Consumer medicine information

Alunbrig

Brigatinib

BRAND INFORMATION

Brand name

Alunbrig

Active ingredient

Brigatinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Alunbrig.

What is in this leaflet

This leaflet answers some common questions about Alunbrig.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available. You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on this medicine. You can also download the most up to date leaflet from https://www.ebs.tga.gov.au.

Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Alunbrig is used for

Alunbrig contains the active ingredient brigatinib.

Alunbrig belongs to a group of medicines called anti-neoplastic (or anti-cancer) agents which are used to treat cancer.

Alunbrig is used to treat adults with a type of lung cancer called non-small cell lung cancer. It is used if your cancer:

  • is ALK-positive – this means your cancer cells have a fault in a gene called anaplastic lymphoma kinase (ALK)
  • is advanced or has spread to another part of your body (metastatic)
  • has previously been treated with a medicine called crizotinib, which is causing too many side effects or has stopped working.

Alunbrig prevents the activity of the ALK protein. This protein is known to be involved in the growth and spread of cancer cells.

Alunbrig may slow down or stop the growth of your cancer. It may also help to shrink your cancer.

Ask your doctor if you have any questions about why it has been prescribed for you. Your doctor may have prescribed it for another purpose.

This medicine is not addictive.

This is available only with a doctor's prescription.

Before you take Alunbrig

When you must not take it

Do not take Alunbrig if you have an allergy to:

  • any medicine containing brigatinib
  • any of the ingredients listed at the end of this leaflet

Some symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body.

Do not take this medicine if you are pregnant. It may affect your developing baby if you take it during pregnancy.

Do not breastfeed if you are taking this medicine.

Do not give Alunbrig to children under the age of 18 years. Safety and effectiveness in children have not been established.

Do not take it after the expiry date printed on the pack or if the packaging is damaged or shows signs of tampering. If it has expired or is damaged return it to your pharmacist for disposal.

Before you start to take it

Tell your doctor if you have any allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • lung or breathing problems
  • high blood pressure
  • a slow heartbeat
  • problems with your vision
  • sore or painful muscles
  • problems with your pancreas
  • high blood sugar

Tell your doctor if you are pregnant or intend to become pregnant. Alunbrig may be harmful to an unborn baby when taken by a pregnant woman. You should not take Alunbrig while you are pregnant.

If you are a woman who could become pregnant, use highly effective contraception (birth control) during treatment, and for at least 4 months after taking the last tablet.

If you are the partner of a woman who could become pregnant, use highly effective contraception during treatment, and for at least 3 months after taking the last tablet.

Talk to your doctor about the right methods of contraception for you and your partner.

Tell your doctor if you are breastfeeding or plan to breastfeed. It is not known whether brigatinib passes into breast milk. It is not recommended that you breastfeed while taking Alunbrig.

If you have not told your doctor about any of the above, tell them before you take Alunbrig.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food store.

Some medicines and Alunbrig may interfere with each other. These include:

  • ketoconazole, itraconazole, voriconazole: medicines to treat fungal infections
  • indinavir, nelfinavir, ritonavir, saquinavir: medicines to treat HIV infection
  • clarithromycin, telithromycin, troleandomycin: medicines to treat bacterial infections
  • St. John's wort: a herbal product used to treat depression
  • carbamazepine: a medicine to treat epilepsy, euphoric/ depressive episodes and certain pain conditions
  • phenobarbital, phenytoin: medicines to treat epilepsy
  • rifabutin, rifampicin: medicines to treat tuberculosis or certain other infections
  • digoxin: a medicine to treat heart weakness
  • dabigatran: a medicine to inhibit blood clotting
  • colchicine: a medicine to treat gout attacks
  • pravastatin, rosuvastatin: medicines to lower elevated cholesterol levels
  • methotrexate: a medicine to treat severe joint inflammation, cancer and the skin disease psoriasis
  • sulfasalazine: a medicine to treat severe bowel and rheumatic joint inflammation
  • efavirenz, etravirine: medicines to treat HIV infection
  • modafinil: a medicine to treat narcolepsy
  • bosentan: a medicine to treat pulmonary hypertension

These medicines may be affected by Alunbrig, or may affect how well it works. You may need to use different amounts of your medicine, or take different medicines.

Your doctor or pharmacist has more information on medicines to be careful with or to avoid while taking Alunbrig.

How to take Alunbrig

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how many tablets you need to take each day. This may depend on your condition, whether you are taking any other medicines and whether you experience side effects.

The usual dose of Alunbrig is one 90 mg tablet once daily for the first 7 treatment days; thereafter, one 180 mg tablet once daily.

How to take it

Swallow the tablets whole with a full glass of water. Do not crush or dissolve the tablets.

Alunbrig tablets can be taken with or without food.

When to take it

Take Alunbrig once a day at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it

The duration of treatment with Alunbrig varies, depending on the nature of your illness and your individual response to treatment.

Continue taking Alunbrig until your doctor tells you to stop.

If you forget to take it

If you forget to take a dose, or if you vomit after taking a dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of getting an unwanted side effect.

If you are not sure what to do, ask your doctor.

If you have trouble remembering when to take your medicine, ask your pharmacist for hints.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone Australia 13 11 26), or go to Accident and Emergency at your nearest hospital, if you think you or anyone else may have taken too much Alunbrig. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you are not sure what to do, ask your doctor.

While you are taking Alunbrig

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Alunbrig.

Tell any other doctors, dentists and pharmacists who treat you that you are taking Alunbrig.

Use highly effective contraception to prevent pregnancy while you are being treated with Alunbrig. Women must avoid pregnancy during treatment with Alunbrig and for at least 4 months after taking the last dose. Men must avoid fathering a child during treatment with Alunbrig and for at least 3 months after taking the last dose.

If you are going to have surgery, tell the surgeon that you are taking this medicine.

If you or your partner becomes pregnant while taking Alunbrig, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor will do blood tests and other tests from time to time to monitor your progress and check for side effects. If necessary, your doctor may decide to reduce your dose, temporarily interrupt your treatment or stop it altogether.

Things you must not do

Do not use this medicine to treat any other complaints unless your doctor tells you to.

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not stop taking Alunbrig, or lower the dosage, without checking with your doctor first.

