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Brigatinib

Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: 5-Chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine
Molecular Formula: C29H39ClN7O2P
CAS Number: 1197953-54-0
Brands: Alunbrig

Medically reviewed on Jun 18, 2018

Introduction

See also: Alunbrig

Antineoplastic agent; an inhibitor of multiple tyrosine kinases, including anaplastic lymphoma kinase (ALK).1 6 7 8 9 11

Uses for Brigatinib

Non-small Cell Lung Cancer (NSCLC)

Treatment of ALK-positive metastatic NSCLC in patients following failure (secondary to resistance or intolerance) of prior crizotinib therapy1 2 (designated an orphan drug by FDA for treatment of ALK-positive, c-ros oncogene-1 [ROS-1]-positive, or epidermal growth factor receptor [EGFR] mutation-positive NSCLC).3

Accelerated approval based on tumor response rate and duration of response; continued approval may be contingent on verification and description of clinical benefit in a confirmatory study.1

About 3–7% of patients with NSCLC have ALK-positive disease; such patients typically are nonsmokers or light smokers, female, and younger in age, and often have adenocarcinoma.6 8 9 10 11

Long-term therapeutic potential of crizotinib (another ALK inhibitor) is limited by eventual development of secondary resistance and development and/or progression of brain metastases (because of poor distribution of crizotinib into CSF).6 7 8 9 11 (See Actions.) Responses to brigatinib in patients with crizotinib-refractory, ALK-positive metastatic NSCLC have included objective CNS responses.1 2

Brigatinib Dosage and Administration

General

  • May cause hypertension; control BP before initiating therapy and then monitor BP 2 weeks after starting therapy and at least monthly thereafter.1 (See Hypertension under Dosage and Administration.) May cause bradycardia.1 Monitor heart rate and BP during therapy.1 (See Bradycardia under Dosage and Administration.)

  • Monitor CK and pancreatic enzyme (e.g., amylase, lipase) concentrations during therapy.1 (See CK Elevation and also see Pancreatic Enzyme Elevation under Dosage and Administration.)

  • Measure fasting serum glucose concentrations prior to initiating therapy and then periodically monitor glucose concentrations during therapy.1 (See Hyperglycemia under Dosage and Administration.)

Restricted Distribution

  • Available through a limited network of specialty pharmacies.12 Consult the Alunbrig website ([Web]) for specific availability information.12

Administration

Oral Administration

Administer once daily without regard to food.1 (See Food under Pharmacokinetics.) Swallow tablets whole; do not crush or chew tablets.1

Dosage

Adults

NSCLC
Oral

90 mg once daily for first 7 days; if tolerated, increase to 180 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

Following treatment interruptions of ≥14 days for reasons other than adverse reactions, resume brigatinib at a dosage of 90 mg once daily for 7 days, then increase to the previously tolerated dosage.1

Dosage Modification for Toxicity
Oral

In the principal efficacy study, 7.3 or 20% of patients receiving 90 mg once daily or 180 mg once daily, respectively, required dosage reduction (most commonly for CK elevations).1 2

If dosage reduction is necessary in patients receiving 90 mg once daily, initially reduce dosage to 60 mg once daily.1 If further dosage reduction is needed, permanently discontinue the drug.1

If dosage reduction is necessary in patients receiving 180 mg once daily, initially reduce dosage to 120 mg once daily.1 If further dosage reduction is needed, reduce dosage to 90 mg once daily.1 If dosage reduction from 90 mg once daily is necessary, reduce dosage to 60 mg once daily.1 If further dosage reduction is needed, permanently discontinue the drug.1

Once dosage has been reduced because of adverse reactions, do not subsequently increase dosage.1

Interstitial Lung Disease/Pneumonitis
Oral

If new grade 1 pulmonary symptoms occur during the first 7 days of treatment, interrupt therapy until recovery to baseline.1 May resume brigatinib at the same dosage; do not increase dosage to 180 mg once daily if interstitial lung disease (ILD)/pneumonitis is suspected.1

