Consumer medicine information

Nerlynx

Neratinib

BRAND INFORMATION

Brand name

Nerlynx

Active ingredient

Neratinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Nerlynx.

SUMMARY CMI

NERLYNX®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using NERLYNX?

NERLYNX contains the active ingredient neratinib. NERLYNX is used for patients who have early-stage breast cancer which:

  • is human epidermal growth factor receptor 2-positive (HER2-positive) and
  • has previously been treated with another medicine called ‘trastuzumab’ and
  • within one year of trastuzumab therapy.

For more information, see Section 1. Why am I using NERLYNX? in the full CMI.

2. What should I know before I use NERLYNX?

Do not use if you have ever had an allergic reaction to neratinib or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use NERLYNX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with NERLYNX and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use NERLYNX?

  • The recommended dose of NERLYNX is six 40 mg tablets once a day (a total of 240 mg).
  • Take the tablets whole with food and a glass of water. Do not crush or dissolve. Do not swallow the desiccant.

Your healthcare provider will prescribe NERLYNX in one of two ways to help manage diarrhoea. More instructions can be found in Section 4. How do I use NERLYNX? in the full CMI.

5. What should I know while using NERLYNX?

Things you must do
  • Remind any doctor, dentist or pharmacist you visit that you are using NERLYNX.
  • If you are about to be started on any new medicine, remind your doctor that you are taking NERLYNX.
  • Use a contraceptive to prevent pregnancy during treatment with NERLYNX and for at least one month after your last dose of NERLYNX.
  • If you become pregnant while taking this medicine, tell your doctor immediately.
Things you must not do
  • Be careful driving or operating machinery until you know how NERLYNX affects you. NERLYNX has minor or moderate influence on the ability to drive and use machines.
Looking after your medicine
  • Store below 25°C in the original container and keep the bottle tightly closed in order to protect from moisture.

For more information, see Section 5. What should I know while using NERLYNX? in the full CMI.

6. Are there any side effects?

Common side effects include feeling very tired, rash, burning sensation during urination, and frequent and urgent need to urinate, dehydration, nosebleed, changes in liver blood test results, changes in kidney function test, weight loss, dry or inflamed mouth (including blisters or mouth ulcers), stomach pain, feeling or being sick, low appetite, mild stomach upset, muscle spasms or cramps, dry skin (including cracked skin) and nail problems (including nail splitting or colour change). Serious side effects that may require urgent medical attention or hospitalisation include allergic reaction, liver problems and severe diarrhoea.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

NERLYNX® (NUR-linx)

Active ingredient(s): neratinib (ne-ra-ti-nib)

Consumer Medicine Information (CMI)

This leaflet provides important information about using NERLYNX. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using NERLYNX.

Where to find information in this leaflet:

1. Why am I using NERLYNX?
2. What should I know before I use NERLYNX?
3. What if I am taking other medicines?
4. How do I use NERLYNX?
5. What should I know while using NERLYNX?
6. Are there any side effects?
7. Product details

1. Why am I using NERLYNX?

NERLYNX contains the active ingredient neratinib.

NERLYNX belongs to a group of medicines called ‘tyrosine kinase inhibitors’ used to block cancer cells and treat breast cancer.

NERLYNX is used for patients who have early-stage breast cancer which:

  • is human epidermal growth factor receptor 2-positive (HER2-positive) and
  • has previously been treated with another medicine called ‘trastuzumab’ and
  • within one year of trastuzumab therapy.

The ‘HER2 receptor’ is a protein found on the surface of healthy breast cells in the body. It helps control how healthy breast cells grow. HER2 is found in large amounts on the surface of cancer cells. When NERLYNX binds to HER2, it stops the growth and spread of cancer cells.

Before NERLYNX is used, your cancer must have been tested to show it is HER2-positive. You must also have previously been treated with trastuzumab.