Things to be careful of

Be careful driving or operating machinery until you know how Alunbrig affects you. Alunbrig may cause visual disturbances, dizziness or tiredness. Do not drive or use machines during treatment if such signs occur.

Avoid any grapefruit products during treatment as they may change the amount of Alunbrig in your body.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Alunbrig.

It helps most people with non-small cell lung cancer, but it may have unwanted side effects in a few people. All medicines have some unwanted side effects. Sometimes they are serious, but most of the time they are not. You may need medical attention if you get some of the side-effects.

Taking Alunbrig may cause serious lung related side-effects in some people, particularly within the first week.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • lung or breathing problems including shortness of breath or difficulty breathing, cough and/or fever, especially within the first week of taking Alunbrig
  • slow heart beat (bradycardia) – symptoms can include chest pain, dizziness, light headedness or fainting – or palpitations
  • new or worsening signs and symptoms of muscle problems, including unexplained muscle pain that does not go away, tenderness or weakness

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor as soon as possible if you notice any of the following:

  • tiredness, headaches, being short of breath when exercising, dizziness and looking pale
  • passing large amounts of urine, excessive thirst and having a dry mouth
  • difficulty sleeping
  • numbness or weakness of the arms and legs
  • change in sense of taste
  • problems with your eyes such as blurred or impaired vision, black dots or white spots in your vision, double vision
  • high blood pressure
  • abdominal pain, nausea and/or vomiting
  • diarrhoea or constipation
  • rash and/or itching
  • pain and swelling of the joints
  • swelling throughout the body
  • fever
  • decrease in appetite or weight loss

The above list includes the more common side effects of your medicine, some of which may require medical attention.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may occur in some people.

Some of these side effects can only be found when your doctor does tests. These tests could show a change in the liver, kidneys, levels of blood cells or changes in heart rate or blood pressure.

After using Alunbrig

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the package they may not keep well.

Keep the medicine in a cool, dry place where the temperature stays below 30°C.

Do not store it or any other medicine in the bathroom, near a sink, or on a windowsill. Do not leave it in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor or pharmacist tells you to stop taking this medicine, or the medicine has passed its expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

Alunbrig 30 mg – white to off-white, round tablet, marked with a "U3" on one side.

Alunbrig 90 mg – white to off-white, oval tablet, marked with a "U7" on one side.

Alunbrig 180 mg – white to off-white, oval tablet, marked with a "U13" on one side.

The 30 mg, 90 mg and 180 mg strengths of Alunbrig are available in boxes of 28 tablets.

The one-month initiation pack contains 1 pack of 7 x 90 mg tablets and 21 x 180 mg tablets.

Ingredients

Alunbrig contains 30, 90 or 180 mg of brigatinib as the active ingredient:

It also contains

  • lactose monohydrate
  • microcrystalline cellulose
  • sodium starch glycollate type A
  • hydrophobic colloidal silica anhydrous
  • magnesium stearate
  • OPADRY II White (PI 11376)

Supplier

Alunbrig is supplied in Australia by:

Takeda Pharmaceuticals
Australia Pty Ltd
Level 52 Chifley Square
Sydney NSW 2000
Ph: 1800 675 957

® Registered Trademark

This leaflet was prepared in March 2019

Australian Registration Number(s)

30 mg tablets: AUST R 299965

90 mg tablets: AUST R 299968

180 mg tablets: AUST R 299964

One-month initiation pack: AUST R 299966

Version No. 1.0

Published by MIMS March 2020

BRAND INFORMATION

Brand name

Alunbrig

Active ingredient

Brigatinib

Schedule

S4

 

1 Name of Medicine

Alunbrig (brigatinib).

2 Qualitative and Quantitative Composition

Alunbrig 30 mg film-coated tablets.

Each film-coated tablet contains 30 mg of brigatinib.

Excipient with known effect.

Each film-coated tablet contains 56 mg of lactose monohydrate.

Alunbrig 90 mg film-coated tablets.

Each film-coated tablet contains 90 mg of brigatinib.

Excipient with known effect.

Each film-coated tablet contains 168 mg of lactose monohydrate.

Alunbrig 180 mg film-coated tablets.

Each film-coated tablet contains 180 mg of brigatinib.

Excipient with known effect.

Each film-coated tablet contains 336 mg of lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Alunbrig 30 mg film-coated tablets.

Round, white to off-white with debossed "U3" on one side and plain on the other side.

Alunbrig 90 mg film-coated tablets.

Oval, white to off-white with debossed "U7" on one side and plain on the other side.

Alunbrig 180 mg film-coated tablets.

Oval, white to off-white with debossed "U13" on one side and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Alunbrig is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC).

4.2 Dose and Method of Administration

ALK-positive NSCLC status should be known prior to initiation of Alunbrig therapy. A validated ALK assay is necessary for the selection of ALK-positive NSCLC patients.
Treatment with Alunbrig should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.
The recommended starting dose of Alunbrig is 90 mg once daily for the first 7 days, then 180 mg once daily. Treatment should continue as long as clinical benefit is observed.
If a dose of Alunbrig is missed, or vomiting occurs after taking a dose, an additional dose should not be administered and the next dose of Alunbrig should be taken at the scheduled time.

Dose adjustments.

Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. Alunbrig dose reduction levels are summarised in Table 1.
Permanently discontinue Alunbrig if patient is unable to tolerate the 60 mg once daily dose.
If Alunbrig is interrupted for 14 days or longer for reasons other than adverse reactions, treatment should be resumed at 90 mg once daily for 7 days before increasing to the previously tolerated dose.
Recommendations for dose modifications of Alunbrig for the management of adverse reactions are summarised in Table 2.

Special patient populations.

Elderly.

The limited data on the safety and efficacy of Alunbrig in patients aged 65 years and older suggest that a dose adjustment is not required in elderly patients. There are limited data on patients over 85 years of age.

Paediatrics.

The safety and efficacy of Alunbrig in patients less than 18 years of age have not been established. No data are available.

Renal impairment.