If new grade 1 pulmonary symptoms occur after the first 7 days of treatment, interrupt therapy until recovery to baseline; may resume brigatinib at same dosage.1

If new grade 2 pulmonary symptoms occur during the first 7 days of treatment, interrupt therapy until recovery to baseline.1 May resume brigatinib at the next lower dosage; do not increase dosage if ILD/pneumonitis is suspected.1

If new grade 2 pulmonary symptoms occur after the first 7 days of treatment, interrupt therapy until recovery to baseline.1 If ILD/pneumonitis is suspected, may resume brigatinib at the next lower dosage; otherwise, may resume therapy at the same dosage.1

If grade 1 or 2 ILD/pneumonitis recurs, permanently discontinue brigatinib.1

If grade 3 or 4 ILD/pneumonitis occurs, permanently discontinue brigatinib.1 (See Interstitial Lung Disease [ILD]/Pneumonitis under Cautions.)

Hypertension
Oral

If grade 3 hypertension (i.e., SBP ≥160 mm Hg or DBP ≥100 mm Hg, requiring medical intervention and >1 antihypertensive agent or more intensive therapy than previously used) occurs, interrupt therapy until recovery to grade 1 or less hypertension (i.e., SBP <140 mm Hg and DBP <90 mm Hg); may then resume brigatinib at the next lower dosage.1

If grade 3 hypertension recurs, interrupt therapy until recovery to grade 1 or less hypertension; may then resume brigatinib at the next lower dosage or permanently discontinue the drug.1

If grade 4 hypertension (i.e., life-threatening consequences, requiring urgent intervention) occurs, interrupt therapy until recovery to grade 1 or less hypertension; may then resume brigatinib at the next lower dosage or permanently discontinue the drug.1

If grade 4 hypertension recurs, permanently discontinue brigatinib.1 (See Hypertension under Cautions.)

Bradycardia
Oral

If symptomatic, but non-life-threatening, bradycardia occurs, interrupt brigatinib therapy until recovery to asymptomatic bradycardia or to a resting heart rate of ≥60 beats/minute.1 If concomitant therapy includes drugs known to cause bradycardia and is modified (dosage adjusted or drug discontinued), may resume brigatinib at same dosage; if such modification is not possible or if no concomitant contributory drugs are identified, may resume brigatinib at next lower dosage.1

If life-threatening bradycardia requiring urgent intervention occurs in patients receiving concomitant contributory drugs known to cause bradycardia, interrupt brigatinib therapy until recovery to asymptomatic bradycardia or to a resting heart rate of ≥60 beats/minute.1 If the concomitant therapy is modified, may resume brigatinib at the next lower dosage with frequent monitoring as clinically indicated; permanently discontinue brigatinib in case of recurrence.1

If life-threatening bradycardia requiring urgent intervention occurs in patients not receiving concomitant contributory drugs, permanently discontinue brigatinib.1 (See Bradycardia under Cautions.)

Visual Disturbances
Oral

If grade 2 or 3 visual disturbance occurs, interrupt therapy until recovery to grade 1 or baseline; may resume therapy at next lower dosage.1

If grade 4 visual disturbance occurs, permanently discontinue brigatinib.1 (See Visual Disturbances under Cautions.)

CK Elevation
Oral

If serum CK concentrations >5 times ULN (i.e., grade 3), interrupt therapy until CK concentrations return to baseline or ≤2.5 times ULN (i.e., grade 1 or less); may resume brigatinib at same dosage.1 If serum CK concentrations >5 times ULN recur, interrupt therapy until CK concentrations return to baseline or ≤2.5 times ULN; may resume brigatinib at the next lower dosage.1

If serum CK concentrations >10 times ULN (i.e., grade 4), interrupt therapy until CK concentrations return to baseline or ≤2.5 times ULN; may resume brigatinib at the next lower dosage.1

Pancreatic Enzyme Elevation
Oral

If serum amylase or lipase concentrations >2 times the ULN (i.e., grade 3), interrupt therapy until amylase or lipase concentrations recover to baseline or ≤1.5 times ULN (i.e., grade 1 or less); may resume brigatinib at same dosage.1 If grade 3 amylase or lipase elevation recurs, interrupt therapy until amylase or lipase concentrations recover to baseline or ≤1.5 times ULN (i.e., grade 1 or less); may resume brigatinib at the next lower dosage.1

If serum amylase or lipase concentrations >5 times ULN (i.e., grade 4), interrupt therapy until amylase or lipase concentrations recover to baseline values or ≤1.5 times ULN (i.e., grade 1 or less); may resume brigatinib at the next lower dosage.1

Hyperglycemia
Oral

If hyperglycemia occurs with serum glucose concentrations >250 mg/dL (i.e., grade 3) and adequate hyperglycemic control cannot be achieved despite optimal antidiabetic agent therapy, interrupt brigatinib therapy until adequate control of hyperglycemia is achieved.1 Consider resuming brigatinib at the next lower dosage or permanent discontinuance of the drug.1 (See Hyperglycemia under Cautions.)

Other Toxicity
Oral

If other grade 3 adverse reaction occurs, interrupt therapy until recovery to baseline; may resume brigatinib at same dosage.1 If the grade 3 adverse reaction recurs, interrupt therapy until recovery to baseline; may resume brigatinib at the next lower dosage or discontinue drug.1

If other grade 4 adverse reaction occurs, interrupt therapy until recovery to baseline; may resume brigatinib at the next lower dosage or permanently discontinue drug.1 If the grade 4 adverse reaction recurs, permanently discontinue brigatinib.1

Special Populations

Hepatic Impairment

Mild hepatic impairment (total bilirubin not exceeding ULN with AST exceeding ULN, or total bilirubin >1 to 1.5 times ULN with any AST): No dosage adjustment needed.1

Moderate or severe hepatic impairment: Pharmacokinetics and safety not established.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild or moderate renal impairment (Clcr 30–89 mL/minute): No dosage adjustment needed.1

Severe renal impairment (Clcr <30 mL/minute): Pharmacokinetics and safety not established.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations.1

Cautions for Brigatinib

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Interstitial Lung Disease (ILD)/Pneumonitis

Severe, life-threatening, or fatal adverse pulmonary reactions consistent with ILD/pneumonitis may occur.1 2 In the principal efficacy study, ILD or pneumonitis occurred in 9.1% of patients receiving the recommended dosage regimen.1 2 Adverse pulmonary symptoms consistent with possible ILD/pneumonitis occurred early (i.e., within 9 days of initiation of therapy; median onset of 2 days).1 2

Monitor patients for new or worsening respiratory symptoms, particularly during first week of therapy.1 2 (See Advice to Patients.) If respiratory symptoms occur, interrupt therapy and promptly evaluate for ILD/pneumonitis or other potential causes (e.g., pulmonary embolism, tumor progression, pneumonia).1 Dosage reduction or discontinuance of therapy may be necessary depending on the severity of the ILD/pneumonitis.1 (See Interstitial Lung Disease/Pneumonitis under Dosage and Administration.)

Hypertension

Hypertension reported.1

Control BP before initiating brigatinib therapy and monitor BP 2 weeks after treatment initiation and at least monthly during treatment.1

If severe hypertension occurs despite optimal antihypertensive therapy, interrupt therapy until BP is controlled; dosage reduction or discontinuance of therapy may be necessary depending on the severity or for recurrent hypertension.1 (See Hypertension under Dosage and Administration.)

Use caution if brigatinib is administered concurrently with antihypertensive agents that cause bradycardia.1 (See Drugs Associated with Bradycardia under Interactions.)

Bradycardia

Bradycardia reported.1

Monitor heart rate and BP periodically during brigatinib therapy; monitor more frequently if concurrent use of a drug known to cause bradycardia cannot be avoided.1 (See Hypertension under Cautions.)

If symptomatic or life-threatening bradycardia occurs, interrupt therapy; dosage reduction or discontinuance of brigatinib therapy may be necessary depending on concomitant use of other drugs known to cause bradycardia.1 Evaluate concomitant therapy to identify any drugs that may cause bradycardia; adjust dosage or discontinue such drugs, if possible.1 (See Bradycardia under Dosage and Administration.)

