entrectinib

ROUTE	ONSET	PEAK	DURATION
PO	unknown	4–6 hr	24 hr

Contraindicated in:

Severe renal impairment;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

History of HF, MI, unstable angina, or coronary artery bypass graft surgery (↑ risk of HF);
Long QT syndrome, bradyarrhythmias, uncontrolled HF, electrolyte abnormalities, or concurrent use of QT interval prolonging medications (↑ risk of QT interval prolongation);
Moderate or severe hepatic impairment;
Rep: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: risk of bone fractures in children;
Pedi: Safety and effectiveness not established in children 18 yr (ROS-1 positive NSCLC); or 1 mo (solid tumors with a NTRK gene fusion) .

Adv. Reactions/Side Effects ⬆ ⬇

CV: edema, hypotension, HF, myocarditis, QT interval prolongation, syncope

Derm: rash

EENT: blurred vision, cataracts, diplopia, eye floaters/flashes, photophobia, visual impairment

Endo: hyperuricemia

F and E: hyperkalemia, hypernatremia, hypocalcemia, hypophosphatemia

GI: abdominal pain, constipation, diarrhea, dysphagia, hypoalbuminemia, ↑amylase, ↑lipase, ↑liver enzymes, nausea, vomiting, HEPATOTOXICITY

GU: dehydration, ↑serum creatinine

Hemat: anemia, lymphopenia, neutropenia

Metab: ↓appetite, ↑weight

MS: arthralgia, bone fractures, muscle weakness, myalgia

Neuro: ataxia, balance disorder, confusion, dizziness, dysgeusia, fatigue, headache, paresthesia, peripheral neuropathy, agitation, amnesia, anxiety, aphasia, attention disturbances, cognitive disorders, depression, delirium, hallucinations, insomnia, memory impairment, mental status changes, sedation

Resp: cough, dyspnea, pleural effusion, PULMONARY EMBOLISM

Misc: fever

Interactions ⬆ ⬇

Drug-drug:

Moderate or strong CYP3A4 inhibitors, including itraconazole, may ↑ levels and risk of toxicity; avoid concurrent use. If must use moderate or strong CYP3A4 inhibitor, ↓ entrectinib dose.
Moderate or strong CYP3A4 inducers, including rifampin, may ↓ levels and effectiveness; avoid concurrent use.
QT interval prolonging medications may ↑ risk of QT interval prolongation; avoid concurrent use.

Grapefruit juice may ↑ levels and risk of toxicity; avoid concurrent use.

Route/Dosage ⬆ ⬇

ROS1-Positive Non-Small Cell Lung Cancer

PO (Adults ): 600 mg once daily until disease progression or unacceptable toxicity. Concurrent use of moderate CYP3A4 inhibitor—200 mg once daily until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor—100 mg once daily until disease progression or unacceptable toxicity.

NTRK Gene Fusion-Positive Solid Tumors

PO (Adults ): 600 mg once daily until disease progression or unacceptable toxicity. Concurrent use of moderate CYP3A4 inhibitor—200 mg once daily until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor—100 mg once daily until disease progression or unacceptable toxicity.
PO (Children ≥2 yr and body surface area [BSA] >1.5 m²): 600 mg once daily until disease progression or unacceptable toxicity. Concurrent use of moderate CYP3A4 inhibitor—200 mg once daily until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor— 100 mg once daily until disease progression or unacceptable toxicity.
PO (Children ≥2 yr and BSA 1.11–1.5 m²): 400 mg once daily until disease progression or unacceptable toxicity. Concurrent use of moderate CYP3A4 inhibitor—200 mg once daily until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor— 50 mg once daily until disease progression or unacceptable toxicity.
PO (Children ≥2 yr and BSA 0.81–1.1 m²): 300 mg once daily until disease progression or unacceptable toxicity. Concurrent use of moderate CYP3A4 inhibitor—100 mg once daily until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor— 50 mg once daily until disease progression or unacceptable toxicity.
PO (Children ≥2 yr and BSA 0.51–0.8 m²): 200 mg once daily until disease progression or unacceptable toxicity. Concurrent use of moderate CYP3A4 inhibitor—50 mg once daily until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor—50 mg every other day until disease progression or unacceptable toxicity.
PO (Children >2 yr and BSA ≤0.5 m²): 300 mg/m² once daily until disease progression or unacceptable toxicity.
PO (Children >6 mo–<2 yr and BSA >1.5 m²): 600 mg once daily until disease progression or unacceptable toxicity.
PO (Children >6 mo–<2 yr and BSA 1.11–1.5 m²): 400 mg once daily until disease progression or unacceptable toxicity.
PO (Children >6 yr–<2 yr and BSA 0.81–1.1 m²): 300 mg once daily until disease progression or unacceptable toxicity.
PO (Children >6 mo–<2 yr and BSA 0.51–0.8 m²): 200 mg once daily until disease progression or unacceptable toxicity.
PO (Children >6 mo–<2 yr and BSA ≤0.5 m²): 300 mg/m² once daily until disease progression or unacceptable toxicity.
PO (Children >1 mo–≤6 mo): 250 mg/m² once daily until disease progression or unacceptable toxicity.

