ALUNBRIG belongs to a class of medications called tyrosine kinase inhibitors (TKIs). These drugs work by targeting specific proteins in cancer cells that drive their growth and spread. In the case of ALUNBRIG, it inhibits the activity of ALK, a protein that becomes overactive due to genetic changes in some lung cancer patients.

Indication and usage:

• ALUNBRIG is prescribed to treat metastatic non-small cell lung cancer (NSCLC) in patients who have anaplastic lymphoma kinase (ALK)-positive tumors and who have either progressed on or are intolerant to crizotinib.

• ALUNBRIG's indication has been approved under accelerated approval based on tumor response rate and duration of response.

• Verification and description of clinical benefit in a confirmatory trial will be necessary to ensure continued approval for this indication.

 

Dosage and Administration of ALUNBRIG

The proper administration and dosage of ALUNBRIG is crucial to ensure its effectiveness and safety. It is important for healthcare providers to carefully follow the recommended dosing guidelines when prescribing ALUNBRIG to patients with ALK-positive metastatic NSCLC.

Recommended Dosing:

The recommended dosing regimen for ALUNBRIG is as follows:

• 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.

Treatment Duration:

• ALUNBRIG should be administered until disease progression or unacceptable toxicity occurs.

• If treatment 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.

Administration:

• ALUNBRIG may be taken with or without food.

• It is recommended for patients to swallow tablets whole and not to crush or chew them.

Missed Dose:

• In the event of a missed dose or vomiting after taking a dose, patients should not take an additional dose of ALUNBRIG.

• Instead, they should take the next scheduled dose at the appropriate time.

 

Dose Modifications for Adverse Reactions to ALUNBRIG

Adverse reactions may occur in patients receiving ALUNBRIG, which can potentially compromise the effectiveness and safety of treatment.

Recommended Dose Reduction Levels:

The recommended dose reduction levels for ALUNBRIG in response to adverse reactions:

• The first dose reduction is from 90 mg once daily to 60 mg once daily.

• The second dose reduction is from 180 mg once daily to 120 mg once daily.

• The third dose reduction is from 120 mg once daily to 90 mg once daily, followed by a final reduction to 60 mg once daily if necessary.

Permanently Discontinue ALUNBRIG:

• If patients are unable to tolerate the 60 mg once daily dose, ALUNBRIG should be permanently discontinued.

• Once the dose of ALUNBRIG has been reduced due to adverse reactions, subsequent dose increases are not recommended.

Recommended ALUNBRIG Dose Modifications for Adverse Reactions

Interstitial Lung Disease (ILD)/Pneumonitis

• Grade 1

  • If new pulmonary symptoms occur during the first 7 days of treatment, withhold ALUNBRIG until recovery to baseline, then resume at the same dose and do not escalate to 180 mg if ILD/pneumonitis is suspected.

  • If new pulmonary symptoms occur after the first 7 days of treatment, withhold ALUNBRIG until recovery to baseline, then resume at the same dose.

  • If ILD/pneumonitis recurs, permanently discontinue ALUNBRIG.

• Grade 2

  • If new pulmonary symptoms occur during the first 7 days of treatment, withhold ALUNBRIG until recovery to baseline. Resume at the next lower dose (Table 1) and do not dose escalate if ILD/pneumonitis is suspected.

  • If new pulmonary symptoms occur after the first 7 days of treatment, withhold ALUNBRIG until recovery to baseline. If ILD/pneumonitis is suspected, resume at the next lower dose (Table 1); otherwise, resume at the same dose.

  • If ILD/pneumonitis recurs, permanently discontinue ALUNBRIG.

• Grade 3 or 4

  • Permanently discontinue ALUNBRIG for ILD/pneumonitis.

Hypertension

• Grade 3 hypertension (SBP ≥160 mmHg or DBP ≥100 mmHg, medical intervention indicated, more than one anti-hypertensive drug, or more intensive therapy than previously used indicated)

  • Withhold ALUNBRIG until hypertension has recovered to Grade 1 or less (SBP <140 mmHg and DBP <90 mmHg), then resume ALUNBRIG at the next lower dose (Table 1).

  • Recurrence: withhold ALUNBRIG until recovery to Grade 1 or less, and resume at the next lower dose (Table 1) or permanently discontinue treatment.

