Version May 2024
Note: Select patients for the treatment of metastatic non-small cell lung cancer based on the presence of anaplastic lymphoma kinase (ALK) positivity in tumor specimens. BP should be controlled prior to initiating brigatinib.
Non–small cell lung cancer, metastatic (ALK-positive): Oral: 90 mg once daily for 7 days; if tolerated, then increase dose to 180 mg once daily; continue until disease progression or unacceptable toxicity (Ref). Note: If therapy is interrupted for ≥14 days due to reasons other than adverse reactions, resume treatment at 90 mg once daily for 7 days before escalating dose to the previously tolerated dose.
Missed dose: If a dose is missed or vomited, do not administer an additional dose; administer the next dose at the regularly scheduled time.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Note: The Cockcroft-Gault formula may be used to estimate CrCl for dosage adjustment purposes.
CrCl 30 to 89 mL/minute: No dosage adjustment is necessary.
CrCl 15 to 29 mL/minute: Reduce dose by ~50% (eg, from 180 mg once daily to 90 mg once daily, from 90 mg once daily to 60 mg once daily).
Hepatic impairment prior to treatment initiation:
Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustment is necessary.
Severe impairment (Child-Pugh class C): Reduce dose by ~40% (eg, from 180 mg once daily to 120 mg once daily, from 120 mg once daily to 90 mg once daily, from 90 mg once daily to 60 mg once daily).
Hepatotoxicity during treatment (ALT or AST elevation):
Grade 3 or 4 elevation (ALT or AST >5 times ULN) with bilirubin ≤2 times ULN: Withhold brigatinib until recovery to ≤ grade 1 (ALT or AST ≤3 times ULN) or baseline, then resume brigatinib at the next lower dose (refer to "Dosing: Adjustment for Toxicity" for dosage adjustment levels).
Grade 2 to 4 elevation (ALT or AST >3 times ULN) with concurrent total bilirubin >2 times ULN in the absence of cholestasis or hemolysis: Permanently discontinue brigatinib.
|
Dosage |
Dosage reductiona | ||
|---|---|---|---|
|
First |
Second |
Third | |
|
a Once the brigatinib dose is reduced for adverse reactions, do not subsequently escalate the dose. | |||
|
90 mg once daily |
60 mg once daily |
Permanently discontinue brigatinib |
|
|
180 mg once daily |
120 mg once daily |
90 mg once daily |
60 mg once daily. Permanently discontinue brigatinib if unable to tolerate the 60 mg once daily dose. |
Cardiac toxicity:
Hypertension (control BP prior to initiating brigatinib):
Grade 3 (systolic blood pressure [SBP] ≥160 mm Hg or diastolic blood pressure [DBP] ≥100 mm Hg, medical intervention indicated, >1 antihypertensive medication necessary, or more intensive therapy than previously used) despite optimal hypertensive therapy: Interrupt brigatinib until hypertension recovers to ≤ grade 1 (SBP <140 mm Hg and DBP <90 mm Hg), then resume at the same dose. If grade 3 hypertension recurs, interrupt brigatinib until recovery to ≤ grade 1 and resume at the next lower dose or permanently discontinue brigatinib.
Grade 4 (life-threatening, urgent intervention required): Interrupt brigatinib until recovery to ≤ grade 1, then resume at the next lower dose or permanently discontinue. If grade 4 hypertension recurs, permanently discontinue brigatinib.
Bradycardia (heart rate <60 bpm):
Symptomatic bradycardia: Interrupt brigatinib until recovery to asymptomatic bradycardia or to a resting heart rate of ≥60 bpm. If a concomitant bradycardia-inducing medication is identified and discontinued (or dose-adjusted), upon recovery to asymptomatic bradycardia or to a resting heart rate of ≥60 bpm, resume brigatinib at the same dose. If no concomitant medication is identified (or cannot be discontinued or dose-adjusted), upon recovery to asymptomatic bradycardia or to a resting heart rate of ≥60 bpm, resume brigatinib at the next lower dose.
Life-threatening bradycardia (urgent intervention required): Permanently discontinue brigatinib if no contributing concomitant medication is identified. If contributing concomitant medication is present and discontinued (or dose-adjusted), upon recovery to asymptomatic bradycardia or to a resting heart rate of ≥60 bpm, resume brigatinib at the next lower dose (with frequent monitoring). If life-threatening bradycardia recurs, permanently discontinue brigatinib.