Visual Disturbances

Visual disturbances, including blurred vision, diplopia, and reduced visual acuity, reported; macular edema and cataract also reported.1

If new or worsening visual disturbances of grade 2 or greater severity occur, interrupt therapy and obtain ophthalmologic evaluation.1 Dosage reduction or drug discontinuance may be required depending on the severity of ocular effects.1 (See Visual Disturbances under Dosage and Administration and also see Advice to Patients.)

CK Elevation

Serum CK elevations reported.1

Monitor serum CK concentrations periodically.1 If CK elevation occurs, temporary interruption followed by resumption of therapy at same dosage or at a reduced dosage may be necessary depending on the severity.1 (See CK Elevation under Dosage and Administration and also see Advice to Patients.)

Pancreatic Enzyme Elevation

Serum amylase and/or lipase elevations reported.1

Monitor serum amylase and lipase concentrations periodically during therapy.1 If amylase and/or lipase elevation occurs, temporary interruption followed by resumption of therapy at same dosage or at a reduced dosage may be necessary depending on the severity.1 (See Pancreatic Enzyme Elevation under Dosage and Administration.)

Hyperglycemia

Hyperglycemia reported.1

Measure fasting serum glucose concentrations prior to initiating therapy and periodically monitor during therapy.1 Initiate or optimize antidiabetic therapy as clinically indicated.1 If adequate glycemic control cannot be achieved despite optimal medical management, interrupt therapy until hyperglycemia is adequately controlled.1 Dosage reduction or discontinuance of therapy may be necessary depending on severity of hyperglycemia.1 (See Hyperglycemia under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; dose-related skeletal abnormalities, increased post-implantation loss, malformations, and decreased fetal body weight observed in animals.1

Avoid pregnancy during therapy.1 Women of childbearing potential should use effective nonhormonal methods of contraception during therapy and for ≥4 months after drug discontinuance.1 (See Specific Drugs and Foods under Interactions and also see Advice to Patients.) If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Men with female partners of childbearing potential should use effective methods of contraception during therapy and for ≥3 months after drug discontinuance.1

Impairment of Fertility

Based on animal studies, may impair male fertility.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether brigatinib is distributed into milk or if drug has any effect on milk production or the nursing infant.1 Women should not breast-feed during therapy and for ≥1 week after drug discontinuance.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1 In the principal efficacy study, no clinically important differences in safety or efficacy observed between geriatric patients and younger adults.1 (See Special Populations under Pharmacokinetics.)

Hepatic Impairment

Mild hepatic impairment (total bilirubin not exceeding ULN with AST exceeding ULN, or total bilirubin >1 to 1.5 times ULN with any AST): Exposure not altered; no dosage adjustment needed.1 (See Special Populations under Pharmacokinetics.)

Moderate or severe hepatic impairment: Pharmacokinetics and safety not studied.1

Renal Impairment

Exposure not altered by mild or moderate renal impairment (Clcr 30–89 mL/minute).1 (See Special Populations under Pharmacokinetics.)

Pharmacokinetics and safety not studied in patients with severe renal impairment (Clcr <30 mL/minute).1

Common Adverse Effects

Nausea,1 2 vomiting,1 2 diarrhea,1 2 fatigue/asthenia,1 2 cough,1 2 headache,1 2 rash (including acneiform dermatitis and exfoliative, pruritic, or pustular rash),1 2 dyspnea,1 2 hypertension,1 2 muscle spasms,1 2 decreased appetite,1 2 constipation,1 2 back pain,1 2 myalgia/musculoskeletal pain,1 arthralgia,1 2 peripheral neuropathy (including paresthesia),1 abdominal pain,1 2 visual disturbances (including diplopia, photophobia, blurred vision, reduced visual acuity, visual impairment, vitreous floaters, visual field defect, macular edema, and vitreous detachment),1 pneumonia,1 ILD/pneumonitis,1 elevated ALT or AST concentrations,1 2 elevated alkaline phosphatase concentrations,1 elevated CK concentrations,1 2 hyperglycemia,1 elevated lipase and/or amylase concentrations,1 2 anemia,1 lymphopenia,1 hypophosphatemia,1 prolonged aPTT.1

