Non-small cell lung cancer, metastatic, ROS1-positive: Oral: 600 mg once daily until disease progression or unacceptable toxicity.
Solid tumors with neurotrophic tyrosine receptor kinase (NTRK) gene fusion: Oral: 600 mg once daily 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.
CrCl 30 to <90 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): No dosage adjustment is necessary.
Moderate (total bilirubin >1.5 to 3 times ULN) or severe (total bilirubin >3 times ULN) impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
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. Permanently discontinue for recurrent grade 4 toxicity.
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: Pediatric drug information")
Solid tumors, neurotrophic tyrosine receptor kinase (NTRK) gene fusion positive: Children ≥12 years and Adolescents:
BSA 0.91 to 1.1 m2: Oral: 400 mg once daily until disease progression or unacceptable toxicity.
BSA 1.11 to 1.5 m2: Oral: 500 mg once daily until disease progression or unacceptable toxicity.
BSA >1.5 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: Children ≥12 years and Adolescents: Note: Severity of toxicity (ie, grade level) is defined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
Recommended dosage reductions for toxicity: Note: In patients unable to tolerate entrectinib after 2 dose reductions, permanently discontinue entrectinib.
BSA 0.91 to 1.10 m2:
Usual dose: 400 mg once daily.
First reduction: 300 mg once daily.
Second reduction: 200 mg once daily.
BSA 1.11 to 1.50 m2:
Usual dose: 500 mg once daily.
First reduction: 400 mg once daily.
Second reduction: 200 mg once daily.
BSA >1.5 m2:
Usual dose: 600 mg once daily.
First reduction: 400 mg once daily.
Second reduction: 200 mg once daily.
Hematologic toxicity: Anemia or neutropenia (grade 3 or 4): Withhold entrectinib until recovery to ≤ grade 2; resume at same dose or reduced dose as clinically appropriate.
Nonhematologic toxicity:
Cardiotoxicity:
Heart failure:
Grade 2 or 3: Withhold entrectinib until recovery to ≤ grade 1; resume at a reduced dose.
Grade 4: Permanently discontinue entrectinib.
QT interval prolongation (QTc >500 msec): Withhold entrectinib until QTc interval recovers to baseline. Resume at same dose if QT prolongation risk factors are identified and corrected; resume at a reduced dose if QT prolongation risk factors are not identified.
Torsade de pointes; polymorphic ventricular tachycardia; signs and/or symptoms of serious arrhythmia: Permanently discontinue entrectinib.
Central nervous system toxicity (including cognitive impairment, mood disorders, dizziness, and sleep disturbances):
Grade 2 (Intolerable): Withhold entrectinib until recovery to ≤ grade 1 or to baseline; resume at same dose or reduced dose as clinically appropriate.
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 urate-lowering medication and withhold entrectinib until improvement of signs and/or symptoms; resume at same dose or reduced dose.
Ocular toxicity: Grade ≥2: Withhold entrectinib until improvement or stabilization; resume at same dose or reduced dose as clinically appropriate.
Other clinically relevant toxicities: Grade 3 or 4: Withhold entrectinib until adverse reaction resolves or improves to grade 1 or baseline. If resolution occurs within 4 weeks, resume at the same or reduced dose. If not resolved within 4 weeks, permanently discontinue. Permanently discontinue for recurrent grade 4 events.
Children ≥12 years and Adolescents:
Mild to moderate renal impairment: No dosage adjustment necessary.
Severe renal impairment: There is no dosing adjustment provided in the manufacturer's labeling (has not been studied).
Children ≥12 years and Adolescents:
Hepatic impairment at initiation (baseline):
Total bilirubin ≤1.5 times ULN: No dosage adjustment necessary.
Total bilirubin >1.5 times ULN: There is no dosing adjustment provided in the manufacturer's labeling (has not been studied).
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.
Refer to adult dosing.
|
a Discontinue permanently if unable to tolerate entrectinib after 2 dose reductions. | |
|
Usual initial dose |
600 mg once daily |
|
First dose reduction level |
400 mg once daily |
|
Second dose reduction levela |
200 mg once daily |
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:
Cardiotoxicity:
New onset worsening heart failure: 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.
Heart failure (grade 2 or 3): Withhold entrectinib until recovery to ≤ grade 1; resume at a reduced dose.
Heart failure (grade 4): Permanently discontinue entrectinib.
QT interval prolongation (>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 system 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 and withhold entrectinib until improvement of signs/symptoms. Resume at the same or reduced dose.
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 or higher: Withhold entrectinib until improvement or stabilization; resume at the same or reduced dose as clinically indicated.
Other toxicity (clinically relevant): 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.
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)]
No
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 a restricted distribution system; distribution information is available at https://www.genentech-access.com/hcp/brands/rozlytrek/learn-about-our-services/product-distribution.html.
Oral: Administer with or without food. Swallow capsules whole; do not open, crush, chew, or dissolve the contents of the capsules.
Oral: Administer with or without food. Swallow capsule whole; do not open, crush, chew, or dissolve the contents of the capsule. Do not administer with grapefruit juice. If vomiting occurs immediately after the dose, repeat the dose. If a dose is missed, administer a make-up dose unless the next dose is within 12 hours.
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.
Non-small cell lung cancer, metastatic: Treatment of metastatic non-small cell lung cancer in adults whose tumors are ROS1-positive (as detected by an approved test).