CPK elevation:
Grade 3 or 4 (CPK >5 times ULN with ≥ grade 2 muscle pain or weakness): Interrupt brigatinib therapy until recovery to ≤ grade 1 (≤2.5 times ULN) or to baseline, then resume at the same dose. If grade 3 or 4 CPK elevation recurs, interrupt brigatinib therapy until recovery to ≤ grade 1 (≤2.5 times ULN) or to baseline, then resume at the next lower dose.
Hyperglycemia: Initiate or optimize antihyperglycemic therapy as needed (may require insulin therapy); if adequate serum glucose control cannot be achieved with optimal medical management, interrupt brigatinib until metabolic control is achieved.
Grade 3 or 4 (glucose ≥250 mg/dL or 13.9 mmol/L): Interrupt brigatinib therapy if adequate hyperglycemic control cannot be achieved with optimal medical management. Once hyperglycemic control is achieved, resume at the next lower dose or permanently discontinue brigatinib.
Lipase/amylase elevation:
Grade 3 (>2 times ULN): Interrupt brigatinib until recovery to ≤ grade 1 (≤1.5 times ULN) or to baseline, then resume at the same dose. If grade 3 lipase/amylase elevation recurs, interrupt brigatinib therapy until recovery to ≤ grade 1 (≤1.5 times ULN) or to baseline, then resume at the next lower dose.
Grade 4 (>5 times ULN): Interrupt brigatinib therapy until recovery to ≤ grade 1 (≤1.5 times ULN) or to baseline, then resume at the next lower dose.
Ocular toxicity:
Grade 2 or 3 visual disturbance: Obtain ophthalmic evaluation and interrupt brigatinib therapy until recovery to grade 1 or baseline, then resume at the next lower dose.
Grade 4 visual disturbance: Permanently discontinue brigatinib and obtain ophthalmic evaluation.
Photosensitivity:Based on the severity, withhold brigatinib until recovery to baseline. If grade 3 photosensitivity, resume brigatinib at the same dose; if grade 4 photosensitivity, resume at the next lower dose. For recurrent grade 3 photosensitivity, withhold brigatinib until recovery to baseline, then resume at the next lower dose; if grade 4 photosensitivity recurs, permanently discontinue brigatinib.
Pulmonary toxicity:
New or worsening respiratory symptoms: Interrupt brigatinib; promptly evaluate for interstitial lung disease (ILD)/pneumonitis or other potential cause of toxicity (eg, pulmonary embolism, tumor progression, or infectious etiology).
Interstitial lung disease/pneumonitis:
Grade 1: If new pulmonary symptoms develop during the first 7 days of therapy, interrupt brigatinib until recovery to baseline, then resume treatment at the same dose; do not escalate to 180 mg once daily if ILD/pneumonitis is suspected. If new pulmonary symptoms occur after the first 7 days of therapy, interrupt brigatinib until recovery to baseline, then resume at the same dose. If ILD/pneumonitis recurs, permanently discontinue brigatinib.
Grade 2: If new pulmonary symptoms develop during the first 7 days of therapy, interrupt brigatinib until recovery to baseline, then resume treatment at the next lower dose; do not escalate to 180 mg once daily if ILD/pneumonitis is suspected. If new pulmonary symptoms occur after the first 7 days of therapy, interrupt brigatinib until recovery to baseline. If ILD/pneumonitis is suspected, resume at the next lower dose; otherwise, resume at the same dose. If ILD/pneumonitis recurs, permanently discontinue brigatinib.
Grade 3 or 4: Permanently discontinue brigatinib for ILD/pneumonitis.
Other toxicities:
Grade 3: Interrupt brigatinib therapy until recovery to baseline, then resume at the same dose. If grade 3 toxicity recurs, interrupt brigatinib until recovery to baseline and then resume at the next lower dose or discontinue brigatinib.