Interactions for Brigatinib

Metabolized principally by CYP isoenzymes 2C8 and 3A4.1

Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro; not a substrate of organic anion transport protein (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion transporter (MATE) 1, MATE2K, or bile salt export pump (BSEP).1

In vitro, inhibits P-gp, BCRP, OCT1, MATE1, and MATE2K; does not inhibit OATP1B1, OATP1B3, OAT1, OAT3, OCT2, or BSEP.1

Induces CYP3A and also may induce CYP2C isoenzymes via activation of the pregnane X receptor (PXR).1 Brigatinib and its principal metabolite do not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5.1

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible pharmacokinetic interaction (increased plasma concentrations of brigatinib and risk of adverse effects).1 Avoid concomitant use.1 If concomitant use cannot be avoided, reduce daily dosage of brigatinib by approximately 50% (e.g., from 180 mg daily to 90 mg daily or from 90 mg daily to 60 mg daily).1 If the potent CYP3A inhibitor is discontinued, resume brigatinib therapy at the dosage that was tolerated prior to initiation of the potent CYP3A inhibitor.1

CYP2C8 inhibitors: Clinically important pharmacokinetic interactions unlikely.1

Potent CYP3A inducers: Possible pharmacokinetic interaction (decreased plasma concentrations of brigatinib and possible reduced efficacy).1 Avoid concomitant use.1

Inhibitors of P-gp or BCRP

Inhibitors of P-gp or BCRP: Clinically important pharmacokinetic interactions unlikely.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Possible pharmacokinetic interaction (decreased plasma concentrations and possible reduced efficacy of CYP3A substrate).1

Substrates of Drug Transport Systems

Substrates of P-gp, BCRP, OCT1, MATE1, or MATE2K: Possible pharmacokinetic interaction (increased plasma concentrations of P-gp, BCRP, OCT1, MATE1, or MATE2K substrate).1

Drugs Associated with Bradycardia

Possible increased risk of bradycardia; use with caution.1 If concomitant use cannot be avoided, monitor heart rate more frequently.1 If clinically important bradycardia occurs, discontinue or adjust dosage of the concomitant drug, if possible.1 (See Bradycardia under Cautions.)

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Antifungals, azoles (e.g., itraconazole, ketoconazole, posaconazole, voriconazole)

Potent CYP3A inhibitors: Possible increased brigatinib concentrations and adverse effects1

Brigatinib AUC and peak concentrations increased by 101 and 21%, respectively1

Potent CYP3A inhibitors: Avoid concomitant use; if concomitant use cannot be avoided, reduce dosage of brigatinib by approximately 50% (e.g., from 180 to 90 mg daily or from 90 to 60 mg daily)1

If the antifungal is discontinued, resume brigatinib at the dosage that was tolerated prior to initiation of the antifungal1

Carbamazepine

Possible decreased brigatinib concentrations1

Avoid concomitant use1

Cobicistat

Possible increased brigatinib concentrations and adverse effects1

Avoid concomitant use; if concomitant use cannot be avoided, reduce dosage of brigatinib by approximately 50% (e.g., from 180 to 90 mg daily or from 90 to 60 mg daily)1

If cobicistat is discontinued, resume brigatinib at the dosage that was tolerated prior to initiation of cobicistat1

Conivaptan

Possible increased brigatinib concentrations and adverse effects1

Avoid concomitant use; if concomitant use cannot be avoided, reduce dosage of brigatinib by approximately 50% (e.g., from 180 to 90 mg daily or from 90 to 60 mg daily)1

If conivaptan is discontinued, resume brigatinib at the dosage that was tolerated prior to initiation of conivaptan1

Contraceptives, hormonal

Possible decreased exposure of hormonal contraceptive and reduced efficacy1

Use effective nonhormonal contraception during and for ≥4 months after discontinuing brigatinib therapy1

Gemfibrozil

Decreased brigatinib AUC and peak concentrations, not considered clinically important1

Grapefruit or grapefruit juice

Possible increased brigatinib concentrations1

Avoid concomitant use1

HIV protease inhibitors that are potent CYP3A inhibitors (e.g., indinavir, lopinavir, nelfinavir, ritonavir, saquinavir)

Possible increased brigatinib concentrations and adverse effects1

Avoid concomitant use; if concomitant use cannot be avoided, reduce dosage of brigatinib by approximately 50% (e.g., from 180 to 90 mg daily or from 90 to 60 mg daily)1

If the potent CYP3A inhibitor is discontinued, resume brigatinib at the dosage that was tolerated prior to initiation of the potent CYP3A inhibitor1

Macrolides (e.g., clarithromycin)

Potent CYP3A inhibitors: Possible increased brigatinib concentrations and adverse effects1

Potent CYP3A inhibitors: Avoid concomitant use; if concomitant use cannot be avoided, reduce dosage of brigatinib by approximately 50% (e.g., from 180 to 90 mg daily or from 90 to 60 mg daily)1

If the macrolide is discontinued, resume brigatinib at the dosage that was tolerated prior to initiation of the macrolide1

Phenytoin

Possible decreased brigatinib concentrations1

Avoid concomitant use1

Rifampin

Brigatinib AUC and peak concentrations decreased by 80 and 60%, respectively1

Avoid concomitant use1

St. John's wort (Hypericum perforatum)

Possible decreased brigatinib concentrations1

Avoid concomitant use1

Brigatinib Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations of brigatinib attained 1–4 hours following oral administration.1

Systemic exposure to brigatinib is dose proportional over an oral dosage range of 60–240 mg following single or repeat dosing.1

Food

High-fat meal decreased peak plasma concentrations of brigatinib by 13% but had no effect on systemic exposure compared with administration in the fasting state.1

Special Populations

Mild hepatic impairment does not affect exposure to brigatinib.1

Mild or moderate renal impairment does not affect exposure to brigatinib.1

Effects of severe renal impairment and moderate to severe hepatic impairment on brigatinib pharmacokinetics not established.1

Age, gender, race, body weight, and serum albumin concentration do not substantially affect brigatinib pharmacokinetics.1

Distribution

Extent

Not known whether distributed into human milk.1

Plasma Protein Binding

66%; independent of drug concentration.1

Elimination

Metabolism

Principally metabolized by CYP2C8 and CYP3A4.1

Major active metabolite (AP26123) inhibits ALK with approximately threefold lower potency than brigatinib.1

Systemic exposure of AP26123 is <10% of parent drug.1

Elimination Route

Eliminated in feces (65%; 41% as unchanged drug) and urine (25%; 86% as unchanged drug).1

Half-life

25 hours.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Inhibits multiple tyrosine kinases, including ALK, c-ros oncogene-1 (ROS-1), insulin-like growth factor receptor-1 (IGFR-1), and fms-like tyrosine kinase 3 (FLT-3) as well as epidermal growth factor receptor (EGFR) deletion and point mutations.1 6 7 8 9 11

  • Inhibits ALK phosphorylation and ALK-mediated activation of the downstream signaling proteins signal transducer and activator of transcription 3 (STAT3), AKT serine/threonine kinase, extracellular signal-regulated kinase (ERK) 1/2, and ribosomal protein S6 in vitro and in vivo.1

  • Activating mutations or translocations of the ALK gene identified in several malignancies and can result in the expression of oncogenic fusion proteins (e.g., echinoderm microtubule-associated protein-like 4 [EML4]-ALK).2 6 8 9 10 11 Formation of ALK fusion proteins results in activation and dysregulation of the gene's expression and signaling, which can contribute to increased cell proliferation and survival in tumors expressing these proteins.9 10 11

  • ALK rearrangements identified in approximately 3–7% of patients with NSCLC.2 6 8 9 10

  • Clinical resistance to crizotinib attributed to several possible mechanisms, including acquired resistance mutations of ALK, amplification of gene expression, and activation of alternate signaling pathways.2 6 8 9 11 CNS is a common site of disease progression in crizotinib-treated patients because of poor distribution of the drug into CSF.2 6 8 9 11

  • Brigatinib is approximately 12-fold more potent than crizotinib against native ALK-positive cell lines in vitro.6

  • Brigatinib is active against cells expressing EML4-ALK and nucleophosmin (NPM)-ALK fusion proteins and many mutant forms associated with resistance to alectinib, ceritinib, and/or crizotinib, as well as EGFR-Del (E746-A750), ROS1-L2026M, FLT3-F691L, and FLT3-D835Y.1 6 7

  • Exhibits dose-dependent antitumor activity in mice bearing NSCLC tumor xenografts expressing EML4-ALK, including several with ALK mutations conferring resistance to crizotinib, ceritinib, and alectinib (e.g., L1196M, G1202R).1 6 8

  • Demonstrates reduced tumor burden and prolonged survival in mice bearing intracranial ALK-positive NSCLC tumor xenografts.1 6 Demonstrated antitumor activity in patients with crizotinib-resistant ALK-positive NSCLC with baseline CNS metastases.1 2

Advice to Patients

  • Importance of instructing patients to read the manufacturer's patient information.1

  • Importance of advising patients to take brigatinib exactly as prescribed and of not altering the dosage or discontinuing therapy unless advised to do so by their clinician.1 Importance of advising patients to swallow brigatinib tablets whole without regard to food and not to crush or chew the tablets.1 If a dose is missed or if vomiting occurs after a dose is administered, the next dose should be taken at the regularly scheduled time; the missed dose should not be taken, and an additional dose should not be administered to replace the vomited dose.1

  • Importance of informing patients of the symptoms and risks of serious adverse pulmonary reactions such as ILD/pneumonitis, which occur particularly during the first week of brigatinib therapy.1 Importance of advising patients to immediately report any new or worsening pulmonary symptoms (e.g., dyspnea or shortness of breath, cough with or without mucus, chest pain, fever) to their clinician and informing them that such symptoms may be similar to those of lung cancer.1

  • Risk of hypertension.1 Importance of promptly reporting signs or symptoms of hypertension (e.g., headache, dizziness, blurred vision, chest pain, shortness of breath).1

  • Risk of bradycardia.1 Importance of patients immediately contacting their clinician if they experience dizziness, lightheadedness, or faintness.1

  • Risk of visual disturbances.1 Importance of informing clinician of any new or worsening visual symptoms (e.g., diplopia, blurred vision, flashes of light, photophobia, new or increased floaters).1

  • Risk of muscle problems or myalgia; importance of CK monitoring.1 Importance of promptly reporting any new or worsening signs or symptoms of muscle problems (e.g., unexplained or persistent muscle pain, tenderness, weakness).1

  • Risk of elevated concentrations of pancreatic enzymes and importance of monitoring amylase and lipase concentrations.1 Importance of patients immediately contacting their clinician if they experience manifestations of pancreatitis (e.g., upper abdominal pain that may spread to the back and get worse with eating, weight loss, nausea).1

  • Risk of new or worsening hyperglycemia and importance of periodically monitoring blood glucose concentrations.1 Importance of immediately informing clinician if manifestations of hyperglycemia occur (e.g., increased thirst, increased urination, increased appetite, nausea, weakness, fatigue, confusion).1 Patients with diabetes mellitus or glucose intolerance may require dosage adjustment of antidiabetic therapy during brigatinib treatment.1

  • Risk of fetal harm.1 Necessity of advising women of childbearing potential that they should use effective, nonhormonal methods of contraception while receiving brigatinib and for ≥4 months after discontinuance of therapy and of also advising such women that oral contraceptives and other hormonal forms of contraception may not be effective during brigatinib therapy.1 Importance of advising men with female partners of childbearing potential to use effective methods of contraception while receiving the drug and for ≥3 months after the drug is discontinued.1 Importance of also advising men that brigatinib may cause fertility problems and to discuss any concerns about fertility with their clinician.1