No dose adjustment of Alunbrig is required for patients with mild or moderate renal impairment (estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2). The dose of brigatinib should be reduced by approximately 50% (i.e. from 180 mg to 90 mg, or from 90 mg to 60 mg) for patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) (see Section 5.2 Pharmacokinetic Properties). These dosing recommendations for patients with severe renal impairment are based on the results of a single-dose pharmacokinetic study. Patients should be closely monitored as the safety of brigatinib has not been studied in patients with severe renal impairment.

Hepatic impairment.

No dose adjustment of Alunbrig is required for patients with mild hepatic impairment (Child-Pugh class A) or moderate hepatic impairment (Child-Pugh class B). The dose of brigatinib should be reduced by approximately 40% (i.e. from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg) for patients with severe hepatic impairment (Child-Pugh class C) (see Section 5.2 Pharmacokinetic Properties). These dosing recommendations are based on the results of a single-dose pharmacokinetic study. Patients should be closely monitored as the safety of brigatinib has not been studied in patients with hepatic impairment.

Method of administration.

Alunbrig is for oral use. The tablets should be swallowed whole and with water. Do not crush or chew tablets. Alunbrig may be taken with or without food.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

Pulmonary adverse reactions.

Severe, life-threatening, and fatal pulmonary adverse reactions, including those with features consistent with ILD/pneumonitis, can occur in patients treated with Alunbrig [see Section 4.8 Adverse Effects (Undesirable Effects)]. Most pulmonary adverse reactions were observed within the first 7 days of treatment. Grade 1-2 pulmonary adverse reactions resolved with interruption of treatment or dose modification. Increased age and shorter interval (less than 7 days) between the last dose of crizotinib and the first dose of Alunbrig were independently associated with an increased rate of these pulmonary adverse reactions. These factors should be considered when initiating treatment with Alunbrig. Patients with a history of ILD or drug-induced pneumonitis were excluded from the pivotal trial. Some patients experienced pneumonitis later in treatment with Alunbrig. Patients should be monitored for and instructed to report any new or worsening respiratory symptoms (e.g. dyspnoea, cough, etc.), particularly in the first week of treatment. Evidence of pneumonitis in any patient with worsening respiratory symptoms should be promptly investigated. If pneumonitis is suspected, Alunbrig should be withheld, and the patient evaluated for other causes of symptoms (e.g. pulmonary embolism, tumour progression, and infectious pneumonia) and dosing modified accordingly (see Section 4.2 Dose and Method of Administration).

Hypertension.

Hypertension has occurred in patients treated with Alunbrig [see Section 4.8 Adverse Effects (Undesirable Effects)]. Blood pressure should be monitored regularly during treatment with Alunbrig. Hypertension should be treated according to standard guidelines to control blood pressure. For severe hypertension (≥ Grade 3), Alunbrig should be withheld until hypertension has recovered to Grade 1 or to baseline. The dose should be modified accordingly (see Section 4.2 Dose and Method of Administration).

Bradycardia.

Bradycardia has occurred in patients treated with Alunbrig [see Section 4.8 Adverse Effects (Undesirable Effects)]. Heart rate and blood pressure should be monitored regularly. Caution should be exercised when administering Alunbrig in combination with other agents known to cause bradycardia. Heart rate should be monitored more frequently in patients if concomitant use of a medicinal product known to cause bradycardia cannot be avoided. If symptomatic bradycardia occurs, treatment with Alunbrig should be withheld and concomitant medications known to cause bradycardia should be evaluated. Upon recovery, the dose should be modified accordingly (see Section 4.2 Dose and Method of Administration). In case of life-threatening bradycardia, if no contributing concomitant medication is identified, or in case of recurrence, treatment with Alunbrig should be discontinued (see Section 4.2 Dose and Method of Administration).

Visual disturbance.

Visual disturbance adverse reactions have occurred in patients treated with Alunbrig [see Section 4.8 Adverse Effects (Undesirable Effects)]. Patients should be advised to report any visual symptoms. For new or worsening severe visual symptoms, an ophthalmologic evaluation and dose reduction should be considered (see Section 4.2 Dose and Method of Administration).

Creatine phosphokinase (CPK) elevation.

Elevations of CPK have occurred in patients treated with Alunbrig [see Section 4.8 Adverse Effects (Undesirable Effects)]; the pathology resulting in CPK elevation is unknown. Significant myopathies (such as rhabdomyolysis or cardiomyopathies) were not observed in the clinical trials. However, the rare occurrence of significant myopathies cannot be ruled out. Patients should be advised to report any unexplained muscle pain, tenderness, or weakness. CPK levels should be monitored regularly during Alunbrig treatment. Based on the severity of the CPK elevation, and if associated with muscle pain or weakness, treatment with Alunbrig should be withheld, and the dose modified accordingly (see Section 4.2 Dose and Method of Administration).

Elevations of pancreatic enzymes.

Elevations of amylase and lipase have occurred in patients treated with Alunbrig [see Section 4.8 Adverse Effects (Undesirable Effects)]. Lipase and amylase should be monitored regularly during treatment with Alunbrig. Based on the severity of the laboratory abnormalities, treatment with Alunbrig should be withheld, and the dose modified accordingly (see Section 4.2 Dose and Method of Administration).

Hepatic enzyme elevation.

Elevations of hepatic enzymes (aspartate aminotransferase, alanine aminotransferase) and bilirubin have occurred in patients treated with Alunbrig (see Section 4.8). Liver function, including AST, ALT and total bilirubin should be assessed prior to the initiation of Alunbrig and then every 2 weeks during the first 3 months of treatment. Thereafter, monitoring should be performed periodically. Based on the severity of the laboratory abnormalities, treatment should be withheld, and the dose modified accordingly (see Section 4.2 Dose and Method of Administration).

Hyperglycaemia.

Elevations of serum glucose have occurred in patients treated with Alunbrig [see Section 4.8 Adverse Effects (Undesirable Effects)]. Fasting serum glucose should be assessed prior to initiation of Alunbrig and monitored periodically thereafter. Antihyperglycaemic medications should be initiated or optimised as needed. If adequate hyperglycaemic control cannot be achieved with optimal medical management, Alunbrig should be withheld until adequate hyperglycaemic control is achieved; upon recovery reducing the dose of Alunbrig as described in Dose and Method of Administration may be considered or Alunbrig may be permanently discontinued.