2. What should I know before I use NERLYNX?

Warnings

Do not use NERLYNX if:

  • you are allergic to neratinib, or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine.
  • you have severe liver disease,
  • you are a child or adolescent or
  • you are taking the following medicines:
    - carbamazepine, phenobarbital, phenytoin (antiepileptic medicines)
    - St John's wort (Hypericum perforatum) (herbal product)
    - rifampin (antimycobacterial)
    - fluconazole (antifungal)
    - diltiazem, verapamil (calcium-channel blockers)
    - erythromycin (antibiotic)

Check with your doctor if you:

  • have any other medical conditions
  • take any medicines for any other condition
  • have any gastrointestinal problems
  • have any liver problems

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Tell your doctor immediately if you become pregnant.

If you become pregnant while taking this medicine, the doctor will assess the potential benefit to you and the risk to the unborn baby, of continuing this medicine.

Women who can become pregnant must use an effective method of contraception, including a barrier method:

  • while taking NERLYNX and
  • for one month after treatment has finished.

Men must use an effective barrier method of contraception such as a condom:

  • while taking NERLYNX and
  • for three months after treatment has finished.

It is not known whether NERLYNX passes into breast milk.

Talk to your doctor before taking this medicine if you are breast-feeding or plan to breast-feed because small amounts of this medicine may pass into your breast milk. Your doctor will discuss with you the benefits of taking NERLYNX during this time.

Gastrointestinal problems

  • NERLYNX can cause diarrhoea when you first start taking it.
  • If your doctor has prescribed the full dose of NERLYNX from the start of your treatment, you should take an anti-diarrhoeal medicine called loperamide during your first 2 cycles (56 days) of treatment with NERLYNX and then as needed to control your diarrhoea from becoming severe, and to prevent you from getting dehydrated during treatment.
  • Alternatively, your doctor may prescribe you loperamide as needed while starting you on a lower dose of NERLYNX for the first 2 weeks of your treatment, and then increase you to the recommended full dose of NERLYNX regimen.
  • Talk to your doctor if you cannot take loperamide.

Liver problems

  • NERLYNX can cause changes in liver function – these are shown in blood tests.
  • Your doctor will do blood tests before and during your treatment with this medicine.
  • Your doctor will stop your treatment with NERLYNX if your liver tests show severe problems.

Use in Children

You should not take this medicine if you are a child or adolescent under 18 years of age. The safety of NERLYNX and how effective it is have not been studied in this age group.

NERLYNX with Food and Drink

Certain foods may interact with NERLYNX and can affect how the medicine works. While you are taking NERLYNX:

  • Do not take grapefruit – this includes eating them, drinking the juice or taking a supplement that might contain them.
  • Avoid eating Star fruit, Pomelos and Seville Oranges.

3. What if I am taking other medicines?

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

Some medicines may interfere with NERLYNX and affect how it works.

In particular tell your doctor or pharmacist if you are taking any of the following medicines:

  • rifampicin - a medicine for tuberculosis
  • carbamazepine, phenobarbital, or phenytoin - medicines for seizures
  • St John's wort - an herbal product for depression
  • ketoconazole, voriconazole, itraconazole or fluconazole - medicines for fungal infections
  • erythromycin or clarithromycin - medicines for bacterial infections
  • protease inhibitors - antiviral medicines
  • nefazodone – a medicine to treat depression
  • diltiazem or verapamil - medicines for high blood pressure and chest pain
  • dabigatran or digoxin - a medicine for heart problems
  • rosuvastatin – a medicine to treat high cholesterolemia
  • irinotecan – a medicine used in colorectal cancers
  • sulfasalazine – an anti-inflammatory intestinal medicine
  • medicines for stomach problems such as:
    - lansoprazole, omeprazole or similar medicines called ‘proton pump inhibitors’ or PPIs are not recommended.
    - ranitidine, cimetidine or similar medicines called “H2 receptor antagonists”. Neratinib should be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor antagonist
    - antacid medicines - the dose of these medicines and NERLYNX should be separated by at least 3 hours.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect NERLYNX.

4. How do I use NERLYNX?

How much to take

  • The recommended dose of NERLYNX is six 40 mg tablets once a day (a total of 240 mg).
  • The course of treatment is one year.
  • Follow the instructions provided and use NERLYNX until your doctor tells you to stop.

When to take NERLYNX

  • Take all the tablets at about the same time each day, preferably in the morning.

How to take NERLYNX

  • Take the tablets whole with food and a glass of water. Do not crush or dissolve. Do not swallow the desiccant (a drying agent used to keep the tablets from becoming moist).

To manage diarrhoea you may need to take an anti-diarrhoea medicine when you start NERLYNX, or commence dose escalation.

NERLYNX can cause diarrhoea when you first start taking it. Diarrhoea may be severe, causing you to get dehydrated, unless anti-diarrhoeal medicine is taken to prevent or reduce the diarrhoea.

  • If you are receiving the full dose of NERLYNX from the start of your treatment, your doctor will prescribe an anti-diarrhoeal medicine called loperamide during your first 2 cycles (56 days) of NERLYNX treatment and then as needed. You should start taking loperamide with your first dose of NERLYNX. Your doctor will tell you if you need to keep taking loperamide after the first 2 cycles (56 days) of treatment with NERLYNX.
  • If you are starting at a lower dose of NERLYNX for the first 2 weeks of treatment, then increasing to a full dose of NERLYNX regimen, please inform your doctor immediately if you develop diarrhoea. You may be prescribed loperamide as needed for the management of your diarrhoea.
  • To help prevent or reduce diarrhoea during NERLYNX treatment:
    1. Your doctor may prescribe you additional anti-diarrhoeal medicines, fluids, and electrolytes to manage diarrhoea when you start treatment with NERLYNX. Follow the instructions on how to take anti-diarrhoeals as provided by your doctor.
    2. While taking anti-diarrhoeals, you and your doctor should try to keep the number of bowel movements that you have at 1 or 2 bowel movements each day.
    3. You need to inform your doctor immediately-
    - If you have more than 2 bowel movements in one day, or
    - You have diarrhoea that does not go away, or
    - If you have diarrhoea that is severe and / or accompanied with weakness, dizziness, or fever
    4. Your doctor will tell you if you need to change the dose of NERLYNX, temporarily stop, or completely stop NERLYNX to manage your diarrhoea.

If you forget to use NERLYNX

NERLYNX should be used regularly at the same time each day.

If you forget a dose, skip the dose you missed and wait until the next day before you take the next dose.

Do not take a double dose to make up for the dose you missed.

Do not stop taking NERLYNX without talking to your doctor.

If you use too much NERLYNX

Some side effects associated with taking more NERLYNX than you should are: diarrhoea, nausea, vomiting and dehydration.

If you think that you have used too much NERLYNX, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using NERLYNX?

Things you must do

  • Take NERLYNX for as long as your doctor recommends.
  • If you are about to be started on any new medicine, remind your doctor that you are taking NERLYNX.
  • Use a contraceptive to prevent pregnancy during treatment with NERLYNX and for at least one month after your last dose of NERLYNX.

Call your doctor straight away if you become pregnant while taking this medicine.

Remind any doctor, dentist or pharmacist you visit that you are using NERLYNX.

Things you must not do

  • Be careful before you drive or use any machines or tools until you know how NERLYNX affects you.

NERLYNX has minor or moderate influence on the ability to drive and use machines. The side effects of NERLYNX (for example, dehydration and dizziness resulting from diarrhoea, fatigue, and fainting) may affect how tasks that require judgment, motor or cognitive skills are carried out.