Grade 4: Interrupt brigatinib therapy until recovery to baseline and resume at the next lower dose. If grade 4 toxicity recurs, permanently discontinue brigatinib.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Cardiovascular: Bradycardia (8% to 12%), edema (18%), hypertension (21% to 32%)
Dermatologic: Pruritus (20%), skin rash (24% to 40%; including palmar-plantar erythrodysesthesia)
Endocrine & metabolic: Decreased serum albumin (15%), decreased serum calcium (15%), decreased serum magnesium (21%), decreased serum phosphate (23% to 41%), hyperglycemia (49% to 56%; including exacerbations), hypokalemia (19%), hyponatremia (20%), increased amylase (39% to 52%), increased serum calcium (22%), increased serum cholesterol (13%), increased serum potassium (24%)
Gastrointestinal: Abdominal pain (10% to 24%), constipation (15% to 18%), decreased appetite (9% to 15%), diarrhea (38% to 53%; grades 3/4: 2%), increased serum lipase (45% to 59%), nausea (30% to 40%; grades 3/4: ≤2%), stomatitis (13%; grades 3/4: <1%), vomiting (21% to 23%; grades 3/4: <1%)
Hematologic & oncologic: Anemia (40%; grades 3/4: <1%), decreased neutrophils (12%), lymphocytopenia (27% to 42%; grades 3/4: 5% to 9%), prolonged partial thromboplastin time (20%; grades 3/4: <1%)
Hepatic: Increased serum alanine aminotransferase (40% to 52%), increased serum alkaline phosphatase (29% to 36%), increased serum aspartate aminotransferase (65% to 72%)
Nervous system: Dizziness (15%), fatigue (32% to 36%), headache (22% to 27%), peripheral neuropathy (11% to 13%; grades 3/4: ≤2%; including hyperesthesia, hypoesthesia, neuralgia, paresthesia, polyneuropathy)
Neuromuscular & skeletal: Arthralgia (14%), back pain (15% to 21%), increased creatine phosphokinase in blood specimen (48% to 81%), muscle spasm (17%), myalgia (15% to 28%; including muscle twitching, musculoskeletal pain)
Renal: Increased serum creatinine (25%)
Respiratory: Cough (34% to 35%), dyspnea (21% to 25%; severe dyspnea: 2%), pneumonia (10% to 15%), upper respiratory tract infection (12%)
Miscellaneous: Fever (6% to 15%)
1% to 10%:
Cardiovascular: Pulmonary embolism (2%)
Dermatologic: Skin photosensitivity (≤4%), xeroderma (5%)
Gastrointestinal: Dysgeusia (3%), dyspepsia (8%)
Genitourinary: Urinary tract infection (6%)
Hematologic & oncologic: Decreased platelet count (10%)
Nervous system: Insomnia (7%), pain (3%)
Neuromuscular & skeletal: Limb pain (4% to 5%), muscle rigidity (1%), severe weakness (2%)
Ophthalmic: Visual disturbance (7% to 10%; including blurred vision, cataract, diplopia, glaucoma, macular edema, papilledema, reduced visual acuity, vitreous detachment)
Respiratory: Hypoxia (3%), interstitial pulmonary disease (≤9%), nasopharyngitis (8%), pneumonitis (≤9%)
<1%:
Gastrointestinal: Gastroesophageal reflux disease
Hepatic: Hepatic injury (hepatocellular)
Frequency not defined: Hypersensitivity: Angioedema
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to brigatinib or any component of the formulation.
Concerns related to adverse effects:
• Cardiac effects: Hypertension was reported commonly in patients receiving brigatinib (including grade 3 hypertension). Bradycardia has also occurred with brigatinib therapy. Use caution when administering brigatinib in combination with antihypertensive medications that cause bradycardia.
• CPK elevation: CPK elevations have been reported in up to ~80% of patients receiving brigatinib (including grade 3 or 4 elevations). A higher incidence was associated with the 180 mg/day dose (compared to 90 mg/day). Advise patients to report unexplained muscle pain, tenderness, or weakness.
• GI toxicity: Pancreatic enzyme elevations (lipase and amylase) have been reported, including grade 3 or 4 elevations. A higher incidence was associated with the 180 mg/day dose (compared to 90 mg/day).
• Hepatotoxicity: ALT and AST elevations have occurred with brigatinib. A higher incidence of ALT or AST elevation was associated with the 180 mg/day dose (compared to 90 mg/day). Grade 3 and 4 ALT and AST elevations were reported.
• Hyperglycemia: More than half of patients receiving brigatinib experienced new or worsening hyperglycemia, including grade 3 toxicity. Some patients with diabetes or glucose intolerance (at baseline) required insulin therapy while receiving brigatinib.
• Ocular toxicity: Visual disturbances such as blurred vision, diplopia, photophobia, photopsia, and reduced visual acuity have been reported. Grade 3 macular edema and cataract also occurred (rare). Advise patients to report visual symptoms.
