with bedaquiline due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 milliseconds. Bedaquiline prolongs the QT interval. Entrectinib has been associated with QT prolongation.
Berotralstat: (Major) Avoid coadministration of entrectinib with berotralstat due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and berotralstat is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Bexarotene: (Major) Avoid coadministration of entrectinib with bexarotene due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; bexarotene is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bosentan: (Major) Avoid coadministration of entrectinib with bosentan due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; bosentan is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Buprenorphine: (Major) Concomitant use of buprenorphine and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Buprenorphine; Naloxone: (Major) Concomitant use of buprenorphine and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Butalbital; Acetaminophen: (Major) Avoid coadministration of entrectinib with butalbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid coadministration of entrectinib with butalbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid coadministration of entrectinib with butalbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid coadministration of entrectinib with butalbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Cabotegravir; Rilpivirine: (Major) Avoid coadministration of entrectinib with rilpivirine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Carbamazepine: (Major) Avoid coadministration of entrectinib with carbamazepine due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
Cenobamate: (Major) Avoid coadministration of entrectinib with cenobamate due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Ceritinib: (Major) Avoid concomitant use of entrectinib with ceritinib due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, ceritinib is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Chloramphenicol: (Major) Avoid coadministration of entrectinib with chloramphenicol due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Chloroquine: (Major) Avoid coadministration of chloroquine with entrectinib due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Entrectinib has been associated with QT prolongation.
Chlorpromazine: (Major) Avoid coadministration of entrectinib with chlorpromazine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP).
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: (Major) Avoid concomitant use of entrectinib with ciprofloxacin due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, ciprofloxacin is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Cisapride: (Contraindicated) Coadministration of cisapride with entrectinib is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride. Entrectinib has been associated with QT prolongation.
Citalopram: (Major) Concomitant use of citalopram and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clarithromycin: (Major) Avoid concomitant use of entrectinib with clarithromycin due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Clofazimine: (Major) Concomitant use of clofazimine and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clozapine: (Major) Avoid coadministration of entrectinib with clozapine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Cobicistat: (Major) Avoid coadministration of entrectinib with cobicistat due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of promethazine and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Codeine; Promethazine: (Major) Concomitant use of promethazine and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Conivaptan: (Major) Avoid coadministration of entrectinib with conivaptan due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and conivaptan is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Crizotinib: (Major) Avoid concomitant use of entrectinib with crizotinib due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, crizotinib is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Cyclosporine: (Major) Avoid coadministration of entrectinib with cyclosporine due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and cyclosporine is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Dabrafenib: (Major) Avoid coadministration of entrectinib with dabrafenib due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; dabrafenib is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Danazol: (Major) Avoid coadministration of entrectinib with danazol due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and danazol is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Darunavir: (Major) Avoid coadministration of entrectinib with darunavir due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Darunavir; Cobicistat: (Major) Avoid coadministration of entrectinib with cobicistat due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold. (Major) Avoid coadministration of entrectinib with darunavir due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of entrectinib with cobicistat due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold. (Major) Avoid coadministration of entrectinib with darunavir due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Dasatinib: (Major) Avoid coadministration of entrectinib with dasatinib due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
Degarelix: (Major) Avoid coadministration of entrectinib with degarelix due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
Delavirdine: (Major) Avoid coadministration of entrectinib with delavirdine due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and delavirdine is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Desflurane: (Major) Avoid coadministration of entrectinib with halogenated anesthetics due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Halogenated anesthetics can prolong the QT interval.
Deutetrabenazine: (Major) Avoid coadministration of entrectinib with deutetrabenazine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dextromethorphan; Quinidine: (Major) Avoid coadministration of entrectinib with quinidine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP).
Diltiazem: (Major) Avoid coadministration of entrectinib with diltiazem due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and diltiazem is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Disopyramide: (Major) Avoid coadministration of entrectinib with disopyramide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Disopyramide administration is associated with QT prolongation and torsade de pointes (TdP).
Dofetilide: (Major) Avoid coadministration of entrectinib with dofetilide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
Dolasetron: (Major) Avoid coadministration of entrectinib with dolasetron due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Dolutegravir; Rilpivirine: (Major) Avoid coadministration of entrectinib with rilpivirine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Donepezil: (Major) Avoid coadministration of entrectinib with donepezil due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
Donepezil; Memantine: (Major) Avoid coadministration of entrectinib with donepezil due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
Dronedarone: (Contraindicated) Dronedarone use is contraindicated with medications that may prolong the QT/QTc interval, such as entrectinib, due to the additive risk for QT/QTc prolongation and torsade de pointes (TdP). Concomitant use may also increase entrectinib exposure. While coadministration is not recommended, if use is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate and dronedarone is a moderate CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 3-fold.
Droperidol: (Major) Avoid coadministration of entrectinib with droperidol due to the risk of QT prolongation. If coadministration cannot be avoided, use extreme caution; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Entrectinib has been associated with QT prolongation. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.
Duvelisib: (Major) Avoid coadministration of entrectinib with duvelisib due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and duvelisib is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Efavirenz: (Major) Avoid coadministration of entrectinib with efavirenz due to additive risk of QT prolongation and decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; efavirenz is a moderate CYP3A4 inducer that has been associated with QTc prolongation. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of entrectinib with efavirenz due to additive risk of QT prolongation and decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; efavirenz is a moderate CYP3A4 inducer that has been associated with QTc prolongation. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of entrectinib with efavirenz due to additive risk of QT prolongation and decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; efavirenz is a moderate CYP3A4 inducer that has been associated with QTc prolongation. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Elagolix: (Major) Avoid coadministration of entrectinib with elagolix due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; elagolix is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of entrectinib with elagolix due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; elagolix is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Eliglustat: (Major) Avoid coadministration of entrectinib with eliglustat due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of entrectinib with cobicistat due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of entrectinib with cobicistat due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid coadministration of entrectinib with rilpivirine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of entrectinib with rilpivirine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Encorafenib: (Major) Avoid concurrent use of encorafenib with entrectinib due to the risk for decreased entrectinib exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Entrectinib is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration of a strong CYP3A inducer decreased the entrectinib overall exposure by 77%.
Enzalutamide: (Major) Avoid coadministration of entrectinib with enzalutamide due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
Eribulin: (Major) Avoid coadministration of entrectinib with eribulin due to the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended. Both entrectinib and eribulin have been associated with QT prolongation.
Erythromycin: (Major) Avoid concomitant use of entrectinib with erythromycin due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, erythromycin is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Escitalopram: (Major) Concomitant use of entrectinib and escitalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Eslicarbazepine: (Major) Avoid coadministration of entrectinib with eslicarbazepine due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; eslicarbazepine is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Etrasimod: (Major) Concomitant use of etrasimod and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Etravirine: (Major) Avoid coadministration of entrectinib with etravirine due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; etravirine is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Fedratinib: (Major) Avoid coadministration of entrectinib with fedratinib due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and fedratinib is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Fexinidazole: (Major) Concomitant use of fexinidazole and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fingolimod: (Major) Avoid coadministration of entrectinib with fingolimod due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Flecainide: (Major) Avoid coadministration of entrectinib with flecainide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
Fluconazole: (Major) Avoid concomitant use of entrectinib with fluconazole due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, fluconazole is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Fluoxetine: (Major) Concomitant use of entrectinib and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fluphenazine: (Minor) Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as entrectinib.
Fluvoxamine: (Major) Avoid concomitant use of entrectinib with fluvoxamine due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, fluvoxamine is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Fosamprenavir: (Major) Avoid coadministration of entrectinib with fosamprenavir due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and fosamprenavir is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Foscarnet: (Major) Avoid coadministration of entrectinib with foscarnet due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet.
Fosphenytoin: (Major) Avoid coadministration of entrectinib with fosphenytoin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; fosphenytoin is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
Fostemsavir: (Major) Avoid coadministration of entrectinib with fostemsavir due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, 4 times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Gemifloxacin: (Major) Avoid coadministration of entrectinib with gemifloxacin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Major) Avoid coadministration of entrectinib with gemtuzumab due to the risk of QT prolongation. If coadministration is necessary, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Entrectinib has been associated with QT prolongation. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
Gilteritinib: (Major) Avoid coadministration of entrectinib with gilteritinib due to the risk of QT prolongation. If coadministration is necessary, monitor for evidence of QT prolongation during treatment. Both entrectinib and gilteritinib have been associated with QT prolongation.
Glasdegib: (Major) Avoid coadministration of glasdegib with entrectinib due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Entrectinib has been associated with QT prolongation.
Goserelin: (Major) Avoid coadministration of entrectinib with goserelin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Androgen deprivation therapy (i.e., goserelin) may prolong the QT/QTc interval.
Granisetron: (Major) Avoid coadministration of entrectinib with granisetron due to the risk of QT prolongation. Both entrectinib and granisetron have been associated with QT prolongation.
Grapefruit juice: (Major) Advise patients to avoid grapefruit juice or grapefruit-containing foods while taking entrectinib due to increased entrectinib exposure. Entrectinib is a CYP3A4 substrate; grapefruit juice is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
Halogenated Anesthetics: (Major) Avoid coadministration of entrectinib with halogenated anesthetics due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Halogenated anesthetics can prolong the QT interval.
Haloperidol: (Major) Avoid coadministration of entrectinib with haloperidol due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
Histrelin: (Major) Avoid coadministration of entrectinib with histrelin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
Hydroxychloroquine: (Major) Concomitant use of hydroxychloroquine and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Major) Concomitant use of hydroxyzine and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ibutilide: (Major) Avoid coadministration of entrectinib with ibutilide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Ibutilide administration can cause QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
Idelalisib: (Major) Avoid coadministration of entrectinib with idelalisib due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Iloperidone: (Major) Avoid coadministration of entrectinib with iloperidone due to the risk of QT prolongation. Both entrectinib and iloperidone have been associated with QT prolongation.
Imatinib: (Major) Avoid coadministration of entrectinib with imatinib due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and imatinib is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Indinavir: (Major) Avoid coadministration of entrectinib with indinavir due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and indinavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab with entrectinib due to the potential for additive QT prolongation and torsade de pointes. If coadministration is unavoidable, obtain ECGs and electrolytes prior to the start of treatment and periodically during treatment. Both entrectinib and inotuzumab have been associated with QT prolongation.
Isavuconazonium: (Major) Avoid coadministration of entrectinib with isavuconazonium due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and isavuconazonium is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Isoflurane: (Major) Avoid coadministration of entrectinib with halogenated anesthetics due

