Brigatinib is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed during treatment with crizotinib or who are unable to tolerate crizotinib therapy.

Brigatinib is a tyrosine kinase inhibitor that demonstrates in-vitro activity against multiple kinases at clinically achievable concentrations, including ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), FLT-3, and certain EGFR mutations. Brigatinib inhibits the autophosphorylation of ALK and suppresses the phosphorylation of downstream signaling proteins such as STAT3, AKT, ERK1/2, and S6, which play important roles in cancer cell proliferation and survival. In both in-vitro and in-vivo studies, Brigatinib inhibited the proliferation of cancer cell lines expressing EML4-ALK and NPM-ALK fusion proteins. Additionally, dose-dependent inhibition of tumor growth was observed in mouse models of EML4-ALK-positive non-small cell lung cancer. However, the relationship between Brigatinib exposure and pharmacodynamic response over time has not been fully established.

Absorption: Following administration of single oral doses ranging from 30 mg to 240 mg, Brigatinib reaches its maximum plasma concentration (Tmax) within approximately 1 to 4 hours.

Distribution: Brigatinib is approximately 66% bound to human plasma proteins, and this binding is not dependent on drug concentration. The blood-to-plasma concentration ratio is about 0.69. After oral administration of Brigatinib 180 mg once daily, the mean apparent volume of distribution (Vz/F) at steady state is approximately 153 liters, indicating extensive tissue distribution.

Elimination: After oral administration of Brigatinib 180 mg once daily, the mean apparent oral clearance (CL/F) at steady state is approximately 12.7 L/h, and the average plasma elimination half-life is around 25 hours.

Metabolism: Brigatinib is primarily metabolized in the liver by the enzymes CYP2C8 and CYP3A4. After administration of a single 180 mg radiolabeled dose, the major metabolic pathways identified were N-demethylation and cysteine conjugation. The main circulating components in plasma were unchanged Brigatinib (92%) and its primary metabolite AP26123 (3.5%). The steady-state exposure (AUC) of AP26123 is less than 10% of the exposure of Brigatinib in patients. In laboratory studies, the metabolite AP26123 showed approximately three-fold lower inhibitory activity against ALK compared with Brigatinib.

Excretion: After administration of a single 180 mg radiolabeled oral dose of Brigatinib, approximately 65% of the dose was recovered in feces and about 25% in urine. Unchanged Brigatinib accounted for approximately 41% of total radioactivity in feces and 86% in urine.

The recommended dosing regimen for Brigatinib is:

• 90 mg orally once daily for the first 7 days;
• If 90 mg is tolerated during the first 7 days, the dose should be increased to 180 mg orally once daily.

Brigatinib should be administered until disease progression or unacceptable toxicity. If Brigatinib is interrupted for 14 days or longer for reasons other than adverse reactions, treatment should be resumed at 90 mg once daily for 7 days before increasing to the previously tolerated dose. Brigatinib may be taken with or without food. Patients should be instructed to swallow tablets whole. Tablets should not be crushed or chewed. If a dose of Brigatinib is missed or vomiting occurs after taking a dose, an additional dose should not be administered and the next dose of Brigatinib should be taken at the scheduled time.

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

Drugs that may Increase Brigatinib Plasma Concentrations: Strong CYP3A inhibitors can significantly increase the plasma concentration of Brigatinib and may raise the risk of adverse reactions. Examples include certain antiviral agents (such as boceprevir, cobicistat, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), macrolide antibiotics (such as clarithromycin), antifungal medications (such as itraconazole, ketoconazole, posaconazole, and voriconazole), and conivaptan. Consumption of grapefruit or grapefruit juice should also be avoided because it may increase Brigatinib levels in the blood. If the use of a strong CYP3A inhibitor cannot be avoided, the Brigatinib dose should generally be reduced by approximately 50%.

Drugs that may Decrease Brigatinib Plasma Concentrations:  Strong CYP3A inducers can reduce the plasma concentration of Brigatinib, potentially decreasing its therapeutic effectiveness. Such agents include rifampin, carbamazepine, phenytoin, and St. John’s Wort. Concomitant use of these drugs with Brigatinib should be avoided whenever possible.

Drugs Whose Plasma Concentrations May Be Altered by Brigatinib: Brigatinib may induce CYP3A enzymes, which can reduce the concentration of drugs that are CYP3A substrates. Co-administration with such medications, including hormonal contraceptives, may decrease their effectiveness and lead to treatment failure.

Brigatinib is contraindicated in patients who have known hypersensitivity to Brigatinib or any component of this medication.

