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Brigatinib

Pronunciation

(bri GA ti nib)

Index Terms

  • AP26113

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Alunbrig: 30 mg

Brand Names: U.S.

  • Alunbrig

Pharmacologic Category

  • Antineoplastic Agent, Anaplastic Lymphoma Kinase Inhibitor
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor

Pharmacology

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

153 L

Metabolism

Primarily hepatic via CYP2C8 and CYP3A4; N-demethylation and cysteine conjugation are the two major metabolic pathways; metabolite AP26123 inhibits ALK with ~3-fold lower potency than brigatinib (in vitro)

Excretion

Feces (65%; 41% as unchanged drug); urine (25%; 86% as unchanged drug)

Time to Peak

1 to 4 hours

Half-Life Elimination

25 hours

Protein Binding

66% bound to plasma proteins (not concentration dependent)

Use: Labeled Indications

Non-small cell lung cancer, metastatic: Treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) in patients who have progressed on or are intolerant to crizotinib

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosing: Adult

Non-small cell lung cancer, metastatic (ALK-positive): Oral: 90 mg once daily for 7 days; if tolerated, increase dose to 180 mg once daily; continue until disease progression or unacceptable toxicity (Kim 2017). Note: If therapy is interrupted for ≥14 days due to reasons other than toxicity, 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; take the next dose at the regularly scheduled time.

Dosage adjustment for concomitant strong CYP3A inhibitors: Avoid concomitant use of strong CYP3A inhibitors; if concurrent therapy cannot be avoided, reduce the brigatinib dose by approximately 50% (eg, from 180 mg once daily to 90 mg once daily, or from 90 mg once daily to 60 mg once daily). After the strong CYP3A inhibitor is discontinued, resume brigatinib dose that was tolerated prior to initiation of the strong CYP3A inhibitor.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl 30 to 89 mL/minute: No dosage adjustment is necessary.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment

Mild (total bilirubin within ULN and AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST) impairment: No dosage adjustment is necessary.

Moderate (total bilirubin >1.5 to 3 times ULN and any AST) or severe (total bilirubin >3 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Adjustment for Toxicity

Note: Once the dose is reduced for toxicity, do not subsequently escalate the dose.

Recommended brigatinib dosage adjustment levels:

If the dose received was 90 mg once daily:

First dose reduction: 60 mg once daily.

Second dose reduction: Permanently discontinue.

If the dose received was 180 mg once daily:

First dose reduction: 120 mg once daily.

Second dose reduction: 90 mg once daily.

Third dose reduction: 60 mg once daily.

Permanently discontinue if unable to tolerate the 60 mg once daily dose.

Cardiac toxicity:

Hypertension:

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): Interrupt brigatinib until hypertension improves to ≤ grade 1 (SBP <140 mm Hg and DBP <90 mm Hg), then resume at the next lower dose. If grade 3 hypertension recurs, interrupt brigatinib until improvement to ≤ grade 1 and resume at the next lower dose or permanently discontinue.

Grade 4 (life-threatening, urgent intervention required): Interrupt brigatinib until improvement to ≤ grade 1, then resume at the next lower dose or permanently discontinue. If grade 4 hypertension recurs, permanently discontinue.

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 previous 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.

Creatine phosphokinase (CPK) elevation:

Grade 3 (CPK >5 times ULN): Interrupt brigatinib therapy until improvement to ≤ grade 1 (≤2.5 times ULN) or to baseline, then resume at the previous dose.

Grade 4 (CPK >10 times ULN) or recurrent grade 3 toxicity: Interrupt brigatinib therapy until improvement to ≤ grade 1 (≤2.5 times ULN) or to baseline, then resume at the next lower dose.

Hyperglycemia: Grade 3 or higher (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, consider dose reduction to the next lower dose or permanently discontinue.

Lipase/amylase elevation:

Grade 3 (>2 times ULN): Interrupt brigatinib until improvement to ≤ grade 1 (≤1.5 times ULN) or to baseline, then resume at the previous dose.

Grade 4 (>5 times ULN) or recurrent grade 3 toxicity: Interrupt brigatinib therapy until improvement 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: Interrupt brigatinib therapy until improvement to grade 1 or baseline, then resume at the next lower dose.

