Alunbrig

Brigatinib may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• nausea
• diarrhea
• vomiting
• constipation
• tiredness
• rash
• headache
• numbness, pain, tingling, or burning feeling in the feet or hands
• back or joint pain
• loss of appetite
• difficulty falling asleep or staying asleep

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately or get emergency medical treatment:

• shortness of breath or difficulty breathing
• chest pain
• cough with or without mucus
• fever
• headache, dizziness, lightheadedness, or feeling faint
• blurred or double vision
• seeing flashes of light
• light hurting your eyes
• seeing ''floaters'' or small specks
• extreme thirst, frequent urination, extreme hunger, blurred vision, or weakness
• upper stomach pain that may spread to the back or get worse with eating; weight loss; or nausea
• slow or irregular heartbeat
• muscle pain, spasms, tenderness, or weakness

Brigatinib may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Brigatinib is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Brigatinib is used to treat non-small cell lung cancer that has spread to other parts of the body.

Brigatinib is for cancer that has a certain abnormal gene, and when treatment with other cancer medicine has not been successful.

Brigatinib may also be used for purposes not listed in this medication guide.

Follow all directions on your prescription label. Your doctor may occasionally change your dose. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Brigatinib is usually taken once per day, with or without food.

Do not crush, chew, or break a brigatinib tablet. Swallow it whole.

If you vomit shortly after taking brigatinib, do not take another dose. Stay on your regular schedule.

You should not stop using brigatinib unless your doctor tells you to.

Store at room temperature away from moisture and heat.

Sometimes it is not safe to use certain medications at the same time. Some drugs can affect your blood levels of other drugs you take, which may increase side effects or make the medications less effective.

Many drugs can interact with brigatinib. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide. Tell your doctor about all your current medicines and any medicine you start or stop using.

Brigatinib has the following uses:

Brigatinib is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.1

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.1

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• CYP3A Inhibitors: Avoid concomitant use of brigatinib with strong CYP3A inhibitors. If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the dose of brigatinib.1

• CYP3A Inducers: Avoid concomitant use of brigatinib with strong CYP3A inducers.1

• CYP3A Substrates: Hormonal contraceptives may be ineffective due to decreased exposure.1

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly. Blood tests may be needed to check for unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. It may also cause birth defects if the father is using it when his sexual partner becomes pregnant. Female patients should use effective birth control during treatment and for at least 4 months after the last dose. Male patients who have female partners should use effective birth control during treatment and for at least 3 months after the last dose. If you think you or your partner becomes pregnant while using the medicine, tell your doctor right away.

This medicine may cause swelling of the lungs (pneumonitis) or interstitial lung disease. These are life-threatening conditions and require immediate medical attention. The symptoms may be similar to the symptoms from lung cancer. Check with your doctor right away if you have new or worsening cough, fever, or trouble breathing.

Contact your doctor right away if you have any changes to your heart rhythm. You might feel dizzy or faint, or you might have a slow, fast, pounding, or uneven heartbeat.

Check with your doctor right away if you have any changes to your eyes, such as eye pain or redness, or vision changes while you are using this medicine. Your doctor may want you to have your eyes checked by an eye doctor.

This medicine may cause muscle damage. Check with your doctor right away if you have muscle pain, tenderness, and weakness.

Check with your doctor right away if you have loss of appetite, nausea, or pains in stomach, side, or abdomen, possibly radiating to the back. These could be symptoms of pancreatitis (swelling of the pancreas).

This medicine may increase your blood sugar levels. Check with your doctor right away if you have the following symptoms: confusion, nausea or vomiting, increased hunger, thirst or urination, or unusual tiredness or weakness.

If you plan to have children, talk with your doctor before using this medicine. Some men and women using this medicine have become infertile (unable to have children).

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (eg, St. John's wort) or vitamin supplements.

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.

Recommended Dosing

The recommended dosing regimen for Alunbrig is:

• 90 mg orally once daily for the first 7 days;
• if 90 mg is tolerated during the first 7 days, increase the dose to 180 mg orally once daily.

Administer Alunbrig until disease progression or unacceptable toxicity.

If Alunbrig is interrupted for 14 days or longer for reasons other than adverse reactions, resume treatment at 90 mg once daily for 7 days before increasing to the previously tolerated dose.

Alunbrig may be taken with or without food. Instruct patients to swallow tablets whole. Do not crush or chew tablets.

If a dose of Alunbrig is missed or vomiting occurs after taking a dose, do not administer an additional dose and take the next dose of Alunbrig at the scheduled time.

Dose Modifications for Adverse Reactions

Alunbrig dose modification levels are summarized in Table 1.

Once reduced for adverse reactions, do not subsequently increase the dose of Alunbrig. Permanently discontinue Alunbrig if patients are unable to tolerate the 60 mg once daily dose.