• Pulmonary toxicity: Severe, life-threatening, and fatal cases of pulmonary toxicity consistent with interstitial lung disease (ILD)/pneumonitis have been reported. ILD/pneumonitis generally occurred within 8 to 9 days of brigatinib initiation (with a median onset of 2 days in one clinical trial) and occurred at both dose levels.
Other warnings/precautions:
• Anaplastic lymphoma kinase testing: Select patients for the treatment of metastatic non-small cell lung cancer based on the presence of anaplastic lymphoma kinase (ALK) positivity in tumor specimens. Information on approved tests for the detection of ALK rearrangements may be found at http://www.fda.gov/companiondiagnostics.
• Photosensitivity: Patients should limit sun exposure (during treatment and for at least 5 days after the last brigatinib dose), wear a hat and protective clothing, and use a broad-spectrum sunscreen and lip balm (SPF ≥30).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Alunbrig: 30 mg, 90 mg, 180 mg
Tablet Therapy Pack, Oral:
Alunbrig: 90 mg (7s) & 180 mg (23s) (30 ea)
No
Tablet Therapy Pack (Alunbrig Oral)
90 & 180 mg (per each): $791.64
Tablets (Alunbrig Oral)
30 mg (per each): $264.00
90 mg (per each): $792.00
180 mg (per each): $791.64
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Alunbrig: 30 mg, 90 mg, 180 mg
Tablet Therapy Pack, Oral:
Alunbrig: 90 & 180 MG (28 ea)
Oral: Administer with or without food. Swallow tablets whole; do not crush or chew.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Brigatinib may cause reproductive toxicity, teratogenicity, and/or has a structural/toxicity profile similar to existing hazardous agents.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Non-small cell lung cancer, metastatic: Treatment of anaplastic lymphoma kinase (ALK)-positive (as detected by an approved test) metastatic non-small cell lung cancer (NSCLC) in adults.
Brigatinib may be confused with alectinib, binimetinib, bosutinib, ceritinib, crizotinib, lorlatinib, pemigatinib.
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
Substrate of BCRP/ABCG2, CYP2C8 (minor), CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces CYP3A4 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Antihypertensive Agents: Brigatinib may diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Risk C: Monitor therapy
Atogepant: CYP3A4 Inducers (Weak) may decrease the serum concentration of Atogepant. Management: For treatment of episodic migraine, the recommended dose of atogepant is 30 mg once daily or 60 mg once daily when combined with CYP3A4 inducers. When used for treatment of chronic migraine, use of atogepant with CYP3A4 inducers should be avoided. Risk D: Consider therapy modification
Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Risk C: Monitor therapy
Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Risk D: Consider therapy modification
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CloZAPine: CYP3A4 Inducers (Weak) may decrease the serum concentration of CloZAPine. Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inducers when possible. If combined, increase the daily dose of brigatinib in 30 mg increments after 7 days of treatment with the current brigatinib dose, up to maximum of twice the dose. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May decrease the serum concentration of Brigatinib. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inhibitors when possible. If such a combination cannot be avoided, reduce the dose of brigatinib by approximately 40% (ie, from 180 mg to 120 mg, from 120 mg to 90 mg, or from 90 mg to 60 mg). Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with strong CYP3A4 inhibitors when possible. If combination cannot be avoided, reduce the brigatinib dose by approximately 50%, rounding to the nearest tablet strength (ie, from 180 mg to 90 mg, or from 90 mg to 60 mg). Risk D: Consider therapy modification
Etrasimod: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Fexinidazole: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole. Risk X: Avoid combination
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fingolimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Fingolimod. Management: Consult with the prescriber of any bradycardia-causing agent to see if the agent could be switched to an agent that does not cause bradycardia prior to initiating fingolimod. If combined, perform continuous ECG monitoring after the first fingolimod dose. Risk D: Consider therapy modification
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Grapefruit Juice: May increase the serum concentration of Brigatinib. Risk X: Avoid combination
Hormonal Contraceptives: Brigatinib may decrease the serum concentration of Hormonal Contraceptives. Management: Use a non-hormonal contraceptive during brigatinib use and for at least 4 months after the last brigatinib dose. Males with partners of reproductive potential should use contraception during treatment with brigatinib and for 3 months after brigatinib use. Risk D: Consider therapy modification
Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Risk C: Monitor therapy
Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Risk C: Monitor therapy
Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Risk C: Monitor therapy
Ozanimod: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Ponesimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Ponesimod. Management: Avoid coadministration of ponesimod with drugs that may cause bradycardia when possible. If combined, monitor heart rate closely and consider obtaining a cardiology consult. Do not initiate ponesimod in patients on beta-blockers if HR is less than 55 bpm. Risk D: Consider therapy modification
Selpercatinib: CYP3A4 Inducers (Weak) may decrease the serum concentration of Selpercatinib. Risk C: Monitor therapy
Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. If combined, consider obtaining a cardiology consult regarding patient monitoring. Risk D: Consider therapy modification
Sirolimus (Conventional): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
Sirolimus (Protein Bound): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Protein Bound). Risk C: Monitor therapy
Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy
St John's Wort: May decrease the serum concentration of Brigatinib. Risk X: Avoid combination
Tacrolimus (Systemic): CYP3A4 Inducers (Weak) may decrease the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Ubrogepant: CYP3A4 Inducers (Weak) may decrease the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a weak CYP3A4 inducer. Risk D: Consider therapy modification
Grapefruit juice may increase serum brigatinib levels. Management: Avoid grapefruit and grapefruit juice.