• Grade 4 hypertension (life-threatening consequences, urgent intervention indicated)

  • Withhold ALUNBRIG until recovery to Grade 1 or less, and resume at the next lower dose (Table 1) or permanently discontinue treatment.

  • Recurrence: permanently discontinue ALUNBRIG for recurrence of Grade 4 hypertension.

Bradycardia (HR <60 bpm)

• Symptomatic bradycardia

  • Withhold ALUNBRIG until recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above.

  • If a concomitant medication known to cause bradycardia is identified and discontinued or dose-adjusted, resume ALUNBRIG at the same dose upon recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above.

  • If no concomitant medication known to cause bradycardia is identified, or if contributing concomitant medications are not discontinued or dose-adjusted, resume ALUNBRIG at the next lower dose upon recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above.

• Symptomatic bradycardia with life-threatening consequences, urgent intervention indicated

  • Permanently discontinue ALUNBRIG if no contributing concomitant medication is identified

  • If contributing concomitant medication is identified and discontinued or dose-adjusted, resume ALUNBRIG at next lower dose (Table 1) upon recovery to asymptomatic bradycardia or resting heart rate of 60 bpm or above, with frequent monitoring as clinically indicated

  • Recurrence: permanently discontinue ALUNBRIG

Visual Disturbance

• Grade 2 or 3 visual disturbance:

  • withhold ALUNBRIG until recovery to Grade 1 or baseline, then resume at the next lower dose (Table 1)

• Grade 4 visual disturbance:

  • permanently discontinue ALUNBRIG

Creatine Phosphokinase (CPK) Elevation

• Grade 3

  • CPK elevation (greater than 5.0 × ULN) or equal to 2.5 × ULN) or to baseline, then resume ALUNBRIG at same dose

• Grade 4

  • CPK elevation (greater than 10.0 × ULN) or recurrence of Grade 3 elevation: withhold ALUNBRIG until recovery to Grade 1 or less (less than or equal to 2.5 × ULN) or to baseline, then resume ALUNBRIG at next lower dose (Table 1)

Lipase/Amylase Elevation

• Grade 3

  • lipase or amylase elevation (greater than 2.0 × ULN): withhold ALUNBRIG until recovery to Grade 1 or less (less than or equal to 1.5 × ULN) or to baseline, then resume ALUNBRIG at same dose

• Grade 4

  • lipase or amylase elevation (greater than 5.0 x ULN) or recurrence of Grade 3 elevation: withhold ALUNBRIG until recovery to Grade 1 or less (less than or equal to 1.5 × ULN) or to baseline, then resume ALUNBRIG at next lower dose (Table 1)

Hyperglycemia

• Grade 3 (greater than 250 mg/dL or 13.9 mmol/L) or greater:

  • if adequate hyperglycemic control cannot be achieved with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved and consider reduction to the next dose or permanently discontinue ALUNBRIG

Other

• Grade 3:

  • withhold ALUNBRIG until recovery to baseline, then resume at same dose

• Recurrence:

  • withhold ALUNBRIG until recovery to baseline, then resume at next lower dose or discontinue ALUNBRIG (Table 1)

• Grade 4:

  • First occurrence: either withhold ALUNBRIG until recovery to baseline

Dose Modification for Strong CYP3A Inhibitors

• Avoid taking strong CYP3A inhibitors while taking ALUNBRIG

• If you can't avoid it, your ALUNBRIG dose may need to be reduced by around 50%

• After stopping the strong CYP3A inhibitor, resume your previous ALUNBRIG dose.

 

Contraindication:

No contraindication is given in the FDA prescribing information.

Warning and precautions:

Interstitial Lung Disease (ILD)/Pneumonitis

• ALUNBRIG can lead to severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis.

• In the ALTA trial, 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).

• Respiratory symptoms (such as dyspnea, cough, etc.) may occur within the first week of initiating ALUNBRIG.

• If this happens, discontinue ALUNBRIG and immediately evaluate the patient for ILD/pneumonitis or other causes of respiratory symptoms.

• ALUNBRIG can be resumed with a dose reduction after recovery to baseline for Grade 1 or 2 ILD/pneumonitis.

• However, permanently discontinue ALUNBRIG for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis.

Hypertension

• ALUNBRIG can cause hypertension.

• In the ALTA trial, 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 before starting ALUNBRIG and monitor it at least monthly during treatment.

