Brigatinib

Brigatinib comes as a tablet to take by mouth. It is usually taken with or without food once daily. Take brigatinib at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take brigatinib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the tablets whole; do not chew or crush them.

If you vomit after taking brigatinib, do not take another dose. Continue your regular dosing schedule.

Your doctor may start you on a low dose of brigatinib and increase your dose once after 7 days of treatment.

Your doctor may need to temporarily or permanently stop your treatment or decrease your dose of brigatinib or other medications that you are taking, depending on the side effects that you experience during your treatment. Talk to your doctor about how you are feeling during your treatment. Do not stop taking brigatinib without talking to your doctor.

Ask your pharmacist or doctor for a copy of the manufacturer's information for the patient.

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Contraindications

None.1

Warnings/Precautions

Interstitial Lung Disease (ILD)/Pneumonitis

Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with brigatinib.1

In Trial ALTA (ALTA), ILD/pneumonitis occurred in 3.7% of patients in the 90 mg group (90 mg once daily) and 9.1% of patients in the 90→180 mg group (180 mg once daily with 7-day lead-in at 90 mg once daily).1

Adverse reactions consistent with possible ILD/pneumonitis occurred early (within 9 days of initiation of brigatinib; median onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in 2.7%.1

Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.), particularly during the first week of initiating brigatinib. Withhold brigatinib in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either resume brigatinib with dose reduction after recovery to baseline or permanently discontinue brigatinib. Permanently discontinue brigatinib for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis.1

Hypertension

In ALTA, hypertension was reported in 11% of patients in the 90 mg group who received brigatinib and 21% of patients in the 90→180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall.1

Control blood pressure prior to treatment with brigatinib. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with brigatinib. Withhold brigatinib for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1 severity, resume brigatinib at a reduced dose. Consider permanent discontinuation of treatment with brigatinib for Grade 4 hypertension or recurrence of Grade 3 hypertension.1

Use caution when administering brigatinib in combination with antihypertensive agents that cause bradycardia.1

Bradycardia

Bradycardia can occur with brigatinib. In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the 90→180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group.1

Monitor heart rate and blood pressure during treatment with brigatinib. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided.1

For symptomatic bradycardia, withhold brigatinib and review concomitant medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume brigatinib at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of brigatinib following resolution of symptomatic bradycardia. Discontinue brigatinib for life-threatening bradycardia if no contributing concomitant medication is identified.1

Visual Disturbance

In ALTA, adverse reactions leading to visual disturbance including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients receiving brigatinib in the 90 mg group and 10% of patients in the 90→180 mg group. Grade 3 macular edema and cataract occurred in one patient each in the 90→180 mg group.1

Advise patients to report any visual symptoms. Withhold brigatinib and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade 1 severity or baseline, resume brigatinib at a reduced dose. Permanently discontinue treatment with brigatinib for Grade 4 visual disturbances.1

Creatine Phosphokinase (CPK) Elevation

In ALTA, creatine phosphokinase (CPK) elevation occurred in 27% of patients receiving brigatinib in the 90 mg group and 48% of patients in the 90 mg→180 mg group. The incidence of Grade 3-4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90→180 mg group.1

Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% in the 90→180 mg group.1

Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during brigatinib treatment. Withhold brigatinib for Grade 3 or 4 CPK elevation. Upon resolution or recovery to Grade 1 or baseline, resume brigatinib at the same dose or at a reduced dose.1

Pancreatic Enzyme Elevation

In ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39% of patients in the 90→180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90→180 mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7% of patients in the 90→180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients in the 90→180 mg group.1

Monitor lipase and amylase during treatment with brigatinib. Withhold brigatinib for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume brigatinib at the same dose or at a reduced dose. 1

Hyperglycemia

In ALTA, 43% of patients who received brigatinib experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or glucose intolerance at baseline required initiation of insulin while receiving brigatinib.1

Assess fasting serum glucose prior to initiation of brigatinib and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold brigatinib until adequate hyperglycemic control is achieved and consider reducing the dose of brigatinib or permanently discontinuing brigatinib.1

Embryo-fetal Toxicity

Based on its mechanism of action and findings in animals, brigatinib can cause fetal harm when administered to pregnant women. There are no clinical data on the use of brigatinib in pregnant women. Administration of brigatinib to pregnant rats during the period of organogenesis resulted in dose-related skeletal anomalies at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily) as well as increased post implantation loss, malformations, and decreased fetal body weight at doses of 25 mg/kg/day (approximately 1.26 times the human exposure at 180 mg once daily) or higher.1

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of brigatinib.1

Specific Populations

Based on its mechanism of action and findings in animals, brigatinib can cause fetal harm when administered to a pregnant woman. There are no clinical data on the use of brigatinib in pregnant women. Administration of brigatinib to pregnant rats during the period of organogenesis resulted in dose-related skeletal anomalies at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily) as well as increased post-implantation loss, malformations, and decreased fetal body weight at doses of 25 mg/kg/day (approximately 1.26 times the human exposure at 180 mg once daily) or greater. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.1

