brigatinib

bri-GA-ti-nib

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

High Alert

Metastatic non-small cell lung cancer (NSCLC) that is positive for anaplastic lymphoma kinase (ALK).

Inhibits receptor tyrosine kinases including ALK, insulin-like growth factor-1 receptor, ROS1, and FMS-like tyrosine kinase-3.

Therapeutic effects:

Improved progression-free survival.

Absorption: Well absorbed following oral administration. Bioavailability ↓ by high fat meals.

Distribution: Extensively distributed to tissues.

Metabolism/Excretion: Mostly metabolized by the liver via the CYP2C8 and CYP3A4 isoenzymes; also induces CYP3A. 27% excreted in feces unchanged, 22% eliminated unchanged in urine.

Half-Life: 25 hr.

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	1–4 hr	unknown

Contraindicated in:

OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Diabetes;
Severe renal impairment (↓ dose);
Severe hepatic impairment (↓ dose);
Rep: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: Safety and effectiveness not established in children.

CV: hypertension, bradycardia

Derm: rash, photosensitivity

EENT: ↓visual acuity, blurred vision, diplopia, cataracts, macular edema, photophobia

Endo: hyperglycemia

F and E: hypophosphatemia

GI: ↑amylase, ↑lipase, ↑liver enzymes, abdominal pain, constipation, diarrhea, nausea, vomiting

Hemat: ↑activated partial thromboplastin time, anemia, lymphopenia

Metab: ↓appetite

MS: ↑CK, arthralgia, back pain, muscle spasms, myalgia

Neuro: fatigue, headache, insomnia, peripheral neuropathy

Resp: cough, dyspnea, hypoxia, INTERSTITIAL LUNG DISEASE (ILD)/PNEUMONITIS, pneumonia

Misc: fever

Drug-drug:

Strong CYP3A inhibitors or moderate CYP3A inhibitors, including, clarithromycin, cobicistat, conivaptan, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, posaconazole, ritonavir, and voriconazole may ↑ levels and risk of toxicity; avoid concurrent use; if concurrent use necessary, ↓ brigatinib dose.
Strong CYP3A inducers or moderate CYP3A inducers, including carbamazepine, phenytoin, and rifampin may ↓ levels and effectiveness; avoid concurrent use; if concurrent therapy needed with moderate CYP3A inducer, ↑ brigatinib dose.
Beta-blockers, verapamil, diltiazem, digoxin, and clonidine may ↑ risk of bradycardia; avoid concurrent use, if possible.

Drug-Natural Products:

St. John's wort may ↓ levels and effectiveness; avoid concurrent use.

Drug-Food:

Grapefruit or grapefruit juice may ↑ levels and risk of toxicity; avoid concurrent use.

PO (Adults ): 90 mg once daily for 7 days, then 180 mg once daily. Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A inhibitor: If previously taking 180 mg once daily, ↓ to 90 mg once daily; if previously taking 90 mg once daily, ↓ to 60 mg once daily; Concurrent use of moderate CYP3A inhibitor: If previously taking 180 mg once daily, ↓ to 120 mg once daily; if previously taking 120 mg once daily, ↓ to 90 mg once daily; if previously taking 90 mg once daily, ↓ to 60 mg once daily; Concurrent use of moderate CYP3A inducer:↑ daily dose in 30-mg increments after 7 days of treatment with the dose used prior to initiation of moderate CYP3A inducer; may ↑ dose up to a max of twice the dose that was tolerated prior to initiating the moderate CYP3A inducer.

Renal Impairment

PO (Adults ): CCr 15–29 mL/min: If previously taking 180 mg once daily, ↓ to 90 mg once daily; if previously taking 90 mg once daily, ↓ to 60 mg once daily.

Hepatic Impairment

PO (Adults ): Severe hepatic impairment: If previously taking 180 mg once daily, ↓ to 120 mg once daily; if previously taking 120 mg once daily, ↓ to 90 mg once daily; if previously taking 90 mg once daily, ↓ to 60 mg once daily.