to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Halogenated anesthetics can prolong the QT interval.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of entrectinib with rifampin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration of rifampin decreased the entrectinib AUC by 77% in a drug interaction study.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of entrectinib with rifampin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration of rifampin decreased the entrectinib AUC by 77% in a drug interaction study.
Itraconazole: (Major) Avoid concomitant use of entrectinib with itraconazole due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, itraconazole is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration increased the overall exposure of entrectinib by 6-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with entrectinib due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Entrectinib has been associated with QT prolongation.
Ketoconazole: (Major) Avoid concomitant use of entrectinib with ketoconazole due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, ketoconazole is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of entrectinib with clarithromycin due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Lapatinib: (Major) Avoid coadministration of entrectinib with lapatinib due to the risk of QT prolongation. If coadministration is necessary, monitor for evidence of QT prolongation during treatment. Entrectinib has been associated with QT prolongation. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
Lefamulin: (Major) Avoid concomitant use of entrectinib with oral lefamulin due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, oral lefamulin is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Lenacapavir: (Major) Avoid coadministration of entrectinib with lenacapavir due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and lenacapavir is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Lenvatinib: (Major) Avoid coadministration of entrectinib with lenvatinib due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Prolongation of the QT interval has also been reported with lenvatinib therapy.
Letermovir: (Major) Avoid concomitant use of entrectinib with letermovir due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For adults and pediatric patients 2 years and older taking combination letermovir plus cyclosporine, a greater entrectinib dosage reduction is required: 600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day. For pediatric patients with an entrectinib starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, letermovir is a moderate CYP3A inhibitor, combination letermovir plus cyclosporine acts as a strong CYP3A inhibitor, and both entrectinib and letermovir have been associated with QT/QTc prolongation. Coadministration of a moderate or strong CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold or 6-fold, respectively.
Leuprolide: (Major) Avoid coadministration of entrectinib with leuprolide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) Avoid coadministration of entrectinib with leuprolide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
Levofloxacin: (Major) Concomitant use of levofloxacin and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Major) Avoid concomitant use of entrectinib with ketoconazole due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, ketoconazole is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Lithium: (Major) Concomitant use of lithium and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Lofexidine: (Major) Avoid coadministration of entrectinib with lofexidine due to the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended. Entrectinib has been associated with QT prolongation. Lofexidine also prolongs the QT interval.
Lonafarnib: (Major) Avoid coadministration of entrectinib with lonafarnib due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Loperamide: (Major) Avoid coadministration of entrectinib with loperamide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Loperamide; Simethicone: (Major) Avoid coadministration of entrectinib with loperamide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Lopinavir; Ritonavir: (Major) Avoid coadministration of entrectinib with ritonavir due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold. (Major) Avoid coadministration of lopinavir with entrectinib due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Both drugs have been associated with QT prolongation.
Lorlatinib: (Major) Avoid coadministration of entrectinib with lorlatinib due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of entrectinib with lumacaftor; ivacaftor due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of entrectinib with lumacaftor; ivacaftor due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
Macimorelin: (Major) Avoid coadministration of macimorelin with entrectinib as concurrent use may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Entrectinib has been associated with QT prolongation.
Maprotiline: (Major) Avoid coadministration of entrectinib with maprotiline due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
Mavacamten: (Major) Avoid coadministration of entrectinib with mavacamten due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A substrate; mavacamten is a moderate CYP3A inducer. Coadministration of a moderate CYP3A inducer is predicted to reduce the entrectinib overall exposure by 56%.
Mefloquine: (Major) Avoid coadministration of entrectinib with mefloquine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation.
Methadone: (Major) Avoid coadministration of entrectinib with methadone due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Methadone is considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
