Dosage guidance:
Safety: Dosing presented as mg/m2 and as a fixed mg dose; use caution.
Clinical considerations: Entrectinib is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting; consider hydration (IV or oral; if at risk for dehydration), electrolyte replacement, and nutritional support as clinically indicated.
Solid tumors, neurotrophic tyrosine receptor kinase (NTRK) gene fusion positive:
Infants >1 month to ≤6 months: Oral: 250 mg/m2 once daily until disease progression or unacceptable toxicity.
Infants >6 months, Children, and Adolescents:
BSA ≤0.5 m2: Oral: 300 mg/m2 once daily until disease progression or unacceptable toxicity.
BSA 0.51 to 0.8 m2: Oral: 200 mg once daily until disease progression or unacceptable toxicity.
BSA 0.81 to 1.1 m2: Oral: 300 mg once daily until disease progression or unacceptable toxicity.
BSA 1.11 to 1.5 m2: Oral: 400 mg once daily until disease progression or unacceptable toxicity.
BSA ≥1.51 m2: Oral: 600 mg once daily until disease progression or unacceptable toxicity.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosing adjustment for toxicity: Note: Severity of toxicity (ie, grade level) is defined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
Starting entrectinib once-daily dose |
First dose reduction once-daily dose |
Second dose reduction once-daily dose |
After 2 dose reductions |
---|---|---|---|
250 mg/m2 or 300 mg/m2 |
Reduce dose to 2/3 the starting dose |
Reduce dose to 1/3 the starting dose |
Permanently discontinue entrectinib if patient does not tolerate after 2 dose reductions |
200 mg |
150 mg |
100 mg | |
300 mg |
200 mg |
100 mg | |
400 mg |
300 mg |
200 mg | |
600 mg |
400 mg |
200 mg |
Adverse reaction |
Severity |
Entrectinib dosage modification |
---|---|---|
Hematologic toxicity | ||
Anemia or neutropenia |
Grade 3 or 4 |
Withhold entrectinib until recovery to ≤ grade 2; resume at the same or reduced dose as clinically indicated. |
Nonhematologic toxicity | ||
Cardiac toxicity: Heart failure |
New onset or worsening |
Withhold entrectinib and manage as clinically appropriate; reassess left ventricular ejection fraction. Based on the severity, resume entrectinib at a reduced dose upon recovery or permanently discontinue. |
Grade 2 or 3 |
Withhold entrectinib until recovery to ≤ grade 1; resume at a reduced dose. | |
Grade 4 |
Permanently discontinue entrectinib. | |
Cardiac toxicity: QT interval prolongation |
QTc >500 msec |
Withhold entrectinib until QTc interval recovers to baseline. Resume at the same dose if QT prolongation risk factors are identified and corrected; resume at a reduced dose if QT prolongation risk factors are not identified. |
Torsades de pointes, polymorphic ventricular tachycardia, signs/symptoms of serious arrhythmia |
Permanently discontinue entrectinib. | |
CNS toxicity |
Grade 2 (intolerable) |
Withhold entrectinib until recovery to ≤ grade 1 or to baseline; resume at the same or reduced dose as clinically indicated. |
Grade 3 |
Withhold entrectinib until recovery to ≤ grade 1 or to baseline; resume at a reduced dose. | |
Grade 4 |
Permanently discontinue entrectinib. | |
Hyperuricemia |
Symptomatic or grade 4 |
Initiate antihyperuricemic therapy. Withhold entrectinib until improvement of signs/symptoms; resume at the same or reduced dose (based on severity). |
Ocular toxicity |
New visual changes or changes interfering with activities of daily living |
Withhold entrectinib until improvement or stabilization and perform an ophthalmic evaluation as clinically necessary. May resume entrectinib at the same or reduced dose when visual changes improve or stabilize. |
≥ Grade 2 |
Withhold entrectinib until improvement or stabilization; resume at the same or reduced dose as clinically indicated. | |
Other adverse reactions |
Grade 3 or 4 |
Withhold entrectinib until adverse reaction resolves or improves to grade 1 or baseline; resume at the same or reduced dose if resolution occurs within 4 weeks. Permanently discontinue if toxicity does not resolve within 4 weeks or for recurrent grade 4 events. |
Infants >1 month, Children, and Adolescents:
Mild to moderate renal impairment: Oral: No dosage adjustment necessary.