Grade 4 visual disturbance: Permanently discontinue.

Pulmonary toxicity (interstitial lung disease [ILD]/pneumonitis):

Grade 1: If new pulmonary symptoms develop during the first 7 days of therapy, interrupt brigatinib until improvement 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 improvement to baseline, then resume at the previous dose. If ILD/pneumonitis recurs, permanently discontinue.

Grade 2: If new pulmonary symptoms develop during the first 7 days of therapy, interrupt brigatinib until improvement 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 improvement to baseline. If ILD/pneumonitis is suspected, resume at the next lower dose; otherwise, resume at the previous dose. If ILD/pneumonitis recurs, permanently discontinue.

Grade 3 or 4: Permanently discontinue.

Other toxicities:

Grade 3: Interrupt brigatinib therapy until improvement to baseline, then resume at the previous dose. If grade 3 toxicity recurs, interrupt brigatinib until improvement to baseline and then resume at the next lower dose or discontinue.

Grade 4: First occurrence: Interrupt brigatinib therapy until recovery to baseline and resume at the next lower dose or permanently discontinue. If grade 4 toxicity recurs, permanently discontinue.

Administration

Administer orally with or without food. Swallow tablets whole; do not crush or chew.

Dietary Considerations

Avoid grapefruit and grapefruit juice.

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).

Drug Interactions

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Antihypertensive Agents: Brigatinib may diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. 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. Avoid combination

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Contraceptives (Estrogens): Brigatinib may decrease the serum concentration of Contraceptives (Estrogens). Management: Females of childbearing potential should use an alternative, non-hormonal contraceptive during brigatinib therapy and for at least 4 months after the final brigatinib dose. Consider therapy modification

Contraceptives (Progestins): Brigatinib may decrease the serum concentration of Contraceptives (Progestins). Management: Females of childbearing potential should use an alternative, non-hormonal contraceptive during brigatinib therapy and for at least 4 months after the final brigatinib dose. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Brigatinib. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

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). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Grapefruit Juice: May increase the serum concentration of Brigatinib. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of Brigatinib. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Hypertension (11% to 21%)

Central nervous system: Fatigue (29% to 36%), headache (27% to 28%), peripheral neuropathy (13%, grades 3/4: ≤2%), insomnia (7% to 11%)

Dermatologic: Skin rash (15% to 24%)

Endocrine & metabolic: Increased serum AST (38% to 65%), hyperglycemia (38% to 49%; including exacerbations), increased serum ALT (34% to 40%), increased amylase (27% to 39%)

Gastrointestinal: Increased serum lipase (21% to 45%), nausea (33% to 40%), diarrhea (19% to 38%), vomiting (23% to 24%), decreased appetite (15% to 22%), constipation (15% to 19%), abdominal pain (10% to 17%)

Hematologic & oncologic: Anemia (23% to 40%; grades 3/4: <1%), lymphocytopenia (19% to 27%; grades 3/4: 3% to 5%), abnormal phosphorus levels (decreased; 15% to 23%; grades 3/4: <1%), prolonged partial thromboplastin time (20% to 22%; grades 3/4: ≤2%)

Hepatic: Increased serum alkaline phosphatase (15% to 29%)

Neuromuscular & skeletal: Increased creatine phosphokinase (27% to 48%), muscle spasm (12% to 17%), back pain (10% to 15%), myalgia (9% to 15%), arthralgia (14%), limb pain (4% to 11%)

Respiratory: Cough (18% to 34%), dyspnea (21% to 27%)

Miscellaneous: Fever (6% to 14%)

1% to 10%:

Cardiovascular: Bradycardia (6% to 8%)

Ophthalmic: Visual disturbance (7% to 10%; including blurred vision, diplopia, and reduced visual acuity)

Respiratory: Interstitial pneumonitis (≤9%), pneumonitis ( ≤9%), hypoxia (≤3%), pneumonia (5% to 10%)

Warnings/Precautions

Concerns related to adverse effects:

