What are the precautions for entrectinib?

In clinical studies of Entrectinib (Entrectinib), warnings and precautions such as congestive heart failure, central nervous system effects, bone fractures, liver toxicity, hyperuricemia, QT interval prolongation, visual impairment, embryo-fetal toxicity, etc. have emerged; doctors may suspend or permanently discontinue Entrectinib depending on the severity of the condition. If discontinued, continue entrectinib at the same or reduced dose.

1. Congestive heart failure (CHF): Before starting entrectinib, assess left ventricular ejection fraction (LVEF). Monitor patients for clinical signs and symptoms, including shortness of breath and edema. In patients with myocarditis with or without reduced ejection fraction, MRI or cardiac biopsy may be needed to make the diagnosis. In patients with new-onset or worsening congestive heart failure, discontinue entrectinib, institute appropriate medical therapy, and reassess LVEF. Depending on the severity of congestive heart failure or worsening LVEF, restart entrectinib at a reduced dose or permanently discontinue it after return to baseline.

2. Central nervous system (CNS) effects: Patients treated with entrectinib experienced a wide range of central nervous system adverse reactions, including cognitive impairment, mood disorders, dizziness and sleep disorders. Cognitive disorders include cognitive impairment, confusional states, attention disorders, memory impairment, amnesia, aphasia, mental status changes, hallucinations, and delirium; mood disorders include anxiety, depression, and agitation; sleep disorders include insomnia, somnolence, hypersomnia, and sleep disorders; inform patients and caregivers of these risks of entrectinib. If patients experience central nervous system adverse effects, advise them not to drive or operate hazardous machinery.

3. Bone fractures: Entrectinib increases the risk of fractures; in adult and pediatric patients, some fractures occur at the site of falls or other injuries; in pediatric patients, some fractures occur without trauma. Promptly evaluate patients with signs or symptoms of fracture (eg, pain, changes in mobility, deformity). There are no data on the effect of entrectinib on known fracture healing and future fracture risk.

4. Hepatotoxicity: including increase in aspartate aminotransferase (AST), increase in alanine aminotransferase (ALT), etc.; In the first month of treatment, monitor liver tests, including ALT and AST, every 2 weeks, and then monitor once a month according to clinical indications.

5. Hyperuricemia: Reported adverse reactions include symptoms and increased uric acid levels. Hyperuricemia resolved in some patients after initiating urate-lowering medications without interrupting or reducing the entrectinib dose. No patient discontinued entrectinib due to hyperuricemia. Assess serum uric acid levels before initiating entrectinib and periodically during treatment. Monitor patients for signs and symptoms of hyperuricemia. Initiate treatment with urate-lowering medications as clinically indicated and discontinue entrectinib for signs and symptoms of hyperuricemia.

6. QT interval prolongation: Monitor patients who have developed or are at high risk for QTc interval prolongation, including patients with known long QT syndrome, clinically significant bradyarrhythmias, severe or uncontrolled heart failure, and patients taking other drugs associated with QT interval prolongation. Assess QT interval and electrolytes before initiating entrectinib and periodically during treatment, adjusting frequency based on risk factors such as congestive heart failure, electrolyte abnormalities, or concomitant medications known to prolong the QTc interval.

7. Visual impairment: including blurred vision, photophobia, diplopia, visual impairment, visual acuity, cataracts and vitreous floaters. For patients who develop new visual changes or changes that affect activities of daily living, withhold entrectinib until their condition improves or stabilizes and obtain an ophthalmological evaluation as clinically appropriate. After the condition improves or stabilizes, resume the same or reduced dose of entrectinib.

8. Embryo-Fetal toxicity: According to the mechanism of action of entrectinib, pregnant women taking entrectinib may cause fetal damage. According to the area under the curve (AUC) calculation, the dose that caused malformations in pregnant rats after taking a dose of 600 mg was approximately 2.7 times that in humans. Inform pregnant women of potential risks to the fetus. It is recommended that female patients of childbearing potential use effective contraception during treatment and for 5 weeks after the last dose; men of childbearing potential who have a female partner are advised to use effective contraception during treatment and for 3 months after the last dose.