Solid tumors: Treatment of solid tumors in adult and pediatric patients ≥12 years of age that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion (as detected by an approved test) 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.
Entrectinib may be confused with alectinib, enasidenib, encorafenib, erdafitinib, erlotinib, fedratinib, larotrectinib
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its lists of drug classes which have a heightened risk of causing significant patient harm when used in error.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Edema (40%), hypotension (18%)
Central nervous system: Fatigue (48%), dizziness (38%), dysesthesia (34%), cognitive dysfunction (27%), headache (18%), peripheral sensory neuropathy (18%; grades ≥3: 1%), ataxia (17%), sleep disorder (14%), myasthenia (12%)
Dermatologic: Skin rash (11%)
Endocrine & metabolic: Hyperuricemia (9% to 52%), hypernatremia (35%), hypocalcemia (34%), hypophosphatemia (30%), hypoalbuminemia (28%), increased amylase (26%), hyperkalemia (25%), weight gain (25%)
Gastrointestinal: Constipation (46%), dysgeusia (44%), diarrhea (35%), nausea (34%), increased serum lipase (28%), vomiting (24%), abdominal pain (16%), decreased appetite (13%)
Genitourinary: Urinary tract infection (13%)
Hematologic & oncologic: Anemia (67%; grades 3/4: 9%), lymphocytopenia (40%; grades 3/4: 12%), neutropenia (28%; grades 3/4: 7%)
Hepatic: Increased serum aspartate aminotransferase (42% to 44%), increased serum alanine aminotransferase (36% to 38%), increased serum alkaline phosphatase (25%)
Neuromuscular & skeletal: Myalgia (28%), bone fracture (children and adolescents: 23%; adults: 5%), arthralgia (21%), back pain (12%), limb pain (11%)
Ophthalmic: Visual disturbance (21%)
Renal: Increased serum creatinine (73%)
Respiratory: Dyspnea (30%), cough (24%)
Miscellaneous: Fever (21%)
1% to 10%:
Cardiovascular: Pulmonary embolism (4%), syncope (4%), cardiac failure (3%), prolonged QT interval on ECG (3%)
Central nervous system: Mood disorder (10%), falling (8%), confusion (7%), drowsiness (7%), insomnia (7%), anxiety (5%), disturbance in attention (5%), memory impairment (4%), amnesia (3%), depression (3%), agitation (2%), aphasia (2%), mental status changes (2%), hallucination (1%), hypersomnia (1%)
Endocrine & metabolic: Dehydration (10%), hyperglycemia (grades 3/4: 4%)
Gastrointestinal: Dysphagia (10%)
Infection: Sepsis (3%)
Ophthalmic: Blurred vision (9%), photophobia (5%), diplopia (3%), visual impairment (2%), cataract (1%), photopsia (1%), vitreous opacity (1%)
Respiratory: Pulmonary infection (10%), pleural effusion (8%), hypoxia (4%), pneumonia (4%), respiratory failure (2%)
<1%: Delirium, myocarditis, suicidal ideation
Frequency not defined:
Cardiovascular: Facial edema, orthostatic hypotension, peripheral edema
Central nervous system: Paresthesia
Dermatologic: Palmar-plantar erythrodysesthesia
Gastrointestinal: Oral hypoesthesia
Ophthalmic: Blindness, corneal erosion, retinal hemorrhage, vitreous detachment
There are no contraindications listed in the US manufacturer's 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. For patients with myocarditis (with or without a decreased ejection fraction), MRI or cardiac biopsy may be necessary to make the diagnosis.
• 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 the majority of 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 (23%) than adults (5%) in clinical trials. In pediatric patients, all fractures occurred with minimal or no trauma; in adults, some fractures occurred due to a fall or other trauma to the affected site. Radiologic abnormalities (possibly indicative of tumor involvement at the site of fracture) were reported in some 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 months in pediatrics (range: 1.8 to 7.4 months). 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. Select for treatment of metastatic non-small cell lung cancer based on the presence of ROS1 rearrangement(s) in tumor specimens. Information on approved tests is available at http://www.fda.gov/CompanionDiagnostics.
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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
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 during treatment with entrectinib. Reduce dose to 200 mg/day if combination cannot be avoided in adults and those 12 yrs of age or older with a BSA of at least 1.5 square meters. Avoid if BSA is less than 1.5 square meters Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Entrectinib. Management: Avoid strong CYP3A4 inhibitors during treatment with entrectinib when possible. If combined in adults and those 12 yrs of age or older with a BSA of at least 1.5 square meters, reduce dose to 100 mg/day. Avoid if BSA is less than 1.5 square meters. 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. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Dronedarone: Entrectinib may enhance the QTc-prolonging effect of Dronedarone. Dronedarone may increase 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). Risk X: Avoid combination
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
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.
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.
It is not known if entrectinib is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 7 days after the last entrectinib dose.
Avoid grapefruit or grapefruit juice during entrectinib therapy.
Assess neurotrophic tyrosine receptor kinase (NTRK) gene fusion status (locally advanced or metastatic solid tumors) or ROS1 rearrangements status (non-small cell lung cancer; in tumor specimen) prior to treatment initiation. 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). Assess left ventricular ejection fraction prior to initiation in patients with heart failure symptoms or risk factors (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). Evaluate pregnancy status prior to treatment (in patients who could become pregnant). 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 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).
Capsules (Rozlytrek Oral)
100 mg (per each): $242.39
200 mg (per each): $242.39
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