• Cardiac effects: Hypertension was reported in ~10% to 20% of patients receiving brigatinib (including grade 3 hypertension). Blood pressure should be controlled prior to initiating brigatinib therapy. Monitor blood pressure after 2 weeks and at least monthly subsequently. May require brigatinib therapy interruption, dose reduction, or permanent discontinuation; may also require antihypertensive therapy. Bradycardia has also occurred with brigatinib therapy; monitor heart rate (more frequently if on concomitant bradycardia-inducing medication). Symptomatic bradycardia may require therapy interruption or dose reduction. Permanently discontinue for life-threatening bradycardia that is not associated with a concomitant medication. Use caution when administering brigatinib in combination with antihypertensive medications that cause bradycardia.

• Creatine phosphokinase (CPK) elevation: CPK elevations have been reported in up to 50% 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). Monitor CPK levels during treatment; advise patients to report unexplained muscle pain, tenderness, or weakness. Elevated CPK levels may require therapy interruption or dose reduction.

• 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). Monitor amylase/lipase during treatment. May require therapy interruption or dose reduction. Nausea, vomiting, diarrhea, constipation, and abdominal pain have also been observed with brigatinib therapy.

• Hyperglycemia: More than 40% 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. Monitor fasting serum glucose at baseline and periodically during treatment. Initiate or optimize antihyperglycemic therapy; if adequate serum glucose control cannot be achieved with optimal medical management, interrupt brigatinib until metabolic control is achieved. Dose reduction or permanent discontinuation may be necessary.

• Ocular toxicity: Visual disturbances such as blurred vision, diplopia, and reduced visual acuity have been reported. Grade 3 macular edema and cataract also occurred (rare). Advise patients to report visual symptoms. Interrupt brigatinib therapy and obtain an ophthalmologic evaluation in patients with new or worsening ≥ grade 2 visual symptoms. May require dose reduction or permanent discontinuation.

• Pulmonary toxicity: Severe, life-threatening, and fatal cases of pulmonary toxicity consistent with interstitial lung disease (ILD)/pneumonitis have been reported. ILD/pneumonitis occurred early (within 9 days of brigatinib initiation; median onset: 2 days) in some patients. A higher incidence was associated with the 180 mg/day dose (compared to 90 mg/day). Monitor for new or worsening pulmonary symptoms (eg, dyspnea, cough), particularly in the first week of therapy. Interrupt brigatinib in any patient with new or worsening respiratory symptoms; promptly evaluate for ILD/pneumonitis or other potential cause of toxicity (eg, pulmonary embolism, tumor progression, or infectious etiology). May require dose reduction or permanent discontinuation.

Concurrent drug therapy issues:

• Drug-drug/drug-food interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Anaplastic lymphoma kinase testing: Approved for use only in patients with metastatic non-small cell lung cancer (NSCLC) who test positive for the abnormal anaplastic lymphoma kinase (ALK) gene.

Monitoring Parameters

ALK positivity; monitor creatine phosphokinase (CPK) and amylase/lipase levels periodically throughout therapy; fasting serum glucose at baseline and periodically thereafter; monitor heart rate and blood pressure (after 2 weeks and at least monthly thereafter); monitor for signs/symptoms of interstitial lung disease (ILD)/pneumonitis (new or worsening pulmonary symptoms), muscular symptoms of CPK elevations, and visual disturbances (obtain ophthalmologic evaluation in patients with new or worsening ≥ grade 2 visual symptoms).

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Based on the mechanism of action, brigatinib may be expected to cause fetal harm if used in pregnant women.

Women of reproductive potential should use an effective nonhormonal contraceptive during therapy and for at least 4 months after the last dose. Males with female partners of reproductive potential should use effective contraception during therapy and for at least 3 months after the last dose. Based on animal data, fertility in males may be reduced.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, diarrhea, constipation, abdominal pain, lack of appetite, back pain, joint pain, or insomnia. Have patient report immediately to prescriber signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), severe headache, severe dizziness, passing out, vision changes, bradycardia, angina, diplopia, sensitivity to light, muscle pain, muscle weakness, muscle spasms, burning or numbness feeling, severe loss of strength and energy, or signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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