Methohexital: (Major) Avoid coadministration of entrectinib with methohexital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; methohexital is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Metronidazole: (Major) Concomitant use of metronidazole and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Midostaurin: (Major) Avoid coadministration of entrectinib with midostaurin due to the risk of QT prolongation. If coadministration cannot be avoided, consider interval assessments of QT by EKG. Entrectinib has been associated with QT prolongation. QT prolongation was reported in patients who received midostaurin in clinical trials.
Mifepristone: (Major) Avoid concomitant use of entrectinib with mifepristone due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, mifepristone is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Mirtazapine: (Major) Concomitant use of entrectinib and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mitotane: (Major) Avoid coadministration of entrectinib with mitotane due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
Mobocertinib: (Major) Concomitant use of mobocertinib and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Modafinil: (Major) Avoid coadministration of entrectinib with modafinil due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; modafinil is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Moxifloxacin: (Major) Avoid coadministration of entrectinib with moxifloxacin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Quinolones have been associated with a risk of QT prolongation. Although extremely rare, TdP has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
Nafcillin: (Major) Avoid coadministration of entrectinib with nafcillin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Nefazodone: (Major) Avoid coadministration of entrectinib with nefazodone due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Nelfinavir: (Major) Avoid coadministration of entrectinib with nelfinavir due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and nelfinavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid coadministration of entrectinib with netupitant due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and netupitant is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Nilotinib: (Major) Avoid concomitant use of entrectinib with nilotinib due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, nilotinib is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Nirmatrelvir; Ritonavir: (Major) Avoid coadministration of entrectinib with ritonavir due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Nirogacestat: (Major) Avoid coadministration of entrectinib with nirogacestat due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and nirogacestat is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Ofloxacin: (Major) Concomitant use of ofloxacin and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine: (Major) Avoid coadministration of entrectinib with olanzapine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Fluoxetine: (Major) Avoid coadministration of entrectinib with olanzapine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. (Major) Concomitant use of entrectinib and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine; Samidorphan: (Major) Avoid coadministration of entrectinib with olanzapine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of entrectinib with rifabutin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Ondansetron: (Major) Concomitant use of ondansetron and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
Osilodrostat: (Major) Avoid coadministration of entrectinib with osilodrostat due to the risk of QT prolongation. If coadministration is necessary, monitor ECGs during treatment. Entrectinib has been associated with QT prolongation. Osilodrostat is associated with dose-dependent QT prolongation.
Osimertinib: (Major) Avoid coadministration of entrectinib with osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Entrectinib has been associated with QT prolongation.
Oxaliplatin: (Major) Avoid coadministration of entrectinib with oxaliplatin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking entrectinib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Entrectinib has been associated with QT prolongation.
Pacritinib: (Major) Concomitant use of pacritinib and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Paliperidone: (Major) Avoid coadministration of paliperidone with entrectinib due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose. Entrectinib has been associated with QT prolongation.
Panobinostat: (Major) Avoid coadministration of entrectinib with panobinostat due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. QT prolongation has also been reported with panobinostat.
Pasireotide: (Major) Avoid coadministration of entrectinib with pasireotide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
Pazopanib: (Major) Avoid coadministration of entrectinib with pazopanib due to the risk of QT prolongation. If coadministration cannot be avoided, closely monitor the patient for QT interval prolongation. Entrectinib has been associated with QT prolongation. Pazopanib has also been reported to prolong the QT interval.
Pentamidine: (Major) Avoid coadministration of entrectinib with pentamidine due to the risk of QT prolongation. Both entrectinib and systemic pentamidine have been associated with QT prolongation.
Perphenazine: (Minor) Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as entrectinib.
Perphenazine; Amitriptyline: (Minor) Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as entrectinib.
Pexidartinib: (Major) Avoid coadministration of entrectinib with pexidartinib due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; pexidartinib is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Phenobarbital: (Major) Avoid coadministration of entrectinib with phenobarbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of entrectinib with phenobarbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