Availability ⬆ ⬇

Capsules: 100 mg; 200 mg
Oral pellets: 50 mg/pkt

Assessment ⬆ ⬇

Assess left ventricular ejection fraction (LVEF) prior to starting therapy. Monitor for signs and symptoms of HF (shortness of breath, edema) periodically during therapy. MRI or cardiac biopsy may be required for diagnosis in patients with myocarditis, with or without a decreased ejection fraction. For new onset or worsening HF, hold entrectinib, manage symptoms, and reassess LVEF. For Grade 2 or 3, hold entrectinib until recovered to ≤Grade 1. Resume at reduced dose. For Grade 4, permanently discontinue entrectinib.
Monitor for signs and symptoms of CNS effects (cognitive impairment, mood disorders, dizziness, sleep disturbances) during therapy. If intolerable Grade 2 effects occur, hold entrectinib until recovery to ≤Grade 1 or baseline. Resume at same or reduced dose. For Grade 3 effects, hold entrectinib until recovery to ≤Grade 1 or baseline. Resume at reduced dose. For Grade 4 effects, discontinue entrectinib permanently.
Assess QT interval and electrolytes prior to and periodically during therapy. For QTc interval >500 ms, hold entrectinib until QTc recovers to baseline. If factors that caused QT prolongation are identified and corrected, resume at same dose. If factors are not identified, resume at reduced dose. If torsades de pointes; polymorphic ventricular tachycardia; or signs/symptoms of serious arrhythmia occur, permanently discontinue entrectinib.
Assess for vision changes periodically during therapy. If Grade 2 vision changes occur, hold entrectinib until improvement or stabilization. Resume at same or reduced dose.
May increase risk of fractures. Promptly evaluate patients with signs or symptoms (pain, changes in mobility, deformity) of fractures.

Lab Test Considerations:

Verify a negative pregnancy test before starting therapy.
- For metastatic NSCLC, select patients for treatment of metastatic NSCLC with entrectinib based on the presence of ROS1 rearrangement(s) in tumor or plasma specimens. Testing using plasma specimens is only appropriate for patients for whom tumor tissue is not available for testing. Information on FDA-approved tests for the detection of ROS1 rearrangement(s) in NSCLC is available at http://www.fda.gov/CompanionDiagnostics. For other tumors, select patients for treatment of locally advanced or metastatic solid tumors with entrectinib based on the presence of a NTRK gene fusion in tumor or plasma specimens. Testing using plasma specimens is only appropriate for patients for whom tumor tissue is not available for testing. Information on FDA-approved tests for the detection of NTRK gene fusion(s) in solid tumors is available at http://www.fda.gov/CompanionDiagnostics.
- Monitor liver tests (ALT, AST) every 2 wk during 1st month of therapy, then monthly thereafter, and as clinically indicated. For Grade 3, hold entrectinib until recovery to ≤Grade 1 or baseline. Resume at same dose if resolution within 4 wk. Permanently discontinue entrectinib if no resolution in 4 wk. For recurrent Grade 3 events that resolve within 4 wk, resume at reduced dose. For Grade 4, hold entrectinib until recovery to ≤Grade 1 or baseline. If resolution within 4 wk, resume at reduced dose. Permanently discontinue if not resolved within 4 wk or for recurrent Grade 4 events. If ALT or AST >3 times upper limit of normal (ULN) with concurrent total bilirubin >1.5 times ULN (in absence of cholestasis or hemolysis) occurs, permanently discontinue entrectinib.
- Assess serum uric acid levels prior to starting therapy and periodically during therapy. Monitor for signs and symptoms of hyperuricemia (gout). For symptomatic or Grade 4 hyperuricemia, begin urate-lowering medications and hold entrectinib until signs and symptoms improve. Resume at same or reduced dose.
- Monitor CBC periodically during therapy. If Grade 3 or 4 anemia or neutropenia occur, hold entrectinib until recovery to ≤Grade 2. Resume at same or reduced dose.