In an embryo-fetal development study in which pregnant rats were administered daily doses of brigatinib during organogenesis, dose-related skeletal (incomplete ossification, small incisors) and visceral anomalies were observed at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily). Malformations observed at 25 mg/kg/day (approximately 1.26 times the human AUC at 180 mg once daily) included anasarca (generalized subcutaneous edema), anophthalmia (absent eyes), forelimb hyperflexion, small, short and/or bent limbs, multiple fused ribs, bent scapulae, omphalocele (intestine protruding into umbilicus), and gastroschisis (intestines protruding through a defect in the abdominal wall) along with visceral findings of moderate bilateral dilatation of the lateral ventricles.1

There are no data regarding the secretion of brigatinib in human milk or its effects on the breastfed infant or milk production. Because of the potential for adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with brigatinib and for 1 week following the final dose.1

Brigatinib can cause fetal harm.1

Advise females of reproductive potential to use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months after the final dose. Counsel patients to use a non-hormonal method of contraception since brigatinib can render some hormonal contraceptives ineffective.1

Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with brigatinib and for at least 3 months after the final dose.1

Based on findings in male reproductive organs in animals, brigatinib may cause reduced fertility in males.1

The safety and efficacy of brigatinib in pediatric patients have not been established.1

Clinical studies of brigatinib did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 222 patients in ALTA, 19.4% were 65-74 years and 4.1% were 75 years or older. No clinically relevant differences in safety or efficacy were observed between patients ≥65 years and younger patients.1

No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin within upper limit of normal [ULN] and AST greater than ULN or total bilirubin greater than 1 and up to 1.5 times ULN and any AST). The pharmacokinetics and safety of brigatinib in patients with moderate or severe hepatic impairment have not been studied.1

No dose adjustment is recommended for patients with mild and moderate renal impairment [creatinine clearance (CLcr 30 to 89 mL/min estimated by Cockcroft-Gault)]. The pharmacokinetics and safety of brigatinib in patients with severe renal impairment (CLcr 15 to 29 mL/min estimated by Cockcroft-Gault) have not been studied.1

Common Adverse Effects

The most common adverse reactions (≥25%) with brigatinib were nausea, diarrhea, fatigue, cough, and headache.1

Brigatinib is used to treat metastatic (cancer that has already spread) non-small cell lung cancer in patients who have certain types of abnormal anaplastic lymphoma kinase (ALK) gene. It is used in patients who have already received crizotinib, but their condition got worse or the medicine has stopped working. Brigatinib is an antineoplastic (cancer) agent. It interferes with the growth of cancer cells, which are eventually destroyed by the body.

brigatinib is available only with your doctor's prescription.

Take brigatinib exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

brigatinib should come with a patient information insert. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Swallow the tablet whole. Do not crush, break, or chew it. You may take brigatinib with or without food.

Do not use grapefruit products while you are using brigatinib. Grapefruit and grapefruit juice may change the amount of medicine that is absorbed in the body.

Dosing

The dose of brigatinib will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of brigatinib. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For non-small cell lung cancer:
    • Adults—At first, 90 milligrams (mg) once a day for the first 7 days. Your doctor may adjust your dose if needed. However, the dose is usually not more than 180 mg once a day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of brigatinib, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you vomit after taking your medicine, call your doctor or pharmacist for instructions.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Abdominal or stomach pain or tenderness
• back pain
• blurred vision
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chest pain or tightness
• chills
• confusion
• cough
• decreased appetite
• difficulty in moving
• dizziness
• fever
• flushed, dry skin
• headache
• increased hunger
• increased thirst
• increased urination
• joint pain
• loss of appetite
• muscle pain, tenderness, or weakness
• nausea and vomiting
• nervousness
• pain in the arms or legs
• pounding in the ears
• skin rash or itching
• slow or fast heartbeat
• sneezing
• sore throat
• swollen joints
• thickening of bronchial secretions
• trouble breathing
• unusual tiredness or weakness
• weakness in the arms, hands, legs, or feet

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Blurred vision or changes in vision
• decreased appetite
• diarrhea
• difficulty having a bowel movement (stool)
• trouble sleeping

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• Swallow whole. Do not chew, break, or crush.
• To gain the most benefit, do not miss doses.
• Keep taking brigatinib as you have been told by your doctor or other health care provider, even if you feel well.
• If you throw up after taking a dose, do not repeat the dose. Take your next dose at your normal time.

What do I do if I miss a dose?

• Skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

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).

>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%)

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.

• 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.

Data not available.

Administration Advice:
-Swallow tablets whole; do not crush or chew them.
-Administer with or without food.
-In the event of a missed or vomited dose, skip that dose and administer the next dose at the regular scheduled time.

Storage Requirements:
-Store at 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit); excursions are permitted between 15 to 30 degrees Celsius (59 to 86 degrees Fahrenheit).

General:
-This drug received accelerated FDA approval based on tumor response rate and duration; continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Monitoring:
-Cardiovascular: Blood pressure (at 2 weeks, then at least monthly), heart rate (during treatment)
-Endocrine: Fasting serum glucose (prior to treatment initiation, then periodically thereafter)
-Gastrointestinal: Amylase and lipase (during treatment)
-Musculoskeletal: Creatine phosphokinase levels (during treatment)
-Respiratory: New or worsening respiratory symptoms (during treatment, particularly during the first week)

Patient Advice:
-This drug may cause side effects such as double vision; avoid potentially dangerous activities such as driving and operating machinery until you know how this drug affects you.
-Avoid grapefruit and grapefruit juice while taking this drug.