Phenytoin: (Major) Avoid coadministration of entrectinib with phenytoin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
Pimavanserin: (Major) Avoid coadministration of entrectinib with pimavanserin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Pimavanserin also prolongs the QT interval.
Pimozide: (Contraindicated) Coadministration of pimozide with entrectinib is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Pimozide is associated with a well-established risk of QT prolongation and TdP. Entrectinib has been associated with QT prolongation.
Pitolisant: (Major) Avoid coadministration of pitolisant with entrectinib as concurrent use may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Pitolisant also prolongs the QT interval.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking entrectinib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If treatment initiation is considered, seek advice from a cardiologist and monitor for signs and symptoms of infection. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Entrectinib has been associated with QT prolongation.
Posaconazole: (Major) Avoid concomitant use of entrectinib with posaconazole due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, posaconazole is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Primaquine: (Major) Avoid coadministration of entrectinib with primaquine due to the risk of QT prolongation. Both entrectinib and primaquine have been associated with QT prolongation.
Primidone: (Major) Avoid coadministration of entrectinib with primidone due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
Procainamide: (Major) Avoid coadministration of entrectinib with procainamide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
Prochlorperazine: (Minor) Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as entrectinib.
Promethazine: (Major) Concomitant use of promethazine and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Dextromethorphan: (Major) Concomitant use of promethazine and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Phenylephrine: (Major) Concomitant use of promethazine and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propafenone: (Major) Concomitant use of propafenone and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Quetiapine: (Major) Concomitant use of quetiapine and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Quinidine: (Major) Avoid coadministration of entrectinib with quinidine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP).
Quinine: (Major) Avoid coadministration of entrectinib with quinine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
Quizartinib: (Major) Concomitant use of quizartinib and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ranolazine: (Major) Avoid coadministration of entrectinib with ranolazine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Relugolix: (Major) Avoid coadministration of entrectinib with relugolix due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of entrectinib with relugolix due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Repotrectinib: (Major) Avoid coadministration of entrectinib with repotrectinib due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A substrate; repotrectinib is a moderate CYP3A inducer. Coadministration of a moderate CYP3A inducer is predicted to reduce the entrectinib overall exposure by 56%.
Ribociclib: (Major) Avoid concomitant use of entrectinib with ribociclib due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, ribociclib is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Ribociclib; Letrozole: (Major) Avoid concomitant use of entrectinib with ribociclib due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, ribociclib is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Rifabutin: (Major) Avoid coadministration of entrectinib with rifabutin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Rifampin: (Major) Avoid coadministration of entrectinib with rifampin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration of rifampin decreased the entrectinib AUC by 77% in a drug interaction study.
Rifapentine: (Major) Avoid coadministration of entrectinib with rifapentine due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; rifapentine is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
Rilpivirine: (Major) Avoid coadministration of entrectinib with rilpivirine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Risperidone: (Major) Avoid coadministration of entrectinib with risperidone due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting.
Ritlecitinib: (Major) Avoid coadministration of entrectinib with ritlecitinib due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and ritlecitinib is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Ritonavir: (Major) Avoid coadministration of entrectinib with ritonavir due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Romidepsin: (Major) Avoid coadministration of entrectinib with romidepsin due to the risk of QT prolongation. If coadministration is necessary, consider monitoring electrolytes and ECGs at baseline and periodically during treatment. Entrectinib has been associated with QT prolongation. Romidepsin has been reported to prolong the QT interval.
Saquinavir: (Major) Avoid concomitant use of entrectinib with saquinavir due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, saquinavir is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
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.
Secobarbital: (Major) Avoid coadministration of entrectinib with secobarbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; secobarbital is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Selpercatinib: (Major) Avoid coadministration of entrectinib with selpercatinib due to the risk of QT prolongation. Monitor ECGs more frequently for QT prolongation if coadministration is necessary. Entrectinib has been associated with QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy.