• If a patient experiences Grade 3 hypertension despite optimal antihypertensive therapy, withhold ALUNBRIG.

• 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.

Bradycardia

• Bradycardia (a heart rate less than 50 beats per minute) can occur with ALUNBRIG.

• In the ALTA trial, heart rates less than 50 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 they are also taking a drug known to cause bradycardia.

• If a patient experiences symptomatic bradycardia, withhold ALUNBRIG and review their medications for those known to cause bradycardia.

• If a 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 medication is identified.

Visual Disturbance

• Visual disturbance like blurred vision, diplopia, and reduced visual acuity were observed in 7.3% and 10% of patients in the 90 mg and 90→180 mg groups, respectively.

• Grade 3 macular edema and cataract were reported in one patient each in the 90→180 mg group.

• Patients should inform the doctor if they experience any visual symptoms.

• The doctor may stop ALUNBRIG and conduct an eye exam if the patient's visual symptoms worsen to Grade 2 or more.

• After the patient's Grade 2 or 3 visual disturbances improve to Grade 1 severity or baseline, ALUNBRIG can be resumed at a reduced dose.

• Treatment with ALUNBRIG should be permanently stopped if there are Grade 4 visual disturbances.

Creatine Phosphokinase (CPK) Elevation

• CPK elevation was observed in 27% and 48% of patients in the 90 mg and 90 mg→180 mg groups, respectively.

• 2.8% and 12% of patients in the 90 mg and 90→180 mg groups, respectively, had Grade 3-4 CPK elevation.

• Dose reduction for CPK elevation was necessary for 1.8% and 4.5% of patients in the 90 mg and 90→180 mg groups, respectively.

• Patients should inform the doctor if they experience any unexplained muscle pain, tenderness, or weakness.

• The doctor should monitor CPK levels during ALUNBRIG treatment.

• ALUNBRIG should be stopped if there is Grade 3 or 4 CPK elevation.

• After the patient's CPK levels improve to Grade 1 or baseline, ALUNBRIG can be resumed at the same dose or at a reduced dose.

Pancreatic Enzyme Elevation

• ALUNBRIG can also increase the levels of certain enzymes in the pancreas, such as amylase and lipase.

• This can cause abdominal pain, nausea, or vomiting.

• If the enzyme elevation is severe, ALUNBRIG may need to be stopped temporarily or permanently.

• Once the enzyme levels return to normal or improve, ALUNBRIG can be resumed at a lower dose.

Hyperglycemia

• Hyperglycemia is a condition where the blood sugar level is too high.

• ALUNBRIG can increase the risk of hyperglycemia in some patients, especially those with diabetes or glucose intolerance.

• Doctors should monitor the blood sugar level regularly and adjust the treatment as needed.

• Patients should inform their doctor if they experience symptoms of hyperglycemia, such as increased thirst, urination, or hunger.

Embryo-Fetal Toxicity

• ALUNBRIG can harm the developing fetus if taken during pregnancy.

• Pregnant women should not take ALUNBRIG unless there is no alternative treatment.

• Women of childbearing age should use effective birth control during treatment and for a few months after the last dose.

• Men with female partners should also use birth control during treatment and for a few months after the last dose.

Side Effects of Alunbrig:
Common Side Effects:

• Nausea

• Diarrhea

• Fatigue

• Cough

• Elevated liver enzymes

• Vomiting

• Decreased appetite

• Shortness of breath

• Upper respiratory tract infection

• Rash

• Constipation

• Headache

• Myalgia

• Dyspnea

Less Common Side Effects:

• Bradycardia

• Hypertension

• Increased amylase

• Edema

• Hyperglycemia

• Insomnia

• Abdominal pain

• Anemia

• Neutropenia

• Thrombocytopenia

• Hypoalbuminemia

• Increased lipase

• Renal impairment

• Dehydration

• Pancreatitis

• QT prolongation

• Hepatotoxicity

Severe Side Effects:

• Interstitial lung disease/pneumonitis

• Hepatotoxicity

• Bradycardia

• Hypertension

• QT prolongation

• Anaphylaxis

• Stevens-Johnson Syndrome

• Toxic Epidermal Necrolysis

• Neutropenic sepsis

• Aseptic meningitis syndrome

 

Drug Interactions with Alunbrig

Drugs That May Increase Brigatinib Plasma Concentrations:

• Strong CYP3A Inhibitors: drugs such as itraconazole, antivirals, macrolide antibiotics, antifungals, and conivaptan may increase brigatinib plasma concentrations. Avoid their concomitant use with ALUNBRIG, and if necessary, reduce the dose of ALUNBRIG by approximately 50%.