Implementation ⬆ ⬇

Dose reduction schedule: For starting dose of 250 mg/m² or 300 mg/m²:
First dose reduction
Reduce once daily dose to two thirds of starting dose.
Second dose reduction
Reduce once daily dose to one third of starting dose. For starting dose of 200 mg/m²:
First dose reduction
150 mg once daily.
Second dose reduction
100 mg once daily. For starting dose of 300 mg/m²:
First dose reduction
200 mg once daily.
Second dose reduction
100 mg once daily. For starting dose of 400 mg/m²:
First dose reduction
300 mg once daily.
Second dose reduction
200 mg once daily. For starting dose of 600 mg/m²:
First dose reduction
400 mg once daily.
Second dose reduction
200 mg once daily. Permanently discontinue entrectinib in patients who are unable to tolerate entrectinib after two dose reductions.
PO: Administer once daily without regard to food. DNC: Swallow capsule whole; do not open, crush or chew. Capsules may be opened and made into oral suspension for patients who cannot swallow capsules or who have an enteral feeding tube. Instruct patients to drink water after taking oral suspension to ensure dose has been completely swallowed.
- Oral suspension: Use an enteral tube that is 8 FR or higher to administer dosing volumes of 3 mL or higher. Instruct patients to divide dosing volumes of 3 mL or higher into at least two aliquots and flush tube after each administration. Flush tube with a volume of water or milk that is equal to the aliquot administered. For a dose volume of 30 mL, divide into at least three (10 mL) aliquots. Tube should be flushed with water or milk after delivering each aliquot of entrectinib. Discard unused suspension within 2 hr.
- Oral pellets
  Sprinkle pellets on one or more spoonfuls of a soft food (applesauce, yogurt, pudding) and take within 20 min of preparation. Do not crush or chew to avoid bitter taste. Patient should drink water after taking pellets to ensure drug has been completely swallowed. Do not attempt to use partial quantities of pellets from 50 mg pellet packets to prepare a dose. Do not use the pellet formulation for enteral tube administration, as the pellets may clog the tube.

Patient/Family Teaching ⬆ ⬇

Instruct patient to take entrectinib as directed. Take missed dose as soon as remembered unless within 12 hr of next dose. If patient vomits immediately after taking, instruct patient to repeat dose. Advise patient to read Patient Information before starting therapy and with each Rx refill in case of changes.
May cause dizziness. Caution patient to avoid driving or other activities requiring alertness until response to entrectinib is known.
Advise patient to notify health care professional promptly if signs and symptoms if HF (persistent coughing or wheezing, increasing shortness of breath, trouble breathing when lying down, tiredness, weakness, fatigue, sudden weight gain, swelling in ankles, feet, or legs), central nervous system effects (dizziness, changes in mood, confusion, hallucinations, problems with concentration, attention, memory, and sleep), liver problems (loss of appetite, nausea or vomiting, pain on upper right side of stomach area) changes in electrical activity of the heart (feeling faint, light-headed, or dizzy or feeling heart beating irregularly or fast) or vision problems (double vision, seeing flashes of light, blurry vision, light hurting your eyes, new or increased floaters) occur.
Inform patient that entrectinib may increase risk of bone fractures. Advise patient to notify health care professional if fractures occur.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraception during and for at least 5 wk after final dose of entrectinib. Advise males with female partners of reproductive potential to use effective contraception during and for 3 mo after final dose. Advise patient to avoid breastfeeding during and for 7 days after final dose.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Time/Action Profile ⬆ ⬇

Contraind./Precautions ⬆ ⬇