Sertraline: (Major) Concomitant use of sertraline and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) Avoid coadministration of entrectinib with halogenated anesthetics due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Halogenated anesthetics can prolong the QT interval.
Siponimod: (Major) Avoid coadministration of entrectinib with siponimod due to the risk of QT prolongation. If coadministration cannot be avoided, consult a cardiologist regarding appropriate monitoring. Entrectinib has been associated with QT prolongation. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Solifenacin: (Major) Avoid coadministration of entrectinib with solifenacin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined.
Sorafenib: (Major) Avoid coadministration of sorafenib with entrectinib due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Entrectinib has also been associated with QT prolongation.
Sotalol: (Major) Concomitant use of sotalol and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sotorasib: (Major) Avoid coadministration of entrectinib with sotorasib due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; sotorasib is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of entrectinib with St. John's Wort due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
Sunitinib: (Major) Avoid coadministration of entrectinib with sunitinib due to the risk of QT prolongation. If coadministration is necessary, monitor for evidence of QT prolongation. Both entrectinib and sunitinib have been associated with QT prolongation.
Tacrolimus: (Major) Avoid coadministration of entrectinib with tacrolimus due to the risk of QT prolongation. If coadministration is necessary, consider ECG and electrolyte monitoring periodically during treatment. Entrectinib has been associated with QT prolongation. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP).
Tamoxifen: (Major) Concomitant use of tamoxifen and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Telavancin: (Major) Avoid coadministration of entrectinib with telavancin due to the risk of QT prolongation. Both entrectinib and telavancin have been associated with QT prolongation.
Tetrabenazine: (Major) Avoid coadministration of entrectinib with tetrabenazine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Tetrabenazine causes a small increase in the corrected QT interval (QTc).
Thioridazine: (Contraindicated) Coadministration of thioridazine with entrectinib is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Thioridazine is associated with a well-established risk of QT prolongation and TdP. Entrectinib has been associated with QT prolongation.
Tipranavir: (Major) Avoid coadministration of entrectinib with tipranavir due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Tolterodine: (Major) Avoid coadministration of entrectinib with tolterodine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Toremifene: (Major) Avoid coadministration of entrectinib with toremifene due to the risk of QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes. Entrectinib has been associated with QT prolongation. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
Trandolapril; Verapamil: (Major) Avoid coadministration of entrectinib with verapamil due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and verapamil is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Trazodone: (Major) Concomitant use of trazodone and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Triclabendazole: (Major) Concomitant use of triclabendazole and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Trifluoperazine: (Minor) Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as entrectinib.
Triptorelin: (Major) Avoid coadministration of entrectinib with triptorelin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval.
Tucatinib: (Major) Avoid coadministration of entrectinib with tucatinib due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Vandetanib: (Major) Avoid coadministration of vandetanib with entrectinib due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Entrectinib has been associated with QT prolongation.
Vardenafil: (Major) Concomitant use of vardenafil and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Vemurafenib: (Major) Avoid coadministration of entrectinib with vemurafenib due to the risk of QT prolongation. If concomitant use is unavoidable, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both entrectinib and vemurafenib have been associated with QT prolongation.
Venlafaxine: (Major) Concomitant use of venlafaxine and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Verapamil: (Major) Avoid coadministration of entrectinib with verapamil due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and verapamil is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Voclosporin: (Major) Avoid concomitant use of entrectinib and voclosporin due to the risk of additive QT prolongation. Entrectinib has been associated with QT prolongation. Voclosporin has been associated with QT prolongation at supratherapeutic doses.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of entrectinib with clarithromycin due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Voriconazole: (Major) Avoid concomitant use of entrectinib with voriconazole due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de p ointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, voriconazole is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Vorinostat: (Major) Avoid coadministration of entrectinib with vorinostat due to the risk of QT prolongation. Both entrectinib and vorinostat have been associated with QT prolongation.
Voxelotor: (Major) Avoid coadministration of entrectinib with voxelotor due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and voxelotor is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Ziprasidone: (Major) Avoid coadministration of entrectinib with ziprasidone due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.

Entrectinib Oral Gran: 50mg
ROZLYTREK Oral Cap: 100mg, 200mg

Adults

600 mg PO once daily.

Geriatric

600 mg PO once daily.

Adolescents

BSA more than 1.5 m2: 600 mg PO once daily.
BSA 1.11 to 1.5 m2: 400 mg PO once daily.
BSA 0.81 to 1.1 m2: 300 mg PO once daily.

Children

BSA more than 1.5 m2: 600 mg PO once daily.
BSA 1.11 to 1.5 m2: 400 mg PO once daily.
BSA 0.81 to 1.1 m2: 300 mg PO once daily.
BSA 0.51 to 0.8 m2: 200 mg PO once daily.
BSA 0.5 m2 or less: 300 mg/m2 PO once daily.

Infants

6 to 11 months of age:
BSA 0.51 to 0.8 m2: 200 mg PO once daily.
BSA 0.5 m2 or less: 300 mg/m2 PO once daily.
6 months of age or less:
250 mg/m2 PO once daily.

Neonates

Safety and efficacy have not been established.

Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2, and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS1 (ROS1), and anaplastic lymphoma kinase (ALK). Entrectinib also inhibits the Janus kinase 2 (JAK2) and Tyrosine Kinase Non Receptor 2 (TNK2). The major active metabolite of entrectinib, M5, showed similar in vitro activity against TRK, ROS1, and ALK. Fusion proteins that include TRK, ROS1, or ALK kinase domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Entrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multiple tumor types harboring NTRK, ROS1, and ALK fusion genes. Entrectinib demonstrated in vivo antitumor activity in mice with intracranial implantation of TRKA-and ALK-driven tumor cell lines.