Looking after your medicine

  • Keep your medicine in a cool dry place where the temperature stays below 25°C.
  • Store in the original container and keep the bottle tightly closed in order to protect from moisture.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
General or affecting different parts of the body:
Very common side effects (may affect more than 1 in 10 people):
  • Feeling very tired
  • Rash

Common side effects (may affect up to 1 in 10 people):

  • Burning sensation during urination, and frequent and urgent need to urinate (may be symptoms of urinary tract infection)
  • Dehydration
  • Nosebleed
  • Changes in liver blood test results
  • Changes in kidney function test
  • Weight loss
Stomach and digestive system related:
Very common side effects (may affect more than 1 in 10 people):
  • Dry or inflamed mouth, including blisters or mouth ulcers
  • Stomach pain, feeling or being sick, low appetite

Common side effects (may affect up to 1 in 10 people):

  • Mild stomach upset
  • Dry mouth
Muscle or pain related:
Very common side effects (may affect more than 1 in 10 people):
  • Muscle spasms or cramps
Skin or nail related:
Common side effects (may affect up to 1 in 10 people):
  • Dry skin including cracked skin
  • Nail problems including nail splitting or colour change
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
General or affecting different parts of the body:
  • Allergic reaction (hypersensitivity)
    Symptoms include:
    - shortness of breath
    - wheezing or difficulty breathing
    - swelling of the face, lips, tongue, throat or other parts of the body
    - rash and itching or hives on the skin
    (The above list includes very serious side effects.)
Call your doctor straight away, or go straight to the Emergency Department at you nearest hospital if you notice any of these serious side effects.
Please also see additional information mentioned below.
Stomach and digestive system related:
  • NERLYNX can cause diarrhoea during treatment. The diarrhoea may be severe. Severe diarrhoea can result in dehydration, dizziness and weakness.
Diarrhoea may be reduced or prevented with dose escalation, or if NERLYNX is taken with loperamide or other antidiarrhoeal medicines. See the section on How it is taken for more information about dose escalation or the antidiarrhoeal medicine you may need to take at the same time as NERLYNX. Talk to your doctor if you have more than 2 bowel movements in 1 day or you are having diarrhoea that does not go away.
Go to the hospital immediately if you feel dizzy or weak or are severely dehydrated from diarrhoea.
Liver problems:
  • NERLYNX can cause changes in liver function – these are shown in blood tests. You may or may not have signs or symptoms of liver problems such as yellow skin and/or eyes, dark urine, or light-coloured stools.
Your doctor will do blood tests before and during your treatment with NERLYNX.
Your doctor will stop your treatment with NERLYNX if your liver tests show severe problems.

This is not a complete list of side effects. For any unexpected effects while taking NERLYNX, contact your doctor immediately.

If you receive NERLYNX and feel any of the symptoms mentioned above during the treatment, your doctor has to be informed.

In case you suffer these symptoms, the NERLYNX dose may be stopped or reduced depending on the severity.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems or to [email protected]. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What NERLYNX contains

Active ingredient
(main ingredient)		Neratinib
Other ingredients
(inactive ingredients)		Tablet core
Mannitol
Microcrystalline cellulose
Crospovidone
Povidone
Colloidal anhydrous silica
Magnesium stearate
Tablet coating
Polyvinyl alcohol
Titanium dioxide
Macrogol 3350
Purified talc
Iron oxide red

Do not take this medicine if you are allergic to any of these ingredients.

What NERLYNX looks like

NERLYNX is a red film-coated tablet. The tablet is oval shaped and debossed with ‘W104’ on one side and plain on the other side. (AUST R 301129).

Who distributes NERLYNX

Specialised Therapeutics PM Pty Ltd
Level 2, 17 Cotham Road, Kew, Victoria 3101

Ph: 1300 798 820
Fax: 1800 798 829
www.stbiopharma.com

This leaflet was prepared in June 2022.

Published by MIMS September 2024

BRAND INFORMATION

Brand name

Nerlynx

Active ingredient

Neratinib

Schedule

S4

 

1 Name of Medicine

Nerlynx (neratinib).

2 Qualitative and Quantitative Composition

Each film-coated tablet contains neratinib maleate, equivalent to 40 mg neratinib.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablet.
Oval, red film-coated tablet with 'W104' debossed on one side and plain on the other side. Tablet dimensions are 10.5 mm x 4.3 mm with thickness of 3.1 mm.

