Entrectinib

Entrectinib is an innovative drug jointly developed by Genentech and Roche Pharmaceuticals. 

Entrectinib was approved for marketing by the US Food and Drug Administration (FDA) on August 16, 2019.Used to treat all solid tumors carrying NTRK gene mutations.

Entrectinib, as a broad-spectrum anti-cancer drug, has broad market application prospects. It is not only suitable for multiple solid tumor patients with NTRK gene fusion positivity, but also for NSCLC patients with ROS1 positivity.

1.Main components

Entrectinib

2.Adapt to the population

Entrectinib is a Broad-spectrum antitumor agents.

3.Medication for special populations

3.1Pregnancy

Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, Entrectinib can cause  fetal harm when administered to a pregnant woman. There are no available data on Entrectinib use in  pregnant women. Administration of entrectinib to pregnant rats during the period of organogenesis resulted in malformations at maternal exposures approximately 2.7 times the human exposure at the 600 mg dose. Advise pregnant women of the potential risk to a fetus.

3.2Lactation

There are no data on the presence of entrectinib or its metabolites in human milk or their effects on either the breastfed child or on milk production. Because of the potential serious adverse reactions in breastfed children from Entrectinib, advise a lactating woman to discontinue breastfeeding during treatment with Entrectinib and for 7 days after the last dose.

3.3Females and Males of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating Entrectinib [see Use in  Specific Populations.

Contraception

Entrectinib can cause embryo-fetal harm when administered to a pregnant woman.

Females

Advise female patients of reproductive potential to use effective contraception during treatment with Entrectinib and for at least 5 weeks following the last dose.

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Entrectinib and for 3 months following the last dose.

3.4Pediatric Use

The safety and effectiveness of Entrectinib have been established in pediatric patients older than 1 month of  age. Use of Entrectinib in these age groups is supported by evidence from adequate and well-controlled studies of Entrectinib in adults and pediatric patients with additional population  pharmacokinetic data demonstrating that the exposure of drug substance in pediatric patients greater than 1 month of age is expected to be in the adult range, and that the course of disease is sufficiently similar in adult and pediatric patients to allow extrapolation of data in adults to pediatric patients.

The safety and effectiveness of Entrectinib have not been established in pediatric patients with ROS1- positive NSCLC.

3.5Geriatric Use

Of the 355 patients who received Entrectinib across clinical trials, 25% were 65 years or older, and 5% were 75 years of age or older. Clinical studies of Entrectinib did not include sufficient numbers of geriatric  patients to determine whether they respond differently from younger patients.

3.6Renal Impairment

No dose adjustment is recommended for patients with mild or moderate renal impairment (CLcr 30 to < 90 mL/min calculated by Cockcroft-Gault equation). Entrectinib has not been studied in patients with severe renal impairment (CLcr < 30 mL/min).

3.7Hepatic Impairment

The effect of moderate hepatic impairment (total bilirubin > 1.5 – 3.0 times ULN with any aspartate  aminotransferase) or severe hepatic impairment (total bilirubin >3.0 times ULN with any aspartate  aminotransferase) on the safety of Entrectinib at the recommended dosage is unknown. Consider the risk-benefit profile of Entrectinib prior to determining whether to administer Entrectinib to patients with moderate to severe hepatic impairment. Monitor for Entrectinib adverse reactions in patients with hepatic impairment more frequently since these patients may be at increased risk for adverse reactions.

4.Drug overdose

Drug overdose is not yet clear.

5.Drug storage

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 Entrectinib capsules in the original container and keep the bottle tightly closed in order to protect from  moisture.

Storage time should not exceed 2 hours (below 30°C (86°F)) if capsules are prepared as an oral suspension  using drinking water or milk. Discard any unused suspension if not used within 2 hours of preparation.

6.Pharmacokinetics

The maximum entrectinib plasma concentration was reached 4–6 hours after oral administration of a 600 mg  dose.

from FDA，2024.01