Entrectinib is administered orally. Both entrectinib and its major active metabolite, M5, are 99% bound to human plasma proteins in vitro. Entrectinib demonstrated steady-state brain-to-plasma concentration ratios of 0.4 to 2.2 in multiple animal species (mice, rats, and dogs). The active metabolite, M5, is the only major active circulating metabolite that has been identified; it has similar pharmacological potency to entrectinib in vitro. Circulating M5 exposures at steady-state in patients were 40% of the corresponding entrectinib exposure. The estimated apparent volume of distribution (Vd) was 551 L for entrectinib and 81.1 L for M5. The estimated apparent clearance was 19.6 L/hour for entrectinib and 52.4 L/hour for M5, with elimination half-lives of 20 hours and 40 hours, respectively. Steady-state is achieved within one week of daily administration for entrectinib and 2 weeks for M5. After oral administration of a single radiolabeled dose, 83% of the radioactivity was excreted in the feces (unchanged entrectinib, 36%; M5, 22%) with minimal excretion in the urine (3%).[64567]
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-glycoprotein (P-gp)
Entrectinib is primarily metabolized by CYP3A4 (approximately 76%) to the active metabolite, M5. M5 is a substrate of P-glycoprotein (P-gp) and BCRP. Entrectinib increased the AUC of midazolam, a sensitive CYP3A substrate, by 50% but reduced the midazolam Cmax by 21%. Entrectinib increased the Cmax and AUC of digoxin, a sensitive P-gp substrate, by 28% and 18%, respectively.[64567]

Oral Route

The pharmacokinetics of entrectinib and M5 are linear and are not dose-dependent or time-dependent. The mean AUC of entrectinib and M5 after the first dose is 31,800 nanoMolar x hour (CV, 48%) and 10,200 nanoMolar x hour (CV, 82%), respectively. The mean Cmax of entrectinib and M5 after the first dose is 2,250 nanoMolar (CV, 58%) and 622 nanoMolar (CV, 79%), respectively. The mean AUC of entrectinib and M5 at steady-state is 48,000 nanoMolar x hour (CV, 77%) and 24,000 nanoMolar x hour (CV, 97%), respectively. The mean Cmax of entrectinib and M5 at steady-state is 3,130 nanoMolar (CV, 80%) and 1,250 nanoMolar (CV, 90%), respectively. The accumulation ratio of entrectinib and M5 is 1.55 (CV, 49%) and 2.84 (CV, 93%), respectively. Maximum entrectinib plasma concentrations are reached 4 to 6 hours after oral administration of a single dose (Tmax).
 
A high-fat, high-calorie meal (approximately 800 to 1,000 calories with 50% fat) did not have a significant effect on the exposure of entrectinib capsules. The difference in entrectinib exposure for entrectinib pellets and capsules was not clinically significant after a light meal (250 calories; 25% fat) in healthy subjects. Exposure of entrectinib capsules as a suspension (mixed with water or milk and administered orally or through a nasogastric or gastric tube) was not significantly different compared to administration of intact entrectinib capsules in healthy subjects under fasted conditions. Coadministration with lansoprazole reduced the AUC of entrectinib capsules by 25% and the Cmax by 23%. Coadministration with lansoprazole increased the AUC of entrectinib capsules as oral suspension in water by 25% and the Cmax by 17%. These changes are not likely to be clinically significant.

Pregnancy

Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, animal studies, and its mechanism of action, entrectinib can cause fetal harm or death when administered during pregnancy. Pregnancy should be avoided by females of reproductive potential during entrectinib treatment and for at least 5 weeks after the final dose. Women who are pregnant or who become pregnant while receiving entrectinib should be apprised of the potential hazard to the fetus. There are no available data on the use of entrectinib in pregnant women. Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis. Administration of entrectinib to pregnant rats during organogenesis resulted in body closure defects (e.g., omphalocele and gastroschisis) and malformations of the vertebrae, ribs, and limbs (micromelia and adactyly) at maternal exposures approximately 2.7 times the human exposure at the recommended dose (600 mg); embryolethality did not occur. Lower fetal weight and reduced skeletal ossification occurred at approximately 0.2 and 0.9 times the human exposure at the recommended dose, respectively.

Due to the potential for serious adverse reactions in a nursing infant from entrectinib, advise women to discontinue breast-feeding during treatment and for 7 days after the final dose. It is not known whether entrectinib is present in human milk, although many drugs are excreted in human milk.[64567]