Photosensitivity.

Photosensitivity to sunlight has occurred in patients treated with brigatinib (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be advised to avoid prolonged sun exposure while taking brigatinib, and for at least 5 days after discontinuation of treatment. When outdoors, patients should be advised to wear a hat and protective clothing, and to use a broad-spectrum Ultraviolet A (UVA/Ultraviolet B (UVB) sunscreen and lip balm (SPF ≥ 30) to help protect against potential sunburn. For severe photosensitivity reactions (≥ Grade 3), brigatinib should be withheld until recovery to baseline. The dose should be modified accordingly (see Section 4.2 Dose and Method of Administration).

Fertility.

Women of childbearing potential should be advised to use effective non-hormonal contraception during treatment with Alunbrig and for at least 4 months following the final dose. Men with female partners of childbearing potential should be advised to use effective contraception during treatment and for at least 3 months after the last dose of Alunbrig (see Section 4.6 Fertility, Pregnancy and Lactation).

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

See Section 4.2 Dose and Method of Administration.

Effects on laboratory tests.

See Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Agents that may increase brigatinib plasma concentrations.

CYP3A inhibitors.

The concomitant use of strong CYP3A inhibitors with Alunbrig, including but not limited to certain antivirals (e.g. indinavir, nelfinavir, ritonavir, saquinavir), macrolide antibiotics (e.g. clarithromycin, telithromycin, troleandomycin), antifungals (e.g. ketoconazole, voriconazole), and nefazodone should be avoided. If concomitant use of strong CYP3A inhibitors cannot be avoided, the dose of Alunbrig should be reduced 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, Alunbrig should be resumed at the dose that was tolerated prior to the initiation of the strong CYP3A inhibitor. In vitro studies demonstrated that brigatinib is a substrate of CYP3A4/5. Coadministration of multiple 200 mg twice daily doses of itraconazole, a strong CYP3A inhibitor, with a single 90 mg brigatinib dose increased brigatinib Cmax by 21%, AUC0-INF by 101% (2-fold), and AUC0-120 by 82% (< 2-fold), relative to a 90 mg brigatinib dose administered alone.
The concomitant use of moderate CYP3A inhibitors (e.g. diltiazem and verapamil) with brigatinib should be avoided. If concomitant use of moderate CYP3A inhibitors cannot be avoided, the dose of brigatinib should be reduced by approximately 40% (i.e. from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg). After discontinuation of a moderate CYP3A inhibitor, brigatinib should be resumed at the dose that was tolerated prior to the initiation of the moderate CYP3A inhibitor.
Grapefruit or grapefruit juice may also increase plasma concentrations of brigatinib and should be avoided.

CYP2C8 inhibitors.

No dose adjustment is required for Alunbrig during coadministration with strong CYP2C8 inhibitors. In vitro studies demonstrated that brigatinib is a substrate of CYP2C8. Coadministration of multiple 600 mg twice daily doses of gemfibrozil, a strong CYP2C8 inhibitor, with a single 90 mg brigatinib dose decreased brigatinib Cmax by 41%, AUC0-INF by 12%, and AUC0-120 by 15%, relative to a 90 mg brigatinib dose administered alone. The effect of gemfibrozil on the pharmacokinetics of brigatinib is not clinically meaningful and the underlying mechanism for the decreased exposure of brigatinib is unknown.

P-gp and BCRP inhibitors.

Brigatinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro. No dose adjustment is required for Alunbrig during coadministration with P-gp and BCRP inhibitors. Brigatinib exhibits high solubility and high permeability. Additionally, simulations from a physiologically-based pharmacokinetic model suggested that inhibition of P-gp and BCRP is not expected to result in a clinically meaningful change in the systemic exposure of brigatinib.

Agents that may decrease brigatinib plasma concentrations.

CYP3A inducers.

The concomitant use of strong CYP3A inducers with Alunbrig, including but not limited to rifampicin, carbamazepine, phenytoin, rifabutin, phenobarbital, and St. John's Wort should be avoided. Coadministration of multiple 600 mg daily doses of rifampicin, a strong CYP3A inducer, with a single 180 mg brigatinib dose decreased brigatinib Cmax by 60%, AUC0-INF by 80% (5-fold), and AUC0-120 by 80% (5-fold), relative to a 180 mg brigatinib dose administered alone.
The concomitant use of moderate CYP3A inducers with Alunbrig, including but not limited to efavirenz, modafinil, bosentan, etravirine, and nafcillin should be avoided. Moderate CYP3A inducers may decrease the AUC of brigatinib by approximately 50% based on simulations from a physiologically-based pharmacokinetic model. If concomitant use of moderate CYP3A inducers cannot be avoided, the dose of brigatinib may be increased in 30 mg increments after 7 days of treatment with the current brigatinib dose as tolerated, up to a maximum of twice the brigatinib dose that was tolerated prior to the initiation of the moderate CYP3A inducer. After discontinuation of a moderate CYP3A inducer, brigatinib should be resumed at the dose that was tolerated prior to the initiation of the moderate CYP3A inducer.

Agents that may have their plasma concentrations altered by brigatinib.

CYP3A substrates.

Brigatinib reduces plasma concentrations of coadministered medicinal products that are predominantly metabolised by CYP3A. Brigatinib may also induce other enzymes and transporters (e.g. CYP2C, P-gp) via the same mechanisms responsible for induction of CYP3A (e.g. pregnane X receptor activation). In vitro studies in hepatocytes have shown that brigatinib is an inducer of CYP3A4. Coadministration of multiple 180 mg daily doses of brigatinib with a single 3 mg oral dose of midazolam, a sensitive CYP3A substrate, decreased midazolam Cmax by 16%, AUC0-inf by 26%, and AUC0-last by 30%, relative to a 3 mg oral dose of midazolam administered alone.

Transporter substrates.

Brigatinib is an inhibitor of P-gp, BCRP, organic cation transporter 1 (OCT1), multidrug and toxin extrusion protein 1 (MATE1), and 2K (MATE2K) in vitro. Coadministration of brigatinib with substrates of P-gp (e.g. digoxin, dabigatran, colchicine, pravastatin), BCRP (e.g. methotrexate, rosuvastatin, sulfasalazine), OCT1, MATE1, and MATE2K may increase their plasma concentrations. Patients should be closely monitored when Alunbrig is coadministered with substrates of these transporters with a narrow therapeutic index (e.g. digoxin, dabigatran, methotrexate).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No human data on the effect of Alunbrig on fertility are available. Based on repeat dose toxicity studies in male animals, Alunbrig may cause reduced fertility in males. The clinical relevance of these findings to human fertility is unknown.
Testicular toxicity was observed in repeat-dose animal studies. In rats, findings included lower weight of testes, seminal vesicles and prostate gland, and testicular tubular degeneration; these effects were not reversible during the recovery period. In monkeys, findings included reduced size of testes; this effect was reversible during the recovery period. Overall, these effects on the male reproductive organs in rats and monkeys occurred at exposures as low as 0.2-times the AUC in patients at the 180 mg once daily dose. No apparent adverse effects on female reproductive organs were observed in general toxicology studies in rats and monkeys.
(Category D)
Alunbrig may cause fetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity. There are no clinical data on the use of Alunbrig in pregnant women. Alunbrig should not be used during pregnancy unless the clinical condition of the mother requires treatment. If Alunbrig is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Women of childbearing age being treated with Alunbrig should be advised not to become pregnant and men being treated with Alunbrig should be advised not to father a child during treatment. Women of reproductive potential should be advised to use effective non-hormonal contraception during treatment with Alunbrig and for at least 4 months following the final dose. Male patients with female partners of reproductive potential should be advised to use effective contraception during treatment and for at least 3 months after the last dose of Alunbrig.
In an embryofetal development study in which pregnant rats were administered daily oral doses of up to 25 mg/kg/day of brigatinib during organogenesis, dose-related skeletal (incomplete ossification, small incisors, wavy/notched/absent ribs) and visceral anomalies were observed at doses as low as 12.5 mg/kg/day (approximately 0.6 times the human exposure by AUC at 180 mg once daily). Malformations observed at 25 mg/kg/day (approximately 1.1 times the human AUC at 180 mg once daily) included anasarca (generalised subcutaneous oedema), 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.
 It is unknown whether Alunbrig is excreted in human milk. Available data cannot exclude potential excretion in human milk. Breast-feeding should be stopped during treatment with Alunbrig.

4.7 Effects on Ability to Drive and Use Machines

There are no data on the effect of Alunbrig on the ability to drive and use machines. Visual disturbance, dizziness, and fatigue have been observed in clinical trials. Patients should be advised not to drive or operate machines if they experience any of these symptoms while taking Alunbrig.

4.8 Adverse Effects (Undesirable Effects)

The adverse reactions described in this section were identified from three clinical trials:
Study 301 (ALTA 1L): A randomised, open label, multicentre trial in patients with advanced ALK positive NSCLC who had not previously received an ALK targeted therapy. Patients were randomised in a 1:1 ratio to receive Alunbrig 180 mg once daily with a 7 day lead in at 90 mg once daily (N = 137) or crizotinib 250 mg orally twice daily (N = 138). The median relative dose intensity was 97% for Alunbrig and 99% for crizotinib.
Study 201 (ALTA): A randomised, open label, multicentre trial in patients treated with Alunbrig with ALK positive NSCLC who previously progressed on crizotinib. Patients were randomised in a 1:1 ratio to receive Alunbrig either 90 mg once daily continuously (90 mg regimen, N = 112) or 180 mg once daily with a 7-day lead in at 90 mg once daily (180 mg regimen, N = 110).
Study 101: An open-label multicentre phase 1/2 dose escalation/expansion trial in patients with advanced malignancies.
Across these three studies, ALK-positive NSCLC patients receiving the recommended dosing regimen had a median duration of treatment of 21.8 months.
The most common adverse reactions reported in patients (≥ 25%) treated with Alunbrig at the 180 mg regimen were increased AST (68%), increased CPK (64%), hyperglycaemia (61%), increased lipase (54%), hyperinsulinemia (53%), diarrhoea (49%), increased ALT (49%), increased amylase (47%), anaemia (47%), nausea (40%), fatigue (40%), hypophosphataemia (39%), decreased lymphocyte count (39%), cough (38%), rash (37%), increased alkaline phosphatase (37%), increased APTT (36%), myalgia (34%), headache (33%), hypertension (30%), decreased WBC count (28%) dyspnoea (27%), and vomiting (26%).
The most common serious adverse reactions reported in 2% or more of patients at the 180 mg regimen, other than events related to neoplasm progression included pneumonia (6.9%), pneumonitis (5.5%), dyspnoea (2.9%) and pyrexia (2.2%).
Treatment-emergent adverse events (TEAE) that led to discontinuation of brigatinib occurred in 12% of patients receiving the 180 mg regimen. The most common TEAEs (occurring in ≥ 2 patients receiving the 180 mg regimen) other than events related to neoplasm progression, that led to brigatinib discontinuation were pneumonitis 3.3%, pneumonia 1.8% and bradycardia 0.7%.
Treatment-emergent adverse events that led to dose reduction occurred in 32.8% of patients receiving the 180 mg regimen. The TEAEs leading to dose reduction that occurred in ≥ 2% of patients receiving the 180 mg regimen were blood CPK increased 10.2%, lipase increased 4.7%, rash 3.3%, and amylase increased 2.9%.
Adverse reactions reported in Table 3 are listed by system organ class, preferred term and frequency. The following convention is used for the classification of the frequency of an adverse drug reaction (ADR) and is based on the Council for International Organisations of Medical Sciences (CIOMS) guidelines: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Description of selected adverse reactions.

Pulmonary adverse reactions.

In ALTA 1L, 2.9% of patients experienced any Grade ILD/pneumonitis early in treatment (within 8 days), with Grade 3-4 ILD/pneumonitis in 2.2% of patients. There were no fatal ILD/pneumonitis. Additionally, 3.7% of patients experienced pneumonitis later in treatment.
In ALTA, pulmonary adverse reactions of any grade, including ILD/pneumonitis, pneumonia and dyspnoea, early in treatment (within 9 days, median onset: 2 days) were experienced in 6.4% of patients; 2.7% of patients had Grade 3-4 pulmonary adverse reactions and 1 patient (0.5%) had fatal pneumonia. Following Grade 1-2 pulmonary adverse reactions, treatment with brigatinib was either interrupted and then restarted or the dose was reduced. Early pulmonary adverse reactions also occurred in a dose escalation study in patients (N = 137) (Study 101) including three fatal cases (hypoxia, acute respiratory distress syndrome and pneumonia). Additionally, 2.3% of patients experienced pneumonitis later in treatment, with 2 patients having Grade 3 pneumonitis (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Hypertension.

Hypertension was reported in 30% of patients treated with brigatinib at the 180 mg regimen with 11% having Grade 3 hypertension. Dose reduction for hypertension occurred in 1.5% of patients at the 180 mg regimen. Systolic and diastolic blood pressure increased over time (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Bradycardia.

Bradycardia was reported in 8.4% of patients treated with brigatinib at the 180 mg regimen. Heart rates of less than 50 beats per minute (bpm) were reported in 8.4% of patients at the 180 mg regimen (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Peripheral neuropathy.

Peripheral neuropathy adverse reactions were reported in 20% of patients treated at the 180 mg regimen with 1.8% having Grade 2 peripheral neuropathy. Thirty-three percent of patients had resolution of all peripheral neuropathy adverse reactions. The median time to onset of peripheral neuropathy was 3.5 months. The median duration of peripheral neuropathy adverse reactions was 6.6 months, with a maximum duration of 28.9 months.

Visual disturbance.

Visual disturbance adverse reactions were reported in 14% of patients treated with brigatinib at the 180 mg regimen. Of these, two grade 3 adverse reactions (1.1%) including macular oedema (1) and cataract (2) were reported. Dose reduction for visual disturbance occurred in two patients (0.7%) at the 180 mg regimen (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Creatine phosphokinase (CPK) elevation.

In ALTA 1L and ALTA, elevations of creatine phosphokinase (CPK) were reported in 64% of patients treated with brigatinib at the 180 mg regimen. The incidence of Grade 3-4 elevations of CPK was 18%. The median time to onset for CPK elevations was 28 days. Dose reduction for CPK elevation occurred in 6.4% of patients at the 180 mg regimen (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Elevations of pancreatic enzymes.

Elevations of amylase and lipase were reported in 47% and 54% of patients treated with brigatinib, respectively at the 180 mg regimen. For elevations to Grades 3 - 4, the incidences for amylase and lipase were 7.7% and 15%, respectively. The median time to onset for amylase elevations and lipase elevations was 16 days and 29 days, respectively. Dose reduction for elevation of lipase and amylase occurred in 4.7% and 2.9% of patients, respectively at the 180 mg regimen (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Elevations of hepatic enzymes.

Elevations of ALT and AST were reported in 49% and 68% of patients treated with Alunbrig, respectively at the 180 mg regimen. For elevations to Grade 3 and 4, the incidences for ALT and AST were 4.7% and 3.6%, respectively. The median time to onset for ALT elevations and AST elevations was 42 days and 28 days, respectively. Dose reduction for elevation of ALT and AST occurred in 0.7% and 1.1% of patients, respectively at the 180 mg regimen (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Hyperglycaemia.

Sixty one percent of patients experienced hyperglycaemia. Grade 3 hyperglycaemia occurred in 6.6% of patients (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use). No patients had dose reductions due to hyperglycaemia.

Photosensitivity.

Photosensitivity was reported in 3.6% patients treated with brigatinib at the 180 mg regimen. Grade 3-4 photosensitivity occurred in 1.1% of patients.
Dose reduction for photosensitivity occurred in two patients (0.7%) at the 180 mg regimen (see Section 4.2 Dose and Method of Administration, Table 2 Other adverse reactions; Section 4.4 Special Warnings and Precautions for Use, Photosensitivity).

Post-marketing.

Not applicable.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no specific antidote for overdose with Alunbrig. In the event of an overdose, monitor the patient for adverse reactions [see Section 4.8 Adverse Effects (Undesirable Effects)] and provide appropriate supportive care.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antineoplastic agent, protein kinase inhibitors.

Mechanism of action.

Brigatinib is a tyrosine kinase inhibitor (ALK) of multiple kinases including ALK, ROS1 and insulin-like growth factor 1 receptor (IGF-1R). Among these, brigatinib is most active against ALK. Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signalling protein STAT3 in in vitro and in vivo assays. Brigatinib inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice. At concentrations (≤ 500 nanoM) that are achieved clinically, brigatinib inhibited the in vitro viability of cells expressing EML4-ALK and most mutant forms associated with resistance to ALK inhibitors including crizotinib. Brigatinib demonstrated in vivo and clinical activity against multiple mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumours in patients who have progressed on crizotinib. Administration of brigatinib resulted in antitumour activity and prolonged survival in mice with an ALK-driven tumour cell line implanted intracranially.

Cardiac electrophysiology.

The QT interval prolongation potential of brigatinib was assessed in 123 patients following once daily Alunbrig doses of 30 mg to 240 mg. Brigatinib did not prolong the QT interval to a clinically relevant extent.

Clinical trials.

ALTA 1L (study 301).