Drugs That May Decrease Brigatinib Plasma Concentrations:

• Strong CYP3A Inducers: drugs such as rifampin, carbamazepine, phenytoin, and St. John’s Wort may decrease brigatinib plasma concentrations. Avoid their concomitant use with ALUNBRIG.

Drugs That May Have Their Plasma Concentrations Altered by Brigatinib:

• CYP3A Substrates: brigatinib induces CYP3A in vitro and may decrease concentrations of CYP3A substrates such as hormonal contraceptives, which can result in decreased concentrations and loss of efficacy of CYP3A substrates.

Alunbrig: Use in Specific Populations

Pregnancy

• ALUNBRIG can cause fetal harm when administered to a pregnant woman.

• Animal studies have shown skeletal anomalies and decreased fetal weight.

• Advise pregnant women of the potential risk to the fetus.

• Estimated background risk of major birth defects and miscarriage is 2% to 4% and 15% to 20%, respectively, in the general population.

Lactation

• There is no data on the secretion of brigatinib in human milk or its effects on the breastfed infant.

• Due to the potential for adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with ALUNBRIG and for 1 week following the final dose.

Females and Males of Reproductive Potential

Contraception

• ALUNBRIG can cause fetal harm, so effective contraception is advised.

• Females should use non-hormonal contraception during treatment and for at least 4 months after the final dose.

• Males with female partners of reproductive potential should use effective contraception during treatment and for at least 3 months after the final dose.

Infertility

• ALUNBRIG may cause reduced fertility in males based on animal studies.

Pediatric Use

• The safety and efficacy of ALUNBRIG have not been established in pediatric patients.

Geriatric Use

• Clinical studies did not include enough patients aged 65 years and older to determine if they respond differently from younger patients.

• No significant differences in safety or efficacy were seen between patients aged 65 years and older and younger patients.

Hepatic Impairment

• Patients with mild hepatic impairment do not require a dose adjustment.

• The pharmacokinetics and safety of ALUNBRIG in patients with moderate or severe hepatic impairment have not been studied.

Renal Impairment

• Patients with mild and moderate renal impairment do not require a dose adjustment.

• The pharmacokinetics and safety of ALUNBRIG in patients with severe renal impairment have not been studied.

 

Alunbrig Mechanism of Action:

• Brigatinib is a type of medication known as a tyrosine kinase inhibitor.

• It can target several different kinases, including ALK, ROS1, IGF-1R, FLT-3, and EGFR.

• Brigatinib can prevent the autophosphorylation of ALK and inhibit signaling proteins downstream from ALK.

• In lab studies, brigatinib has been shown to inhibit the growth of cells expressing EML4-ALK and NPM-ALK fusion proteins.

• It has also been shown to inhibit the growth of tumors with mutations associated with resistance to other ALK inhibitors.

Pharmacodynamics

• It is currently unknown how brigatinib's effects relate to its exposure and over what period of time the medication's effects will be seen.

Cardiac Electrophysiology

• ALUNBRIG has been tested in 123 patients for its effect on the QT interval.

• Results showed that ALUNBRIG did not cause a significant prolongation of the QT interval, which is an important measurement of heart function.

Pharmacokinetics of Brigatinib

Steady-State Concentration:

• Cmax at 90mg dose: 552 ng/mL, 180mg dose: 1452 ng/mL

• AUC0-Tau at 90mg dose: 8165 ng·h/mL, 180mg dose: 20276 ng·h/mL

Absorption:

• Median Tmax: 1-4 hours

• ALUNBRIG doses of 30 to 240 mg

Effect of Food:

• 13% reduction in Cmax with high-fat meal

• No effect on AUC

• Healthy subjects

Distribution:

• 66% bound to plasma proteins

• Blood-to-plasma concentration ratio: 0.69

• Mean Vz/F at steady-state: 153 L

Elimination:

• Mean CL/F at steady-state: 12.7 L/h

• Mean plasma elimination half-life: 25 hours

Metabolism:

• CYP2C8 and CYP3A4 in vitro

• N-demethylation and cysteine conjugation

• Unchanged brigatinib and metabolite AP26123 major circulating radioactive components

Excretion:

• 65% recovered in feces

• 25% recovered in urine

• 41% and 86% of total radioactivity in feces and urine respectively

Nonclinical Toxicology

Carcinogenesis

• No studies have been conducted to evaluate the carcinogenic potential of brigatinib.