Severe renal impairment: There is no dosing adjustment provided in the manufacturer's labeling (has not been studied).
Infants >1 month, Children, and Adolescents: Oral:
Hepatic impairment at initiation (baseline):
Mild impairment (total bilirubin ≤1.5 × ULN with AST > ULN or total bilirubin >1 to 1.5 × ULN with any AST): There are no dosage adjustments provided in the manufacturer's labeling. Patients with hepatic function impairment may be at increased risk for adverse effects; monitor more frequently.
Moderate (total bilirubin >1.5 to 3 × ULN with any AST) or severe (total bilirubin >3 × ULN with any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling (the effect of moderate or severe impairment on the safety of entrectinib at the recommended dose is unknown). Consider risks versus benefits to determine appropriateness of entrectinib therapy. Patients with hepatic function impairment may be at increased risk for adverse effects; monitor more frequently.
Hepatotoxicity during therapy:
Grade 3: Withhold entrectinib until recovery to ≤ grade 1 or to baseline. If resolution within 4 weeks, resume at same dose. If not resolved within 4 weeks, permanently discontinue. Resume at reduced dose for recurrent grade 3 events that resolve within 4 weeks.
Grade 4: Withhold entrectinib until recovery to ≤ grade 1 or to baseline. If resolution within 4 weeks, resume at reduced dose. If not resolved within 4 weeks, permanently discontinue. Permanently discontinue for recurrent grade 4 events.
ALT or AST >3 times ULN with concurrent total bilirubin >1.5 times ULN (in the absence of cholestasis or hemolysis): Permanently discontinue entrectinib.
(For additional information see "Entrectinib: Drug information")
Dosage guidance:
Dosage form information: Entrectinib is available in capsules and pellets; select appropriate dosage form based on dose required and patient needs. Capsules are intended for patients with doses in multiples of 100 mg increments who can swallow whole capsules or for patients who are unable to swallow capsules or require enteral administration and/or with doses in multiples of 10 mg increments. Pellets may be used in patients unable to swallow capsules but can swallow soft food and with doses in multiples of 50 mg.
Non–small cell lung cancer, metastatic, ROS1-positive: Note: Select patients for treatment based on the presence of ROS1 rearrangement(s) in tumor or plasma specimens (testing using plasma specimens is only appropriate when tumor tissue is unavailable for testing).
Oral: 600 mg once daily; continue until disease progression or unacceptable toxicity.
Solid tumors, locally advanced or metastatic, NTRK gene fusion–positive: Note: Select patients for treatment based on the presence of NTRK gene fusion in tumor or plasma specimens (testing using plasma specimens is only appropriate when tumor tissue is unavailable for testing).
Oral: 600 mg once daily; continue until disease progression or unacceptable toxicity.
Missed doses: Make up the missed dose unless the next dose is within 12 hours. If vomiting occurs immediately after dose administration, repeat the entrectinib dose.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Note: Kidney function estimated using the Cockcroft-Gault equation.
CrCl ≥30 mL/minute: No dosage adjustment is necessary.
CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Hepatic impairment prior to treatment initiation:
Mild impairment (total bilirubin ≤1.5 times ULN with AST > ULN or total bilirubin >1 to 1.5 times ULN with any AST): There are no dosage adjustments provided in the manufacturer's labeling. Patients with hepatic function impairment may be at increased risk for adverse effects; monitor more frequently.
Moderate (total bilirubin >1.5 to 3 times ULN with any AST) or severe (total bilirubin >3 times ULN with any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling (the effect of moderate or severe impairment on the safety of entrectinib at the recommended dose is unknown). Consider risks versus benefits to determine appropriateness of entrectinib therapy. Patients with hepatic function impairment may be at increased risk for adverse effects; monitor more frequently.
Hepatotoxicity during treatment:
Grade 3: Withhold entrectinib until recovery to ≤ grade 1 or to baseline; resume at the same dose if recovery occurs within 4 weeks. Permanently discontinue entrectinib if recovery does not occur within 4 weeks. For recurrent grade 3 toxicity, resume at a reduced dose if toxicity resolves within 4 weeks.
Grade 4: Withhold entrectinib until recovery to ≤ grade 1 or to baseline; resume at a reduced dose if recovery occurs within 4 weeks. Permanently discontinue entrectinib if recovery does not occur within 4 weeks. For recurrent grade 4 toxicity, permanently discontinue entrectinib.
ALT or AST >3 times ULN with concurrent total bilirubin >1.5 times ULN (in the absence of cholestasis or hemolysis): Permanently discontinue entrectinib.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in children, adolescents, and adults unless otherwise indicated.
>10%:
Cardiovascular: Edema (40%, including facial edema, peripheral edema), hypotension (18%, including orthostatic hypotension)
Dermatologic: Pruritus (children and adolescents: <20%), skin rash (11%)
Endocrine & metabolic: Decreased serum glucose (children and adolescents: 26%), hyperkalemia (25%), hypermagnesemia (children and adolescents: 32%), hypernatremia (35%), hyperuricemia (9% to 52%), hypoalbuminemia (24% to 28%), hypocalcemia (34%), hypophosphatemia (30%), increased serum calcium (children and adolescents: 21%), increased serum potassium (children and adolescents: 25%), increased serum sodium (children and adolescents: 38%), weight gain (25% to 39%)
Gastrointestinal: Abdominal pain (16% to 20%), constipation (41% to 46%), decreased appetite (13% to 24%), diarrhea (35% to 37%; grades 3/4: 2%), dysgeusia (44%), increased serum amylase (26%), increased serum lipase (28%), nausea (34%; grades 3/4: <1%), vomiting (24% to 38%; grades 3/4: <1%)
Genitourinary: Urinary incontinence (children and adolescents: <20%), urinary tract infection (13% to 20%)
Hematologic & oncologic: Anemia (53% to 67%; grades 3/4: 7% to 9%), leukopenia (children and adolescents: 46%; grades 3/4: 1%), lymphocytopenia (40%; grades 3/4: 12%), lymphocytosis (children and adolescents: 33%; grades 3/4: 3%), neutropenia (28% to 53%; grades 3/4: 7% to 22%)
Hepatic: Increased serum alanine aminotransferase (36% to 53%), increased serum alkaline phosphatase (25%), increased serum aspartate aminotransferase (42% to 61%), increased serum bilirubin (children and adolescents: 20%)
Nervous system: Ataxia (17%), cognitive dysfunction (8% to 27%, including amnesia [3%], aphasia [2%], confusion [7%], delirium [<1%], disturbance in attention [5%], hallucination [1%], memory impairment [4%], mental status changes [2%]), dizziness (38%), dysesthesia (34%, including oral hypoesthesia, palmar-plantar erythrodysesthesia, paresthesia), fatigue (30% to 48%), headache (18% to 22%), myasthenia (12%), peripheral sensory neuropathy (18%; grades 3/4: 1%), sleep disturbance (≤14%, including drowsiness [7%], hypersomnia [1%], insomnia [7%])
Neuromuscular & skeletal: Arthralgia (21%), back pain (12%), bone fracture (5% to 25%), limb pain (11% to 26%), myalgia (28%)
Ophthalmic: Eye pain (children and adolescents: <20%), visual disturbance (21%, including blindness, blurred vision [9%], cataract [1%], corneal erosion, diplopia [3%], photophobia [5%], photopsia [1%], retinal hemorrhage, visual impairment [2%], vitreous detachment, vitreous opacity [1%])
Renal: Increased serum creatinine (73% to 84%)
Respiratory: Cough (24% to 33%), dyspnea (30%), nasal congestion (children and adolescents: 20%), upper respiratory tract infection (children and adolescents: 20%)
Miscellaneous: Fever (21% to 43%)
1% to 10%:
Cardiovascular: Heart failure (3%), prolonged QT interval on ECG (3%), pulmonary embolism (4%), syncope (4%)
Endocrine & metabolic: Dehydration (10%), hyperglycemia (grades 3/4: 4%)
Gastrointestinal: Dysphagia (10%)
Infection: Sepsis (3%)
Nervous system: Abnormal gait (children and adolescents: 3%), falling (8%), hydrocephalus (children and adolescents: 5%), mood disorder (10%, including agitation [2%], anxiety [5%], depression [3%]), pain (children and adolescents: 3%)
Respiratory: Hypoxia (4%), pleural effusion (8%), pneumonia (4% to 5%), pulmonary infection (10%), respiratory failure (2%)
<1%:
Cardiovascular: Myocarditis
Gastrointestinal: Intestinal perforation
Hematologic & oncologic: Tumor lysis syndrome
Nervous system: Suicidal ideation
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to entrectinib or any component of the formulation.