The safety and efficacy of Alunbrig was evaluated in a randomised (1:1), open label, multicentre trial (ALTA 1L) in 275 adult patients with advanced ALK positive NSCLC who had not previously received an ALK targeted therapy. Eligibility criteria permitted enrolment of patients with a documented ALK rearrangement based on a local standard of care testing and an ECOG Performance status of 0 2 Patients were allowed to have up to 1 prior regimen of chemotherapy in the locally advanced or metastatic setting. Neurologically stable patients with treated or untreated central nervous system (CNS) metastases, including leptomeningeal metastases, were eligible. Patients with a history of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis were excluded.
Patients were randomised in a 1:1 ratio to receive Alunbrig 180 mg once daily with a 7 day lead in at 90 mg once daily (N = 137) or crizotinib 250 mg orally twice daily (N = 138). Randomisation was stratified by brain metastases (present, absent) and prior chemotherapy use for locally advanced or metastatic disease (yes, no).
Patients in the crizotinib arm who experienced disease progression were offered crossover to receive treatment with Alunbrig. Among all 121 patients who were randomized to the crizotinib arm and discontinued the study treatment by the time of the final analysis, 99 (82%) patients received subsequent ALK TKIs. Eighty (66%) patients who were randomized to the crizotinib arm received subsequent Alunbrig treatment, including 65 (54%) patients who crossed over in the study.
The major outcome measure was progression free survival (PFS) according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1) as evaluated by a Blinded Independent Review Committee (BIRC). Additional outcome measures as evaluated by the BIRC include confirmed objective response rate (ORR), duration of response (DOR), time to response, disease control rate (DCR), intracranial ORR, intracranial PFS, and intracranial DOR. Investigator assessed outcomes include PFS and overall survival.
Baseline demographics and disease characteristics in ALTA 1L were median age 59 years old (range 27 to 89; 32% 65 and over), 59% White and 39% Asian, 55% female, 39% ECOG PS 0, and 56% ECOG PS 1, 58% never smokers, 93% Stage IV disease, 96% adenocarcinoma histology, 30% CNS metastases at baseline, 14% prior radiotherapy to the brain, and 27% prior chemotherapy. Sites of extra thoracic metastases include brain (30% of patients), bone (31% of patients), and liver (20% of patients).
At the primary analysis performed at a median follow-up duration of 11 months (range: 0-20) in the Alunbrig arm, the ALTA 1L study met its primary endpoint demonstrating a statistically significant improvement in PFS by BIRC. A protocol specified interim efficacy analysis performed at a median follow up duration of 24.9 months (range: 0-34.1) in the Alunbrig arm formed the basis for the results from this study (Table 4 and Figure 1). In addition, results from final analysis performed at median follow-up duration of 40.4 months (range: 0-52.4) in the Alunbrig arm are presented (Table 4).
The PFS for patients with CNS metastases at baseline (HR = 0.25, 95% CI: 0.14 0.46, median PFS for Alunbrig = 24 months, 95% CI: 18.37 NE, median PFS for crizotinib = 5.6 months, 95% CI: 3.84 9.4) and without CNS metastases at baseline (HR = 0.65, 95% CI: 0.44 0.97, median PFS for Alunbrig = 24 months, 95% CI: 15.67 NE, median PFS for crizotinib = 13 months, 95% CI: 9.46-21.13), indicated benefit of Alunbrig over crizotinib in both subgroups.
At the data cut off point overall survival data was not mature.
BIRC assessment of intracranial efficacy according to RECIST v1.1 in patients with any brain metastases and patients with measurable brain metastases (≥ 10 mm in longest diameter) at baseline are summarised in Table 5 and Figure 2.

ALTA.

The safety and efficacy of Alunbrig was evaluated in a randomised (1:1), open-label, multicentre trial (ALTA) in 222 adult patients with locally advanced or metastatic ALK-positive NSCLC who had progressed on crizotinib. Eligibility criteria permitted enrolment of patients with a documented ALK rearrangement based on the Vysis ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit test either from clinical practice or confirmed by central laboratory, ECOG Performance Status of 0-2, prior chemotherapy, and central nervous system (CNS) metastases provided they were neurologically stable and did not require an increasing dose of corticosteroids. Patients with a history of pulmonary interstitial disease or drug-related pneumonitis were excluded. Patients were randomised in a 1:1 ratio to receive brigatinib either 90 mg once daily (90 mg regimen, n=112) or 180 mg once daily with 7-day lead-in at 90 mg once daily (180 mg regimen, n=110). The median duration of follow-up was 17.9 months. Randomisation was stratified by brain metastases (present, absent) and best prior response to crizotinib therapy (complete or partial response, any other response/unknown). The major outcome measure was confirmed objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1) as evaluated by investigator. Additional outcome measures included confirmed ORR as evaluated by an Independent Review Committee (IRC); time to response; progression free survival (PFS); duration of response (DOR); overall survival; quality of life; and intracranial ORR, intracranial DOR and intracranial PFS as evaluated by an IRC. The analysis of study measured outcomes across both arms informed the recommended dose.
Baseline demographics and disease characteristics in ALTA were median age 54 years old (range 18 to 82; 23% 65 and over), 67% White and 31% Asian, 57% female, 36% ECOG PS 0 and 57% ECOG PS 1, 95% never or former smokers, 98% Stage IV, 97% adenocarcinoma, and 74% prior chemotherapy. The most common sites of extra-thoracic metastasis included 69% brain (of whom 62% had received prior radiation to the brain), 40% bone, and 26% liver.
Efficacy results from ALTA analysis are summarised in Table 6 and the Kaplan-Meier (KM) curves for investigator-assessed and IRC-assessed systemic PFS are shown in Figure 3 and Figure 4, respectively.
In ALTA, 201 patients had at least 1 evaluable post-baseline assessment out of the 222 patients. Waterfall plots displaying the maximum decrease from baseline in the sum of the longest tumour diameters shows that the majority of patients treated with Alunbrig had a reduction in tumour burden in both the 90 mg and 180 mg regimens in ALTA (Figure 5 and Figure 6).
Of the 222 enrolled patients, baseline tumour tissue samples were evaluable in 17 patients. Responses were seen in patients with and without secondary ALK kinase domain mutations, including one patient with a secondary ALK kinase domain mutation of G1202R.
IRC assessments of intracranial ORR and duration of intracranial response in patients from ALTA with measurable brain metastases (≥ 10 mm in longest diameter) at baseline are summarised in Table 7.
In ALTA, patients overall experienced positive changes relative to baseline in quality-of-life (QOL) during treatment with brigatinib. The mean QOL, measured by the summary Global Health Status/QOL score of the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (QLQ)-C30, was maintained above baseline mean values throughout follow-up (median: 17.9 months) across both dose groups.
In Study 101, 25 patients with ALK-positive NSCLC that progressed on crizotinib were administered brigatinib at 180 mg once daily with 7-day lead-in at 90 mg once daily regimen. Of these, 19 patients had an investigator-assessed confirmed objective response (76%; 95% CI: 55, 91) the KM median PFS was 16.3 months (95% CI: 9.2, NE) and the 12-month probability of overall survival was 84.0% (95% CI: 62.8, 93.7).

5.2 Pharmacokinetic Properties

Absorption.