Mutagenesis

• Brigatinib did not show any mutagenic activity in the Ames or in vitro mammalian chromosome aberration tests.

• However, it did result in chromosomal damage in an in vivo mammalian erythrocyte micronucleus test in rats.

Impairment of Fertility

• Brigatinib was not tested for its effect on animal fertility.

• In repeat-dose animal studies, testicular toxicity was observed in rats and monkeys.

• The effects in rats included lower weight of testes, seminal vesicles and prostate gland, and testicular tubular degeneration, which were not reversible.

• In monkeys, reduced size of testes along with microscopic evidence of hypo spermatogenesis were observed, but these effects were reversible during the recovery period.

How supplied/storage and handling

Brigatinib is available in two different strengths, 30 mg and 90 mg, and comes in the following packaging:

• 30 mg tablets: round, white to off-white film-coated tablet with “U3” debossed on one side and plain on the other side. It is available in bottles of 21 tablets (NDC 76189-113-21) and 180 tablets (NDC 76189-113-18).

• 90 mg tablets: oval, white to off-white film-coated tablet with “U7” debossed on one side and plain on the other side. It is available in bottles of 7 tablets (NDC 76189-119-07) and 30 tablets (NDC 76189-119-30).

Brigatinib should be stored at controlled room temperature between 20°C to 25°C (68°F to 77°F), with an excursion permitted between 15°C to 30°C (59°F to 86°F), as per the USP guidelines.

 

Patient Counseling Information for ALUNBRIG

• Advise the patient to read the FDA-approved patient labeling (Patient Information).

Interstitial Lung Disease (ILD)/Pneumonitis

• Inform patients of the symptoms and risks of serious pulmonary adverse reactions such as ILD/pneumonitis.

• Advise patients to immediately report any new or worsening respiratory symptoms.

Hypertension

• Advise patients of risks of hypertension.

• Promptly report signs or symptoms of hypertension.

Bradycardia

• Advise patients to report any symptoms of bradycardia.

• Inform healthcare provider about the use of heart and blood pressure medications.

Visual Disturbance

• Advise patients to inform their healthcare provider of any new or worsening vision symptoms.

Creatine Phosphokinase (CPK) Elevation

• Inform patients of the signs and symptoms of creatinine phosphokinase (CPK) elevation and the need for monitoring during treatment.

• Advise patients to inform their healthcare provider of any new or worsening symptoms of unexplained muscle pain, tenderness, or weakness.

Pancreatic Enzyme Elevation

• Inform patients of the signs and symptoms of pancreatitis.

• Monitor for amylase and lipase elevations during treatment.

Hyperglycemia

• Inform patients of the risks of new or worsening hyperglycemia.

• Periodically monitor glucose levels.

• Advise patients with diabetes mellitus or glucose intolerance that anti-hyperglycemic medications may need to be adjusted during treatment with ALUNBRIG.

Females and Males of Reproductive Potential Embryo-Fetal Toxicity

• Advise females and males of reproductive potential that ALUNBRIG can cause fetal harm.

• Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy and to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months after the final dose.

• Advise males with female partners of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 3 months after the final dose.

Lactation

• Advise females not to breastfeed during treatment with ALUNBRIG and for at least 1 week following the final dose.

Infertility

• Advise males of reproductive potential of the potential for reduced fertility from ALUNBRIG.

Drug Interactions

• Advise patients to inform their health care provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.

• Inform patients to avoid grapefruit or grapefruit juice while taking ALUNBRIG.

Dosing and Administration

• Instruct patients to start with 90 mg of ALUNBRIG once daily for the first 7 days and if tolerated, increase the dose to 180 mg once daily.

• Advise patients to take ALUNBRIG with or without food.

Missed Dose

• Advise patients that if a dose of ALUNBRIG is missed or if the patient vomits after taking a dose of ALUNBRIG, not to take an extra dose, but to take the next dose at the regular time.