Concerns related to adverse effects:
• Cardiac effects: Heart failure, including grade 3 events, has been reported; myocarditis (in the absence of heart failure) has been observed rarely. Baseline and routine cardiac monitoring (other than electrocardiograms) were not performed in clinical trials, and patients with symptomatic heart failure, myocardial infarction, unstable angina, and coronary artery bypass graft within 3 months of study entry were excluded from studies. The median time to onset of heart failure was 2 months (range: 11 days to 12 months); heart failure resolved in one-half of patients following therapy interruption or discontinuation and with appropriate medical management.
• CNS effects: Cognitive impairment, mood disorders, dizziness, and sleep disturbances have been reported with entrectinib. Approximately one-quarter of patients experienced cognitive impairment (including cognitive disorders, confusion, attention disturbance, memory impairment, amnesia, aphasia, mental status changes, hallucinations, and delirium); symptoms occurred within 3 months of entrectinib initiation in most patients. Grade 3 cognitive impairment was reported. Mood disorders and sleep disturbances were reported in ≥10% of patients. Mood disorders included anxiety, depression, and agitation and occurred at a median onset of 1 month (range: 1 day to 9 months); grade 3 mood disorders occurred rarely. One completed suicide was reported (11 days after entrectinib completion). Sleep disturbances included insomnia, somnolence, hypersomnia, and sleep disorder; grade 3 events were rare. The incidence of CNS adverse events was similar between patients with and without CNS metastases; however, dizziness, headache, paresthesia, balance disorder, and confusion appeared to occur more frequently in patients with CNS metastases who had received prior CNS irradiation (compared to those who did not receive CNS radiation). Caution patients about performing tasks that require mental alertness (eg, operating machinery or driving).
• Fractures: The risk of skeletal fractures is increased with entrectinib therapy; fractures occurred more frequently in pediatric patients (25%) than adults (5%) in clinical trials. In adults and pediatrics, some fractures occurred due to a fall or other trauma to the affected site; in pediatric patients, some fractures occurred with no trauma. Radiologic abnormalities (possibly indicative of tumor involvement at the site of fracture) were reported in some adult patients, although there was inadequate assessment for tumor involvement at fracture sites. Most fractures (in adults and pediatrics) involved the hip or other lower extremity (femoral or tibial shaft); bilateral femoral neck fractures occurred rarely. The median time to fracture was 3.8 months in adults (range: 0.3 to 18.5 months) and 4.3 months in pediatrics (range: 2 to 28.7 months). Entrectinib was interrupted more frequently in adult patients (41%) than pediatric patients (16%) in clinical trials; a small number of pediatric patients discontinued therapy due to fractures. Promptly evaluate for signs/symptoms of fractures, such as pain, changes in mobility, or deformity. No data is available on entrectinib effects on healing of confirmed fractures or risk of future fractures.
• Hepatotoxicity: Increased AST and ALT (any grade) occurred in close to one-half and one-third of patients, respectively; grade 3 and 4 transaminase elevations have been reported. The median time to onset of elevated AST and ALT was 2 weeks (range: 1 day to 29.5 months for AST; 1 day to 9.2 months for ALT).
• Hyperuricemia: Hyperuricemia has been reported, including grade 4 events; one patient died due to tumor lysis syndrome. Hyperuricemia resolved in close to three-quarters of patients following initiation of antihyperuricemic therapy (without entrectinib therapy interruption or dose reduction).
• Ocular toxicity: Vision changes were reported in approximately one-fifth of patients in clinical trials; grade 1 toxicity was most common, although grade 2 and 3 events also occurred. Vision disorders included blurred vision, photophobia, diplopia, visual impairment, photopsia, cataract, and vitreous floaters.
• QT interval prolongation: QTcF interval prolongation >60 msec was reported in a small percentage of patients with at least one postbaseline ECG assessment; QTcF interval >500 msec occurred rarely. Patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure, and/or those taking concomitant medications associated with QT prolongation are at significant risk of developing QTc interval prolongation.
Special populations:
• Pediatrics: Based on limited data in pediatric patients with solid tumors, grade 3 or 4 neutropenia, bone fractures, weight gain, thrombocytopenia, lymphopenia, increased gamma-glutamyl transferase, and device-related infections occurred more frequently in pediatric patients compared with adults.
Other warnings/precautions:
• Appropriate use: Select patients for treatment of locally advanced or metastatic solid tumors based on the presence of a neurotrophic tyrosine receptor kinase (NTRK) gene fusion in tumor or plasma specimens (use plasma specimen only if tumor tissue is not available). Select for treatment of metastatic non-small cell lung cancer based on the presence of ROS1 rearrangement(s) in tumor or plasma specimens (use plasma specimen only if tumor tissue is not available). Information on approved tests is available at http://www.fda.gov/CompanionDiagnostics.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Rozlytrek: 100 mg
Rozlytrek: 200 mg [contains fd&c yellow #6 (sunset yellow)]
Packet, Oral:
Rozlytrek: 50 mg (1 ea, 42 ea)
No
Capsules (Rozlytrek Oral)
100 mg (per each): $267.24
200 mg (per each): $267.24
Pack (Rozlytrek Oral)
50 mg (per each): $133.61
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Rozlytrek: 100 mg
Rozlytrek: 200 mg [contains fd&c yellow #6 (sunset yellow)]
Entrectinib is available through specialty pharmacies and various specialty institutions or accounts; distribution information is available at https://www.genentech-access.com/hcp/brands/rozlytrek/learn-about-our-services/product-distribution.html.
Note: Entrectinib is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting. Provide standard antidiarrheals; consider hydration (IV or oral; if at risk for dehydration), electrolyte replacement, and nutritional support as clinically indicated.
Oral: Administer with or without food; if vomiting occurs immediately after the dose, repeat the dose.
Capsule: Swallow capsule whole; do not open, crush, chew, or dissolve the contents of the capsule.
Oral pellets: Appropriate for dose increments in multiples of 50 mg and if able to swallow soft food: Sprinkle oral pellets on one or more spoonfuls of soft food (eg, applesauce, yogurt, pudding). Administer within 20 minutes of preparation; do not crush or chew (crushing or chewing may result in bitter taste). Instruct patient to drink water after administration to ensure entire dose is consumed. Do not attempt to use partial quantities of pellets from a 50 mg packet to prepare a dose. Do not use pellet formulation for enteral tube administration (may clog tube).
Suspension: The capsule may be opened and prepared as an oral suspension by adding capsule dose contents to an appropriate volume of room temperature drinking water or milk to a final concentration of 20 mg/mL (5 mL of water or milk per 100 mg of entrectinib). Let suspension sit for 15 minutes, then administer immediately; discard if not used within 2 hours. Instruct patient to drink water after administration of the oral suspension to ensure entire dose is consumed. Use an appropriate measuring device for preparation. Do not use pellet formulation for preparation of suspension.
Enteral tube (gastric or NG) administration (8 French or higher for doses ≥3 mL): Using oral suspension prepared from capsules, divide dosing volumes of ≥3 mL into at least 2 aliquots; administer immediately after preparation. Following administration of each aliquot, flush tube with a volume of water or milk that is equal to the aliquot administered. Do not use pellet formulation for enteral tube administration.
Missed dose: If a dose is missed, administer a make-up dose unless the next dose is within 12 hours.
Oral: Administer with or without food.
Capsules: Swallow capsules whole; do not crush or chew.
Suspension: For patients with difficulty swallowing capsules or who require enteral administration, the capsule may be opened and prepared as an oral suspension by adding to an appropriate volume of room temperature drinking water or milk to a final concentration of 20 mg/mL (5 mL of water or milk per 100 mg of entrectinib). Let suspension sit for 15 minutes, then administer immediately; discard if not used within 2 hours. Instruct patient to drink water after administration of the oral suspension to ensure entire dose is consumed. Use an appropriate measuring device for preparation. Do not use pellet formulation for preparation of suspension.
Enteral tube (gastric or NG) administration of suspension prepared from capsules (8 French or higher for doses ≥3 mL): Divide dosing volumes of ≥3 mL into at least 2 aliquots; administer immediately after preparation. Following administration of each aliquot, flush tube with a volume of water or milk that is equal to the aliquot administered. Do not use pellet formulation for enteral tube administration.
Pellets: For patients with doses in multiples of 50 mg and with difficulty swallowing the capsule but can swallow soft food, sprinkle oral pellets on one or more spoonfuls of soft food (eg, applesauce, yogurt, pudding). Administer within 20 minutes of preparation; do not crush or chew (crushing or chewing may result in bitter taste). Instruct patient to drink water after administration to ensure entire dose is consumed. Do not attempt to use partial quantities of pellets from a 50 mg packet to prepare a dose. Do not use pellet formulation for enteral tube administration (may clog tube).
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Entrectinib may cause teratogenicity.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Capsules: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Store in original container and keep bottle closed tightly to protect from moisture. If capsules are prepared as an oral suspension using drinking water or milk, storage time should not exceed 2 hours (below 30°C [86°F]); discard unused suspension if not used within 2 hours.
Pellets: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Store in original container and keep bottle closed tightly to protect from moisture.
Treatment of solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have either progressed following treatment or have no satisfactory alternative therapy (FDA approved in ages >1 month and adults).
Treatment of metastatic non-small cell lung cancer in patients whose tumors are ROS1-positive (FDA approved in adults).
Entrectinib may be confused with alectinib, enasidenib, encorafenib, erdafitinib, erlotinib, fedratinib, larotrectinib, pacritinib.
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (chemotherapeutic agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program
Amisulpride (Oral): May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk C: Monitor therapy
Azithromycin (Systemic): QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Azithromycin (Systemic). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CloZAPine: May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Entrectinib. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Entrectinib. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Entrectinib. Management: Avoid moderate CYP3A4 inhibitors if possible. If needed, reduce entrectinib dose to 50 mg/day if starting dose 200 mg; to 100 mg/day if starting dose 300 mg; to 200 mg if starting dose 400 mg or 600 mg. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Entrectinib. Management: Avoid strong CYP3A4 inhibitors if possible. If needed, reduce entrectinib dose to 50 mg on alternating days if starting dose 200 mg; to 50 mg/day if starting dose 300 mg or 400 mg; to 100 mg/day if starting dose 600 mg. Risk D: Consider therapy modification
Dabrafenib: May enhance the QTc-prolonging effect of Entrectinib. Dabrafenib may decrease the serum concentration of Entrectinib. Risk X: Avoid combination
Domperidone: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone. Risk X: Avoid combination
Dronedarone: Entrectinib may enhance the QTc-prolonging effect of Dronedarone. Dronedarone may increase the serum concentration of Entrectinib. Risk X: Avoid combination
Encorafenib: May enhance the QTc-prolonging effect of Entrectinib. Encorafenib may decrease the serum concentration of Entrectinib. Risk X: Avoid combination
Fexinidazole: QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Fexinidazole. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Fluorouracil Products: May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider therapy modification
Grapefruit Juice: May increase the serum concentration of Entrectinib. Risk X: Avoid combination
Haloperidol: QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Lefamulin: May enhance the QTc-prolonging effect of QT-prolonging CYP3A4 Substrates. Management: Do not use lefamulin tablets with QT-prolonging CYP3A4 substrates. Lefamulin prescribing information lists this combination as contraindicated. Risk X: Avoid combination
Levoketoconazole: QT-prolonging CYP3A4 Substrates may enhance the QTc-prolonging effect of Levoketoconazole. Levoketoconazole may increase the serum concentration of QT-prolonging CYP3A4 Substrates. Risk X: Avoid combination
Midostaurin: May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
OLANZapine: May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Ondansetron: May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
PAZOPanib: QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of PAZOPanib. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Pentamidine (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combination
Piperaquine: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Piperaquine. Risk X: Avoid combination
Posaconazole: May increase the serum concentration of QT-prolonging CYP3A4 Substrates. Such increases may lead to a greater risk for proarrhythmic effects and other similar toxicities. Risk X: Avoid combination
QT-prolonging Agents (Highest Risk): Entrectinib may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk X: Avoid combination
QT-prolonging Antidepressants (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Antipsychotics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Class IC Antiarrhythmics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-Prolonging Inhalational Anesthetics (Moderate Risk): QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-Prolonging Inhalational Anesthetics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Kinase Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of other QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Miscellaneous Agents (Moderate Risk): QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): Entrectinib may enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Entrectinib. Risk X: Avoid combination
QT-prolonging Quinolone Antibiotics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of Entrectinib. QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk) may increase the serum concentration of Entrectinib. Risk X: Avoid combination
QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): Entrectinib may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Entrectinib. Risk X: Avoid combination
RisperiDONE: QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of RisperiDONE. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Sertindole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combination
Grapefruit may increase entrectinib plasma levels. Management: Avoid grapefruit or grapefruit juice during therapy.