Evaluate pregnancy status prior to therapy initiation in patients who could become pregnant. Patients who could become pregnant should use an effective contraceptive during therapy and for at least 4 months after the last brigatinib dose. Patients with partners who could become pregnant should use effective contraception during therapy and for at least 3 months after the last dose.
Based on the mechanism of action and adverse events observed in animal reproduction studies, brigatinib may be expected to cause fetal harm if used during pregnancy.
It is not known if brigatinib is present in breast milk.
Due to the potential for adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 1 week after the last brigatinib dose.
Avoid grapefruit and grapefruit juice.
Anaplastic lymphoma kinase (ALK) positivity. Monitor ALT, AST, and total bilirubin during treatment, particularly during the initial 3 months; monitor CPK and amylase/lipase levels periodically throughout therapy; fasting serum glucose at baseline and periodically thereafter. Monitor heart rate (regularly; monitor more frequently if on concomitant bradycardia-inducing medication) and BP (after 2 weeks and at least monthly thereafter). Evaluate pregnancy status prior to therapy initiation in patients who could become pregnant. Monitor for signs/symptoms of interstitial lung disease/pneumonitis (new or worsening pulmonary symptoms such as dyspnea and cough, particularly in the first week of therapy), muscular symptoms of CPK elevations (eg, muscle pain, tenderness, weakness), photosensitivity, and visual disturbances (obtain ophthalmologic evaluation in patients with new or worsening ≥ grade 2 visual symptoms). Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Additional cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017]; ESC [Lyon 2022]). Consider home BP monitoring (ESC [Lyon 2022]).
Brigatinib is a broad spectrum multikinase inhibitor with activity against anaplastic lymphoma kinase (ALK), ROS1, insulin-like growth factor-1 receptor (IGF-1R), and FLT-3, as well as EGFR deletion and point mutations. ALK autophosphorylation and ALK-mediated phosphorylation of downstream signaling proteins STAT3, AKT, ERK1/2, and S6 are inhibited by brigatinib. In vitro, brigatinib also inhibited proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins. Brigatinib has activity against cells expressing EML4-ALK and 17 mutant forms associated with ALK inhibitor resistance, as well as EGFR-Del (E746-A750), ROS1-L2026M, FLT3-F691L, and FLT3-D835Y. Clinically, brigatinib showed anti-tumor activity against EML4-ALK mutant forms (including G1202R and L1196M) which were identified in NSCLC cells in patients who progressed on crizotinib.
Distribution: 307 L.
Protein binding: 91% bound to plasma proteins (not concentration dependent).
Metabolism: Primarily hepatic via CYP2C8 and CYP3A4; N-demethylation and cysteine conjugation are the two major metabolic pathways.
Half-life elimination: 25 hours.
Time to peak: 1 to 4 hours.
Excretion: Feces (65%; 41% as unchanged drug); urine (25%; 86% as unchanged drug).
Altered kidney function: Following a single brigatinib 90 mg dose, systemic exposure (AUC0-inf) of unbound brigatinib was 86% higher in subjects with severe renal impairment (CrCl 15 to 29 mL/minute) compared with subjects with normal renal function.
Hepatic function impairment: Following a single brigatinib 90 mg dose, systemic exposure (AUC0-inf) of unbound brigatinib was 37% higher in subjects with severe hepatic impairment (Child-Pugh class C) compared with subjects with normal hepatic function.
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