4 Clinical Particulars

4.1 Therapeutic Indications

Nerlynx is indicated for the extended adjuvant treatment of adult patients with early-stage human epidermal growth factor receptor 2 (HER2)-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab based therapy.

4.2 Dose and Method of Administration

Nerlynx treatment should be initiated and supervised by a physician experienced in the administration of anti-cancer medicinal products.
Instruct patients to take Nerlynx at approximately the same time every day. Nerlynx should be taken with food, preferably in the morning. The tablets should be swallowed whole, preferably with water, and should not be chewed, crushed, split or dissolved prior to swallowing.
The recommended dose of Nerlynx is 240 mg (six 40 mg tablets) taken orally once daily, continuously for one year. Patients should initiate treatment within 1 year after completion of trastuzumab-based therapy.

Management of diarrhoea.

The diarrhoea associated with Nerlynx can be managed with either anti-diarrhoeal prophylaxis during the first 56 days of treatment and initiated with the first dose of Nerlynx, or by a two week Nerlynx dose escalation approach prior to initiation of the recommended Nerlynx treatment regimen.

Anti-diarrhoeal prophylaxis.

Anti-diarrhoeal prophylaxis is recommended during the first 2 cycles (56 days) of treatment and should be initiated with the first (240 mg) dose of Nerlynx.
Instruct patients to take loperamide as directed in Table 1, titrating dose to achieve 1-2 bowel movements per day.
If diarrhoea occurs despite prophylaxis, treat with additional anti-diarrhoeals, fluids and electrolytes as clinically indicated. Nerlynx dose interruptions and dose reductions may also be required to manage diarrhoea (see Table 3).

Nerlynx dose escalation.

In order to improve patient tolerance to Nerlynx-treatment (see Section 4.8 Adverse Effects (Undesirable Effects)), dose escalation may be considered prior to initiation of the recommended treatment regimen. A two week dose escalation approach, starting at 120 mg daily is recommended (Table 2).
If diarrhoea occurs, treat with anti-diarrhoeals, fluids and electrolytes as clinically indicated. Nerlynx dose interruptions and dose reductions may also be required to manage diarrhoea.
Guidelines for adjusting doses of Nerlynx in the setting of diarrhoea are shown in Table 3. Diarrhoea management requires the correct use of an anti-diarrhoeal medicinal product, dietary changes, and appropriate dose modifications of Nerlynx.

Dose modifications for adverse reactions.

Nerlynx dose modification is recommended based on individual safety and tolerability. Management of some adverse reactions may require dose interruption and/or dose reduction as shown in Table 4, Table 5, and Table 6.
Discontinue Nerlynx for patients:
with treatment related adverse reactions that fail to recover to Grade 0 to 1 or baseline;
with toxicities that result in a treatment delay > 3 weeks; or
who are unable to tolerate 120 mg daily.
Additional clinical situations may result in dose adjustments as clinically indicated (e.g. intolerable toxicities, persistent Grade 2 adverse reactions, etc.).

Missed dose.

Missed doses should not be replaced and treatment should resume with the next scheduled daily dose.

Use of gastric acid-reducing agents.

Proton pump inhibitors (PPI).

Avoid concomitant use with Nerlynx (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

H2-receptor antagonists.

Nerlynx must be taken at least 2 hours before the next dose of the H2-receptor antagonist or 10 hours after the H2-receptor antagonist (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Antacids.

Separate dosing of Nerlynx and antacids by 3 hours after antacids (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Grapefruit and pomegranate.

Concomitant administration of neratinib with grapefruit or pomegranate/ grapefruit or pomegranate juice is not recommended (see Section 4.4; Section 4.5).

Use of CYP3A4/P-gp inhibitors.