Avoid grapefruit or grapefruit juice during entrectinib therapy.
Evaluate pregnancy status prior to treatment initiation in patients who could become pregnant. Patients who could become pregnant should use effective contraception during therapy and for at least 5 weeks after the last entrectinib dose. Patients with partners who could become pregnant should use effective contraception during therapy and for 3 months after the last entrectinib dose.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to entrectinib may cause fetal harm.
Entrectinib inhibits specific tropomyosin tyrosine receptor kinases (TRK). In persons with congenital mutations in TRK pathway proteins, anhidrosis, cognitive impairment, developmental delay, obesity, and insensitivity to pain have been observed following decreased TRK-mediated signaling.
Assess NTRK gene fusion status (locally advanced or metastatic solid tumors; in tumor or plasma specimen) or ROS1 rearrangement status (non–small cell lung cancer; in tumor or plasma specimen) prior to treatment initiation; testing using plasma specimens is only appropriate when tumor tissue is unavailable for testing. Monitor liver functions tests (including ALT and AST) every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated; serum uric acid level (prior to initiation and periodically throughout therapy). Evaluate pregnancy status prior to treatment (in patients who could become pregnant). Assess left ventricular ejection fraction prior to initiation in patients with heart failure symptoms or known risk factors for heart failure (for patients with myocarditis [with or without a decreased ejection fraction], MRI or cardiac biopsy may be necessary for diagnosis). Assess QT interval and electrolytes at baseline and periodically throughout therapy (monitor at-risk patients and those with current QT prolongation closely; monitor more frequently based on risk factors such as heart failure, electrolyte abnormalities, or concomitant medications known to prolong the QT interval). Perform an ophthalmic evaluation as clinically necessary. Monitor for signs/symptoms of heart failure (eg, shortness of breath, edema); monitor for signs/symptoms of CNS adverse effects (cognitive impairment, mood disorders, dizziness, sleep disturbances), fractures (promptly evaluate signs/symptoms such as pain, changes in mobility, or deformity), tumor lysis syndrome/hyperuricemia, and visual changes. Monitor more frequently in patients with hepatic function impairment. Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Entrectinib inhibits tropomyosin tyrosine receptor kinases (TRK) TRKA, TRKB, and TRKC. TRKA, TRKB, and TRKC are encoded by neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1, NTRK2, and NTRK3, respectively. Entrectinib also inhibits proto-oncogenic tyrosine-protein kinase ROS1 and anaplastic lymphoma kinase (ALK). M5 (the major active entrectinib metabolite) demonstrated similar activity (in vitro) against TRK, ROS1, and ALK. Fusion proteins that include TRK, ROS1, or ALK kinase domains act as oncogenic drivers to promote hyperactivation of downstream signaling pathways, resulting in unchecked cell proliferation.
Distribution: Entrectinib: 551 L; M5 (active metabolite): 81.1 L.
Protein binding: Entrectinib and M5 (active metabolite): >99% to plasma proteins.
Metabolism: Primarily hepatic via CYP3A4 to form the active metabolite M5.
Half-life elimination: Entrectinib: 20 hours; M5 (active metabolite): 40 hours.
Time to peak: 4 to 6 hours.
Excretion: Feces (83%; 36% as unchanged parent drug and 22% as M5); urine (3%).
Clearance: 19.6L/h (entrectinib); 52.4 L/h (M5).
Hepatic function impairment: Following a single entrectinib 100 mg oral dose (1/6 of the recommended dose), the entrectinib AUCINF was increased by 39% in mild and moderate hepatic impairment and by 23% in severe hepatic impairment, compared to normal hepatic function. The combined AUClast of entrectinib and M5 was increased by 16% in mild and moderate hepatic impairment and by 4% in severe hepatic impairment, compared to normal hepatic function. Large variability in entrectinib systemic exposure was observed in the hepatic impairment.
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