Some important adverse reactions associated with Brigatinib include:

• Interstitial lung disease (ILD) or pneumonitis
• Hypertension
• Bradycardia
• Visual disturbances
• Elevated creatine phosphokinase (CPK) levels
• Increased pancreatic enzyme levels
• Hyperglycemia

Pregnancy: There are currently no adequate clinical data regarding the use of Brigatinib in pregnant women. If Brigatinib is used during pregnancy or if a patient becomes pregnant while taking this medication, the patient should be informed of the potential risk to the developing fetus.

Lactation: There is no information regarding the presence of Brigatinib in human breast milk or its effects on a breastfed infant. Due to the possibility of serious adverse reactions in breastfed infants, women are advised not to breastfeed during treatment with Brigatinib and for at least one week after the last dose.

Females of Reproductive Potential: Women of reproductive potential should use effective non-hormonal contraception during Brigatinib treatment and for at least 4 months after the final dose, because Brigatinib may reduce the effectiveness of hormonal contraceptives.

Males of Reproductive Potential: Male patients with female partners of reproductive potential should use effective contraception during Brigatinib treatment and for at least 3 months after the last dose.

Infertility: Based on findings from animal studies, Brigatinib may impair male fertility.

Interstitial Lung Disease (ILD) / Pneumonitis: Brigatinib may cause severe, life-threatening, or even fatal pulmonary reactions, including interstitial lung disease (ILD) or pneumonitis. Patients who develop new or worsening respiratory symptoms such as cough, shortness of breath, or breathing difficulty should temporarily discontinue Brigatinib and undergo prompt evaluation to determine whether the symptoms are related to ILD/pneumonitis or other causes such as pulmonary embolism, infection, or tumor progression. Brigatinib should be permanently discontinued in patients with Grade 3 or Grade 4 ILD/pneumonitis or if Grade 1 or Grade 2 ILD/pneumonitis recurs.

Hypertension: Hypertension has been observed in patients receiving Brigatinib. Approximately 11% of patients receiving 90 mg and 21% of patients receiving 90–180 mg experienced hypertension, while Grade 3 hypertension occurred in about 5.9% of patients. Blood pressure should be adequately controlled before initiating Brigatinib therapy. During treatment, blood pressure should be monitored after 2 weeks and then at least monthly. Brigatinib should be withheld in patients who develop Grade 3 hypertension despite optimal antihypertensive therapy. Permanent discontinuation should be considered if Grade 4 hypertension or recurrent Grade 3 hypertension occurs. Caution is advised when Brigatinib is administered with antihypertensive drugs that may also cause bradycardia.

Bradycardia: Brigatinib may cause slowing of the heart rate (bradycardia). Heart rate and blood pressure should be monitored regularly during treatment. Patients taking medications that can cause bradycardia should be monitored more frequently if concomitant use cannot be avoided.

Visual Disturbances: Visual side effects such as blurred vision, double vision (diplopia), or decreased visual acuity have been reported in patients treated with Brigatinib. These reactions occurred in approximately 7.3% of patients receiving 90 mg and 10% of patients receiving 90–180 mg. Patients should report any visual symptoms immediately. Brigatinib should be withheld and an ophthalmologic examination should be performed in patients experiencing Grade 2 or more severe visual disturbances. After recovery to Grade 1 severity or baseline, treatment may be resumed at a reduced dose. Brigatinib should be permanently discontinued if Grade 4 visual disturbances occur.

Creatine Phosphokinase (CPK) Elevation: Elevated levels of creatine phosphokinase (CPK) have been reported in patients receiving Brigatinib. Approximately 27% of patients in the 90 mg group and 48% in the 90–180 mg group experienced increased CPK levels. Patients should report unexplained muscle pain, tenderness, or weakness. CPK levels should be monitored during treatment, and Brigatinib should be withheld if Grade 3 or Grade 4 CPK elevation occurs.

Pancreatic Enzyme Elevation:  Elevations in pancreatic enzymes such as amylase and lipase have been observed during Brigatinib therapy. Amylase increases occurred in about 27% of patients in the 90 mg group and 39% of patients in the 90→180 mg group. Lipase elevations occurred in approximately 21% and 45% of patients in these groups, respectively. Amylase and lipase levels should be monitored during treatment. Brigatinib should be withheld if Grade 3 or Grade 4 pancreatic enzyme elevation occurs.

Hyperglycemia: New or worsening hyperglycemia occurred in approximately 43% of patients treated with Brigatinib. Grade 3 hyperglycemia occurred in about 3.7% of patients based on laboratory measurements of fasting serum glucose. Some patients with pre-existing diabetes or glucose intolerance required insulin therapy during treatment. Fasting blood glucose should be assessed before starting Brigatinib and monitored periodically during therapy. Antihyperglycemic treatment should be initiated or adjusted as needed. If blood glucose cannot be adequately controlled despite optimal management, Brigatinib should be withheld until control is achieved and dose reduction should be considered.

Cytotoxic Chemotherapy

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