Following administration of single oral doses of brigatinib of 30 to 240 mg, the median time to peak concentration (Tmax) ranged from 1 to 4 hours post dose. The geometric mean (CV%) steady-state Cmax of brigatinib at doses of 90 mg and 180 mg once daily was 552 (65%) and 1452 (60%) nanogram/mL, respectively, and the corresponding AUC0-tau was 8165 (57%) and 20,276 (56%) h.nanogram/mL, respectively. After a single dose and repeat dosing of brigatinib, systemic exposure was dose proportional over the dose range of 60 mg to 240 mg once daily. The mean accumulation ratio after repeat dosing was 1.9 to 2.4. Brigatinib Cmax was reduced by 13% with no effect on AUC in healthy subjects administered Alunbrig after a high-fat meal compared to the Cmax and AUC after overnight fasting.

Distribution.

Brigatinib was 91% bound to human plasma proteins and the binding was not concentration-dependent. The blood-to-plasma concentration ratio is 0.69. Following oral administration of brigatinib 180 mg once daily, the geometric mean apparent volume of distribution (Vz/F) at steady-state was 307 L.

Metabolism.

In vitro studies demonstrated that brigatinib is primarily metabolised by CYP2C8 and CYP3A4. Following oral administration of a single 180 mg dose of [14C]-brigatinib to healthy subjects, N-demethylation and cysteine conjugation were the two major metabolic clearance pathways. Unchanged brigatinib (92%) and its primary metabolite, AP26123 (3.5%), were the major circulating radioactive components. In patients, the steady-state AUC of AP26123 was less than 10% of brigatinib exposure. The metabolite, AP26123, inhibited ALK with approximately 3-fold lower potency than brigatinib in vitro.

Excretion.

Following oral administration of brigatinib 180 mg once daily, the geometric mean apparent oral clearance (CL/F) of brigatinib at steady-state was 8.9 L/h and the mean plasma elimination half-life was 25 h. Following administration of a single 180 mg oral dose of [14C]-brigatinib to 6 healthy male subjects, 65% of the administered dose was recovered in faeces and 25% of the administered dose was recovered in urine. Unchanged brigatinib represented 41% and 86% of the total radioactivity in faeces and urine, respectively.

Special populations.

Renal impairment.

The pharmacokinetics of brigatinib is similar in patients with normal renal function and in patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m2) based on the results of population pharmacokinetic analyses. In a pharmacokinetic study, unbound AUC0-INF was 92% higher in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2, N=8) as compared to patients with normal renal function (eGFR ≥ 90 mL/min/1.73 m2, N=8) (see Section 4.2 Dose and Method of Administration).

Hepatic impairment.

The pharmacokinetics of brigatinib was characterised in patients with normal hepatic function (N=9), mild hepatic impairment (Child-Pugh class A, N=6), moderate hepatic impairment (Child-Pugh class B, N=6), or severe hepatic impairment (Child-Pugh class C, N=6). The pharmacokinetics of brigatinib were similar between patients with normal hepatic function and patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Unbound AUC0-INF was 37% higher in patients with severe hepatic impairment (Child-Pugh class C) as compared to patients with normal hepatic function (see Section 4.2 Dose and Method of Administration).

Age, gender, race.

Population pharmacokinetic analyses showed that age, gender or race had no clinically meaningful effect on the pharmacokinetics of brigatinib.

5.3 Preclinical Safety Data

Genotoxicity.

Brigatinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) or the mammalian cell chromosomal aberration assays, but slightly increased the number of micronuclei in a rat bone marrow micronucleus test and induced polyploidy, endoreduplication and centromeric disruption in human lymphocytes in vitro. The mechanism of micronucleus induction was probably abnormal chromosome segregation (aneugenicity) and not a clastogenic effect on chromosomes. Brigatinib potentially induces numerical chromosomal aberrations in vivo.

Carcinogenicity.

Carcinogenicity studies have not been performed with brigatinib.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, microcrystalline cellulose, sodium starch glycollate type A, hydrophobic colloidal silica anhydrous, magnesium stearate, Opadry II White (PI 11376).

6.2 Incompatibilities

Not Applicable.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Alunbrig 30 mg film-coated tablets.

PCTFE (Aclar)/Aluminium blister in a pack size of 28 film-coated tablets.
High density polyethylene (HDPE) bottles with a polypropylene (PP) child resistant closure, containing 30 film-coated tablets, and includes a desiccant canister.

Alunbrig 90 mg film-coated tablets.

PCTFE (Aclar)/Aluminium blister in a pack size of 28 film-coated tablets.
High density polyethylene (HDPE) bottles with a polypropylene (PP) child resistant closure, containing 7 or 30 film-coated tablets, and includes a desiccant canister.

Alunbrig 180 mg film-coated tablets.

PCTFE (Aclar)/Aluminium blister in a pack size of 28 film-coated tablets.
High density polyethylene (HDPE) bottles with a polypropylene (PP) child resistant closure, containing 30 film-coated tablets, and includes a desiccant canister.

One-month initiation pack.

PCTFE (Aclar)/Aluminium foil blister strips containing 7 of the 90 mg film-coated tablets (1 blister of 7 tablets in a carton box) and 21 of the 180 mg film-coated tablets (3 blisters of 7 tablets in a carton box), co-packaged in a single outer carton box.
Not all presentations may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

The chemical name for brigatinib is 5-chloro-N4-[2-(dimethylphosphoryl) phenyl]-N2-{2-methoxy-4-[4(4-methylpiperazin-1-yl) piperidin-1-yl] phenyl}pyrimidine-2,4-diamine. The molecular formula is C29H39ClN7O2P which corresponds to a formula weight of 584.1 g/mol. Brigatinib has no chiral centres. The chemical structure is:
Brigatinib is an off-white to beige/tan solid. It is very slightly soluble in water, highly soluble from pH 1.5-6.5, slightly soluble in ethanol and soluble in methanol. The pKas were determined to be: 1.73 ± 0.02 (base), 3.65 ± 0.01 (base), 4.72 ± 0.01 (base), and 8.04 ± 0.01 (base).

CAS number.

1197953-54-0.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (Schedule 4).

Summary Table of Changes