Recommendations for dose modifications of Alunbrig for the management of adverse reactions are provided in Table 2.

Dose Modification for Strong CYP3A Inhibitors

Avoid concomitant use of strong CYP3A inhibitors during treatment with Alunbrig [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. If concomitant use of a strong CYP3A inhibitor cannot be avoided, reduce the Alunbrig once daily dose by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg). After discontinuation of a strong CYP3A inhibitor, resume the Alunbrig dose that was tolerated prior to initiating the strong CYP3A inhibitor.

None.

Interstitial Lung Disease (ILD)/Pneumonitis

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

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).

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

Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.), particularly during the first week of initiating Alunbrig. Withhold Alunbrig 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 Alunbrig with dose reduction according to Table 1 after recovery to baseline or permanently discontinue Alunbrig. Permanently discontinue Alunbrig for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Hypertension

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

Control blood pressure prior to treatment with Alunbrig. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with Alunbrig. Withhold Alunbrig for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1 severity, resume Alunbrig at a reduced dose. Consider permanent discontinuation of treatment with Alunbrig for Grade 4 hypertension or recurrence of Grade 3 hypertension [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Use caution when administering Alunbrig in combination with antihypertensive agents that cause bradycardia [see Warnings and Precautions (5.3)].

Bradycardia

Bradycardia can occur with Alunbrig. 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.

Monitor heart rate and blood pressure during treatment with Alunbrig. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided [see Warnings and Precautions (5.2)].

For symptomatic bradycardia, withhold Alunbrig 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 Alunbrig at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of Alunbrig following resolution of symptomatic bradycardia. Discontinue Alunbrig for life-threatening bradycardia if no contributing concomitant medication is identified [see Dosage and Administration (2.2)].

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 Alunbrig 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.

Advise patients to report any visual symptoms. Withhold Alunbrig 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 Alunbrig at a reduced dose. Permanently discontinue treatment with Alunbrig for Grade 4 visual disturbances [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Creatine Phosphokinase (CPK) Elevation

In ALTA, creatine phosphokinase (CPK) elevation occurred in 27% of patients receiving Alunbrig 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.

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.

Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during Alunbrig treatment. Withhold Alunbrig for Grade 3 or 4 CPK elevation. Upon resolution or recovery to Grade 1 or baseline, resume Alunbrig at the same dose or at a reduced dose as described in Table 2 [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

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.

Monitor lipase and amylase during treatment with Alunbrig. Withhold Alunbrig for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume Alunbrig at the same dose or at a reduced dose as described in Table 2 [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Hyperglycemia

In ALTA, 43% of patients who received Alunbrig 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 Alunbrig.

Assess fasting serum glucose prior to initiation of Alunbrig and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold Alunbrig until adequate hyperglycemic control is achieved and consider reducing the dose of Alunbrig as described in Table 1 or permanently discontinuing Alunbrig [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Embryo-Fetal Toxicity

Based on its mechanism of action and findings in animals, Alunbrig can cause fetal harm when administered to pregnant women. There are no clinical data on the use of Alunbrig 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.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with Alunbrig 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 Alunbrig [see Use in Specific Populations (8.1 and 8.3) and Clinical Pharmacology (12.1)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with brigatinib.

Treatment with brigatinib resulted in chromosomal damage in an in vivo mammalian erythrocyte micronucleus in the rat, but was not mutagenic in the Ames or in vitro mammalian chromosome aberration tests.

Dedicated animal fertility studies were not conducted with brigatinib. Testicular toxicity was observed in repeat-dose animal studies at doses resulting in exposure as low as 0.2 times the exposure in patients at the 180 mg dose. In rats, findings included lower weight of testes, seminal vesicles and prostate gland, and testicular tubular degeneration; these effects were not reversible during the 2-month recovery period. In monkeys, findings included reduced size of testes along with microscopic evidence of hypospermatogenesis; these effects were reversible during the recovery period.

Common side effects of Alunbrig include: asthenia, blurred vision, cough, decreased visual acuity, diplopia, dyspnea, hyperglycemia, hypertension, increased amylase, increased creatine phosphokinase, increased serum lipase, myalgia, and visual disturbance. Other side effects include: interstitial pulmonary disease, pneumonitis, and bradycardia. See below for a comprehensive list of adverse effects.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of high blood pressure like very bad headache or dizziness, passing out, or change in eyesight.
• Signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
• Signs of a pancreas problem (pancreatitis) like very bad stomach pain, very bad back pain, or very bad upset stomach or throwing up.
• Slow heartbeat.
• Chest pain.
• Change in eyesight.
• Seeing double.
• If bright lights bother your eyes.
• Muscle pain or weakness.
• Muscle spasm.
• Fever.
• A burning, numbness, or tingling feeling that is not normal.
• Feeling very tired or weak.
• Very bad and sometimes deadly lung problems have happened with this drug. Call your doctor right away if you have lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse.