Entrectinib

Dosage Forms

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)]

Pharmacology

Mechanism of Action

Entrectinib inhibits tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, and TRKC. TRKA, TRKB, and TRKC are encoded by neurotrophic receptor tyrosine 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.

Pharmacokinetics/Pharmacodynamics

Distribution

Entrectinib: 551 L; M5 (active metabolite): 81.1 L.

Metabolism

Primarily hepatic via CYP3A4 to form the active metabolite M5.

Excretion

Feces (83%; 36% as unchanged parent drug and 22% as M5); urine (3%).

Clearance: 19.6L/h (entrectinib); 52.4 L/h (M5)

Time to Peak

4 to 6 hours.

Half-Life Elimination

Entrectinib: 20 hours; M5 (active metabolite): 40 hours.

Protein Binding

Entrectinib and M5 (active metabolite): >99% to plasma proteins.

Use: Labeled Indications

Non-small cell lung cancer, metastatic: Treatment of metastatic non-small cell lung cancer in adults whose tumors are ROS1-positive.

Solid tumors: Treatment of solid tumors in adult and pediatric patients ≥12 years of age that have a neurotrophic tyrosine receptor kinase 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.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosage and Administration

Dosing: Adult

Non-small cell lung cancer (metastatic), ROS1-positive: Oral: 600 mg once daily until disease progression or unacceptable toxicity.

Solid tumors (with neurotrophic receptor tyrosine kinase gene fusion): Oral: 600 mg once daily until disease progression or unacceptable toxicity.

Dosage adjustment for CYP3A inhibitors (with BSA >1.5 m²):

Strong CYP3A inhibitors: Avoid concomitant use of entrectinib with strong CYP3A inhibitors. If concomitant use cannot be avoided, reduce the entrectinib dose to 100 mg once daily. When the strong CYP3A inhibitor is discontinued, increase the entrectinib dose (after 3 to 5 elimination half-lives of the strong CYP3A4 inhibitor have elapsed) to the dose that was used prior to initiation of the CYP3A inhibitor.

Moderate CYP3A inhibitors: Avoid concomitant use of entrectinib with moderate CYP3A inhibitors. If concomitant use cannot be avoided, reduce the entrectinib dose to 200 mg once daily. When the moderate CYP3A inhibitor is discontinued, increase the entrectinib dose (after 3 to 5 elimination half-lives of the moderate CYP3A4 inhibitor have elapsed) to the dose that was used prior to initiation of the CYP3A inhibitor.

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.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

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.

Dosing adjustment for concomitant therapy: Children ≥12 years and Adolescents: Oral:

Moderate CYP3A inhibitors:

BSA ≤1.5 m²: Avoid concomitant use of entrectinib with moderate CYP3A inhibitors.

BSA >1.5 m²: Avoid concomitant use of entrectinib with moderate CYP3A inhibitors. If concomitant use cannot be avoided, reduce the entrectinib dose to 200 mg once daily. When the moderate CYP3A inhibitor is discontinued, increase the entrectinib dose (after 3 to 5 elimination half-lives of the moderate CYP3A4 inhibitor have elapsed) to the dose that was used prior to initiation of the CYP3A inhibitor.

Strong CYP3A inhibitors:

BSA ≤1.5 m²: Avoid concomitant use of entrectinib with strong CYP3A inhibitors.

BSA >1.5 m²: Avoid concomitant use of entrectinib with strong CYP3A inhibitors. If concomitant use cannot be avoided, reduce the entrectinib dose to 100 mg once daily. When the strong CYP3A inhibitor is discontinued, increase the entrectinib dose (after 3 to 5 elimination half-lives of the strong CYP3A4 inhibitor have elapsed) to the dose that was used prior to initiation of the CYP3A inhibitor.

Moderate or strong CYP3A4 inducers: Avoid concomitant use of entrectinib with moderate and strong CYP3A inducers.

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.

Dosing: Adjustment for Toxicity

Recommended dosage reduction levels:

Usual initial dose: 600 mg once daily.

First dose reduction level: 400 mg once daily.

Second dose reduction level: 200 mg once daily.

Discontinue permanently if unable to tolerate entrectinib after 2 dose reductions.

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:

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 (≥ grade 2): 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.

Administration

Oral: Administer with or without food. Swallow capsules whole; do not open, crush, chew, or dissolve the contents of the capsules.

Dietary Considerations

Avoid grapefruit or grapefruit juice during entrectinib therapy.

Storage

Store below 30°C (86°F).

Drug Interactions

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Entrectinib. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Entrectinib. 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. No alternative dosing provided for others. Exceptions: Crizotinib; Erythromycin (Systemic); Fluconazole; Nilotinib; Ribociclib. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Entrectinib. Management: Avoid strong CYP3A4 inhibitors during treatment with entrectinib. Reduce dose to 100 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. No alternative dosing provided for others. Exceptions: Ceritinib; Clarithromycin; Saquinavir; Voriconazole. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

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. Consider therapy modification

Dronedarone: Entrectinib may enhance the QTc-prolonging effect of Dronedarone. Dronedarone may increase the serum concentration of Entrectinib. Avoid combination

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fexinidazole [INT]: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Avoid combination

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Grapefruit Juice: May increase the serum concentration of Entrectinib. 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. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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. Avoid combination

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

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. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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. Monitor therapy

Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). 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. Avoid combination

QT-prolonging Agents (Highest Risk): Entrectinib may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Exceptions: Dronedarone. 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. 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. Exceptions: Pimozide. 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. 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. 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. Exceptions: Domperidone. 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. 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. Monitor therapy

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. Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Adverse Reactions

>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

Warnings/Precautions

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. Assess left ventricular ejection fraction (LVEF) prior to entrectinib initiation in patients with heart failure symptoms or known risk factors; monitor for clinical signs/symptoms of heart failure, including shortness of breath and edema. For patients with myocarditis (with or without a decreased ejection fraction), MRI or cardiac biopsy may be necessary to make the diagnosis. Interrupt entrectinib therapy for new onset or worsening heart failure, initiate appropriate medical management, and then reassess LVEF. May require dose reduction or permanent discontinuation (based on the severity of heart failure or worsening LVEF).
• 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). Cognitive impairment, mood disorders, dizziness, and sleep disturbances may require therapy interruption, dose reduction, and/or therapy discontinuation (based on toxicity severity). 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; may require therapy interruption. 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). Monitor liver function tests, including ALT and AST, every 2 weeks during the first month of therapy, then monthly thereafter, and as clinically indicated. May require therapy interruption, dose reduction, and/or permanent discontinuation.
• 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). Monitor serum uric acid levels prior to entrectinib initiation and periodically throughout therapy; monitor for signs/symptoms of hyperuricemia. Initiate urate-lowering medications as clinically necessary and interrupt entrectinib treatment for signs/symptoms of hyperuricemia. May require dose reduction (based on severity).
• 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. Interrupt entrectinib therapy for new visual changes or changes that interfere with activities of daily living 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.
• 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; monitor at risk patients as well as those with current QT interval prolongation closely. Assess QT interval and electrolytes at baseline and periodically throughout therapy; more frequent monitoring may be necessary based on risk factors such as heart failure, electrolyte abnormalities, or concomitant medications known to prolong the QT interval. May require entrectinib therapy interruption, dose reduction, and/or permanent discontinuation.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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 receptor tyrosine kinase gene fusion. Select for treatment of metastatic non-small cell lung cancer based on the presence of ROS1 rearrangement(s) in tumor specimens.

Monitoring Parameters

Assess neurotrophic receptor tyrosine kinase 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; assess QT interval and electrolytes at baseline and periodically throughout therapy (more frequently as clinically indicated); pregnancy test (prior to treatment in females of reproductive potential). Monitor for signs/symptoms of heart failure, CNS adverse effects (cognitive impairment, mood disorders, dizziness, sleep disturbances), fractures, tumor lysis syndrome, and visual changes. Monitor adherence.

Pregnancy

Pregnancy Considerations

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 receptor tyrosine 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.

Evaluate pregnancy status prior to treatment initiation in females of reproductive potential. Females of reproductive potential should use effective contraception during therapy and for 5 weeks after the last entrectinib dose. Males with female partners of reproductive potential should use effective contraception during therapy and for 3 months after the last entrectinib dose.

Patient Education

What is this drug used for?

• It is used to treat cancer.

Frequently reported side effects of this drug

• Constipation
• Abdominal pain
• Diarrhea
• Nausea
• Vomiting
• Lack of appetite
• Change in taste
• Muscle pain
• Muscle weakness
• Back pain
• Painful extremities
• Weight gain
• Cough
• Headache

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Nerve problems like a burning, numbness, or tingling feeling; change in balance; confusion; dizziness; sensing things that seem real but are not; trouble with memory; new or worse behavior or mood changes like anxiety, depression, or thoughts of suicide; trouble focusing; trouble sleeping; or trouble thinking or speaking
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, not passing urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting
• Urinary tract infection like blood in your urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain
• Fast heartbeat
• Abnormal heartbeat
• Passing out
• Joint pain
• Joint swelling
• Stiffness
• Shortness of breath
• Excessive weight gain
• Swelling in arms or legs
• Bone pain
• Vision changes
• Light sensitivity
• Swelling
• Severe dizziness
• Severe loss of strength and energy
• Chills
• Sore throat
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.