Film-coated tablets: 30 mg; 90 mg; 180 mg

Assess respiratory function (lung sounds, dyspnea, oxygen saturation) periodically during therapy.
Monitor for signs/symptoms of ILD or pneumonitis (difficulty breathing, shortness or breath, cough with/without mucus, fever) periodically during therapy. If Grade 1 ILD/pneumonitis occurs:If new pulmonary symptoms occur during 1st 7 days of therapy, hold brigatinib until recovery to baseline, then resume at same dose; do not ↑ to 180 mg if ILD/pneumonitis suspected. If new pulmonary symptoms occur after 1st 7 days of therapy, hold brigatinib until recovery to baseline, then resume at same dose. If ILD/pneumonitis recurs, permanently discontinue brigatinib. If Grade 2 ILD/pneumonitis occurs: If new pulmonary symptoms occur during 1st 7 days of therapy, hold brigatinib until recovery to baseline, then resume at same dose; do not ↑ to 180 mg if ILD/pneumonitis suspected. If new pulmonary symptoms occur after 1st 7 days of therapy, hold brigatinib until recovery to baseline. If ILD/pneumonitis suspected, resume at next lower dose; if not, resume at same dose. If ILD/pneumonitis recurs, permanently discontinue brigatinib. If Grade 3 or 4 ILD/pneumonitis occurs, permanently discontinue brigatinib.
Monitor BP before therapy, after 2 wk, and monthly during therapy. Control BP prior to therapy. If Grade 3 hypertension (SBP ≥160 mm Hg or DBP ≥100 mm Hg) occurs, hold brigatinib until hypertension Grade ≤1 (SBP <140 mm Hg and DBP <90 mm Hg), then resume brigatinib at next lower dose. If Grade 3 hypertension recurs, hold brigatinib until recovery to Grade ≤1, and resume at next lower dose or permanently discontinue brigatinib. If Grade 4 hypertension (life-threatening consequences, urgent intervention indicated) occurs, hold brigatinib until Grade ≤1, and resume at next lower dose or permanently discontinue brigatinib. If Grade 4 hypertension recurs, permanently discontinue brigatinib.
Monitor for bradycardia (HR <60 bpm) periodically during therapy, especially if concurrent medications ↓ HR. If symptomatic bradycardia (dizziness, lightheadedness, fainting) occurs, hold brigatinib until asymptomatic bradycardia or resting HR ≥60 bpm. If concurrent medication known to cause bradycardia is identified and discontinued or dose adjusted, resume brigatinib at same dose once asymptomatic or resting HR ≥60 bpm. If no concurrent medication known to cause bradycardia, or if contributing concurrent medications are not discontinued or dose adjusted, resume brigatinib at next lower dose upon recovery to asymptomatic bradycardia or to resting HR ≥60 bpm. If bradycardia with life-threatening consequences or urgent intervention needed, permanently discontinue brigatinib if no contributing concurrent medication is identified. If contributing concurrent medication is identified and discontinued or dose adjusted, resume brigatinib at next lower dose when recovered to asymptomatic bradycardia or to a resting HR ≥60 bpm, with frequent monitoring. If life-threatening bradycardia recurs, permanently discontinue brigatinib.
Monitor for visual changes (blurred vision, diplopia, reduced visual acuity) periodically during therapy. If Grade 2 or 3 visual disturbance occurs, hold brigatinib until recovery to Grade ≤1, then resume brigatinib at next lower dose. If Grade 4 visual disturbance occurs, permanently discontinue brigatinib.