  • Importance of women informing their clinicians if they are or plan to become pregnant.1 If pregnancy occurs, advise of potential fetal risk.1

  • Importance of advising women to avoid breast-feeding while receiving brigatinib and for ≥1 week after discontinuance of therapy.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., cardiac or antihypertensive agents, antidiabetic agents) and dietary or herbal supplements (e.g., St. John's wort, grapefruit-containing products), as well as any concomitant illnesses (e.g., cardiovascular disease, diabetes mellitus, pancreatitis).1

  • Importance of advising patients to avoid grapefruit and grapefruit juice while taking brigatinib.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of brigatinib is restricted.12 (See Restricted Distribution under Dosage and Administration.)

Brigatinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

30 mg

Alunbrig

Ariad

90 mg

Alunbrig

Ariad

180 mg

Alunbrig

Ariad

AHFS DI Essentials. © Copyright 2018, Selected Revisions June 18, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Ariad Pharmaceuticals, Inc. Alunbrig (brigatinib) tablets prescribing information. Cambridge, MA; 2017 Oct.

2. Kim DW, Tiseo M, Ahn MJ et al. Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial. J Clin Oncol. 2017; 35:2490-2498. http://www.ncbi.nlm.nih.gov/pubmed/28475456?dopt=AbstractPlus

3. Food and Drug Administration. FDA Application: Search orphan drug designations and approvals. Silver Spring, MD. From FDA website. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

4. Markham A. Brigatinib: First Global Approval. Drugs. 2017; 77:1131-1135. http://www.ncbi.nlm.nih.gov/pubmed/28597393?dopt=AbstractPlus

5. ALTA-1L study: a phase 3 study of brigatinib versus crizotinib in ALK-positive advanced non-small cell lung cancer patients (ALTA-1L). From ClinicalTrials.gov registry. Accessed 2017 Sep 14. https://clinicaltrials.gov/ct2/show/NCT02737501

6. Zhang S, Anjum R, Squillace R et al. The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models. Clin Cancer Res. 2016; 22:5527-5538. http://www.ncbi.nlm.nih.gov/pubmed/27780853?dopt=AbstractPlus

7. Sabari JK, Santini FC, Schram AM et al. The activity, safety, and evolving role of brigatinib in patients with ALK-rearranged non-small cell lung cancers. Onco Targets Ther. 2017; 10:1983-1992. http://www.ncbi.nlm.nih.gov/pubmed/28435288?dopt=AbstractPlus

8. Sullivan I, Planchard D. ALK inhibitors in non-small cell lung cancer: the latest evidence and developments. Ther Adv Med Oncol. 2016; 8:32-47. http://www.ncbi.nlm.nih.gov/pubmed/26753004?dopt=AbstractPlus

9. Awad MM, Shaw AT. ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol. 2014; 12:429-39. http://www.ncbi.nlm.nih.gov/pubmed/25322323?dopt=AbstractPlus

10. Sasaki T, Jänne PA. New strategies for treatment of ALK-rearranged non-small cell lung cancers. Clin Cancer Res. 2011; 17:7213-8. http://www.ncbi.nlm.nih.gov/pubmed/22010214?dopt=AbstractPlus

11. Wu J, Savooji J, Liu D. Second- and third-generation ALK inhibitors for non-small cell lung cancer. J Hematol Oncol. 2016; 9:19. http://www.ncbi.nlm.nih.gov/pubmed/26951079?dopt=AbstractPlus

12. Biologics, Inc. Alunbrig (brigatinib) approved for the treatment of ALK+ metastatic non-small cell lung cancer, available for order at Biologics, Inc. Press release. 2017 May 11. From McKesson Specialty Health website. Accessed 2018 Jan 26. http://www.mckesson.com/about-mckesson/newsroom/press-releases/2017/alunbrig-approved-for-the-treatment-of-alk-metastatic-non-small-cell-lung-cancer/

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