Trepmac Tablet

Brigatinib is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test.

Brigatinib is a tyrosine kinase inhibitor with in vitro activity at clinically achievable concentrations against multiple kinases including ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), and FLT-3 as well as EGFR deletion and point mutations. Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signalin  proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays. Brigatinib also inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition ofEML4-ALK-positive NSCLC xenograft growth in mice.

At clinically achievable concentrations (≤500 nM), brigatinib inhibited the in vitro viability of cells expressing EML4-ALK and 17 mutant forms associated with resistance to ALK inhibitors including crizotinib, as well as EGFR-Del (E746-A750), ROS1 L2026M, FLT3-F691L, and FLT3-D835Y. Brigatinib exhibited in vivo antitumor activity against 4 mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumors in patients who have progressed on crizotinib. Brigatinib also reduced tumor burden and prolonged survival in mice implanted intracranially with an ALK-driven tumor cell line.

The recommended dosage for Brigatinib is 90 mg orally once daily for the first 7 days; then increase the dose to 180 mg orally once daily. Administer Brigatinib until disease progression or unacceptable toxicity. If Brigatinib is interrupted for 14 days or longer for reasons other than adverse reactions, resume treatment at 90 mg once daily for 7 days before increasing to the previously tolerated dose. Brigatinib may be taken with or without food. Instruct patients to swallow tablets whole. Do not crush or chew tablets.

• CYP3A Inhibitors: Avoid coadministration of Brigatinib with strong or moderate CYP3A inhibitors. If coadministration of a strong or moderate CYP3A inhibitor is unavoidable, reduce the dose of Brigatinib.
• CYP3A Inducers: Avoid coadministration of Brigatinib with strong or moderate CYP3A inducers. If coadministration of a moderate CYP3A inducer is unavoidable, increase the dose of Brigatinib.

The most common adverse reactions (≥25%) with Brigatinib were diarrhea, fatigue, nausea, rash, cough, myalgia, headache, hypertension, vomiting, and dyspnea.

Based on its mechanism of action and findings in animals, Brigatinib can cause fetal harm when administered to a pregnant woman. There are no clinical data on the use of Brigatinib in pregnant women. There are no data regarding the secretion of Brigatinib in human milk or its effects on the breastfed infant or milk production. Because of the potential for adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with Brigatinib and for 1 week following the final dose.

• Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening respiratory symptoms, particularly during the first week of treatment. Withhold Brigatinib for new or worsening respiratory symptoms and promptly evaluate for ILD/pneumonitis. Upon recovery, either dose reduce or permanently discontinue Brigatinib.
• Hypertension: Monitor blood pressure after 2 weeks and then at least monthly during treatment. For severe hypertension, withhold Brigatinib, then dose reduce or permanently discontinue.
• Bradycardia: Monitor heart rate and blood pressure regularly during treatment. If symptomatic, withhold Brigatinib, then dose reduce or permanently discontinue.
• Visual Disturbance: Advise patients to report visual symptoms. Withhold Brigatinib and obtain ophthalmologic evaluation, then dose reduce or permanently discontinue Brigatinib.
• Creatine Phosphokinase (CPK) Elevation: Monitor CPK levels regularly during treatment. Based on the severity and with muscle pain or weakness, withhold Brigatinib, then resume or reduce dose.
• Pancreatic Enzymes Elevation: Monitor lipase and amylase levels regularly during treatment. Based on the severity, withhold Brigatinib, then resume or reduce dose.
• Hyperglycemia: Assess fasting serum glucose prior to starting Brigatinib and regularly during treatment. If not adequately controlled with optimal medical management, withhold Brigatinib, then consider dose reduction or permanently discontinue, based on severity.
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use a non-hormonal method of effective contraception.

Cytotoxic Chemotherapy

Pediatric Use: The safety and effectiveness of Brigatinib in pediatric patients have not been established.

Geriatric Use: Of the 359 patients enrolled in the ALTA 1L Brigatinib arm and in ALTA, 26.7% were 65 and older
and 7.5% were 75 and older. No overall differences in safety or effectiveness were observed between patients ≥65 years and younger patients.

Hepatic Impairment: No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A) or
moderate hepatic impairment (Child-Pugh B). Reduce the dose of Brigatinib for patients with severe hepatic impairment (Child-Pugh C)

Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment ClCr 30 to 89 mL/min by Cockcroft-Gault. Reduce the dose of Brigatinib for patients with severe renal impairment (ClCr 15 to 29 mL/min)

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.