Lab Test Considerations:

Verify negative pregnancy before starting therapy.
Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.
Monitor CK levels periodically during therapy. If Grade 3 CK ↑ (>5 times upper limit of normal [ULN]) occurs, hold brigatinib until CK ≤2.5 times ULN, then resume brigatinib at same dose. If Grade 4 CK ↑ (>10 times ULN) or recurrence of Grade 3 ↑ occurs, hold brigatinib until CK ≤2.5 times ULN), then resume brigatinib at next lower dose.
Monitor serum lipase and amylase periodically during therapy. If Grade 3 lipase or amylase ↑ (>2 times ULN) occurs, hold brigatinib until amylase or lipase ≤1.5 times ULN, then resume brigatinib at same dose. If Grade 4 lipase or amylase ↑ (>5 times ULN) or recurrence of Grade 3 ↑ occurs, hold brigatinib until amylase or lipase ≤1.5 times ULN), then resume therapy at next lower dose.
Monitor fasting serum glucose before starting and periodically during therapy. May cause new or worsening hyperglycemia. Use antihyperglycemic medications as needed. If Grade 3 (>250 mg/dL) or Grade 4 hyperglycemia occurs, hold brigatinib until adequate hyperglycemic control is achieved and resume at next lower dose or discontinue brigatinib.
Monitor AST, ALT, and total bilirubin during therapy, every 2 wk during 1st 3 mo, then once a month, and as clinically indicated. If Grade 3 or 4 elevation of either AST or ALT (>5 times ULN) with bilirubin ≤2 times ULN, hold brigatinib until AST or ALT ≤ 3 times ULN, then resume brigatinib at next lower dose. If Grade 2– 4 elevation of AST or ALT (>3 times ULN) with total bilirubin elevation >2 times ULN in the absence of cholestasis or hemolysis, permanently discontinue brigatinib.
Monitor for hemolytic anemia. If hemolytic anemia suspected, hold brigatinib. If resolved, resume brigatinib at next lower dose or permanently discontinue brigatinib.

Dose reductions for adverse reactions:Patients taking 90 mg once daily:1st reduction: 60 mg once daily. 2nd reduction: permanently discontinue brigatinib. Patients taking 180 mg once daily: 1st reduction: 120 mg once daily. 2nd reduction: 90 mg once daily. 3rd reduction: 60 mg once daily.
PO: Administer without regard to food. DNC: Swallow tablets whole; do not crush, break, or chew. If therapy is interrupted for ≥14 days, other than for adverse reactions, resume therapy at 90 mg once daily for 7 days before ↑ to previously tolerated dose.

Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy. Advise to take brigatinib as directed. If patient vomits or misses a dose, omit dose and take next dose as scheduled. Do not double doses.
Advise patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care provider before taking any new medications, especially St. John's wort.
Advise patient to avoid eating grapefruit or drinking grapefruit juice during therapy.
Advise patient to notify health care provider if signs/symptoms of lung problems, hypertension (headaches, dizziness, blurred vision, chest pain, shortness of breath), bradycardia (dizziness, lightheadedness, feeling faint), visual changes, pancreatitis (upper abdominal pain, weight loss, nausea), myalgia (unexplained muscle pain, tenderness, or weakness), hepatotoxicity (fatigue, jaundice, upper right quadrant pain), or hyperglycemia (feeling very thirsty, needing to urinate more than usual, feeling very hungry, nausea, feeling weak or tired, feeling confused) occur, may require dose ↓ or discontinuation.
Advise patient to limit sun exposure while taking brigatinib, and for >5 days after stopping therapy. Wear a hat and protective clothing, and use a broad-spectrum Ultraviolet A/ Ultraviolet B sunscreen and lip balm (SPF ≥30) to help protect against sunburn. Sunburn may require interrupting or discontinuing therapy based on severity.
Rep: May cause fetal harm. Advise women of reproductive potential to use effective non-hormonal contraception during and for >4 mo after final dose. Advise men with female partners of reproductive potential to use effective contraception during and for >3 mo after last dose of brigatinib. Advise patient to avoid breastfeeding during and for 1 wk after last dose. Inform men that brigatinib may impair fertility.

Improved progression-free survival.

Alunbrig

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US Brand Names ⬆