If the inhibitor cannot be avoided, reduce Nerlynx dose:
To 40 mg (one 40 mg tablet) taken once daily with a strong CYP3A4/P-gp inhibitor.
To 40 mg (one 40 mg tablet) taken once daily with a moderate CYP3A4/P-gp inhibitor. If well tolerated, increase to 80 mg for at least 1 week, then to 120 mg for at least 1 week, and to 160 mg as a maximal daily dose. Patient should be monitored carefully, especially GI effects including diarrhoea and hepatotoxicity.
After discontinuation of a strong or moderate CYP3A4/P-gp inhibitor, resume previous dose of Nerlynx 240 mg (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Patients with hepatic impairment.

No dose adjustment is required in patients with Child Pugh A or B (mild to moderate) hepatic impairment. Treatment of patients with Child Pugh C hepatic impairment is not recommended (see Section 4.4 Special Warnings and Precautions for Use; Section 4.3 Contraindications).

Dose modifications for hepatotoxicity.

Guidelines for dose adjustment of Nerlynx in the event of liver toxicity are shown in Table 6. Patients who experience ≥ Grade 3 diarrhoea requiring IV fluid treatment or any signs or symptoms of hepatotoxicity, such as worsening of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia, should be evaluated for changes in liver function tests. Fractionated bilirubin and prothrombin time should also be collected during hepatotoxicity evaluation (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients contained in Nerlynx.
Co-administration with the following medical products that are strong inducers of the CYP3A4/Pgp isoform of cytochrome P450: carbamazepine, phenobarbital, phenytoin (antiepileptics); St. John's wort (Hypericum perforatum) (herbal product); rifampin (antimycobacterial).
Severe hepatic impairment (Child-Pugh C).

4.4 Special Warnings and Precautions for Use

Diarrhoea.

Diarrhoea has been reported during treatment with Nerlynx. The diarrhoea may be severe and associated with dehydration. Diarrhoea generally occurs early during the first or second week of treatment with Nerlynx and may be recurrent (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).
The diarrhoea associated with Nerlynx can be managed with either anti-diarrhoeal prophylaxis during the first 56 days of treatment and initiated with the first dose of Nerlynx, or by a two week Nerlynx dose escalation approach prior to initiation of the recommended Nerlynx treatment regimen.

Anti-diarrhoeal prophylaxis.

Patients should be instructed to initiate prophylactic treatment with an anti-diarrhoeal medicinal product (e.g. loperamide) with the first dose of Nerlynx, and maintain regular dosing of the anti-diarrhoeal medicinal product during the first 2 cycles (56 days) of Nerlynx treatment, titrating dose to achieve 1-2 bowel movements per day. Continue prophylactic anti-diarrhoeal medicinal product (e.g. loperamide) for subsequent months as needed. Do not exceed 16 mg loperamide per day. Proactive management of diarrhoea including adequate hydration combined with anti-diarrhoeal medicinal product, especially within the first 2 cycles (56 days) of Nerlynx treatment, should start at the first signs of diarrhoea. As necessary, the dose of anti-diarrhoeal medicinal product should be escalated to the highest recommended approved dose; they should be readily available to patients and continued until loose bowel movements cease for 12 hours.

Nerlynx dose escalation.

Alternatively, a two week Nerlynx dose escalation approach prior to initiation of the recommended treatment regimen with Nerlynx can also be considered for diarrhoea management (see Section 4.2 Dose and Method of Administration). Grade 3 diarrhoea was observed in 13% of patients who used Nerlynx dose escalation. The median time to first onset of Grade ≥ 3 diarrhoea was 45 days (range, 15-132) and the median cumulative duration of Grade ≥ 3 diarrhoea was 2.5 days (range, 1-6) (see Section 4.8 Adverse Effects (Undesirable Effects)).
Severe diarrhoea occurrences, despite prophylaxis treatment, should be aggressively managed with additional anti-diarrhoeal agents, electrolytes and fluids replacement, and/or interruption, reduction, or discontinuation of therapy with Nerlynx.

Patients with a significant chronic gastrointestinal disorder.

Patients with a significant chronic gastrointestinal disorder with diarrhoea as a major symptom were not included in the pivotal study and should be carefully monitored.

Left ventricular function.

Left ventricular dysfunction has been associated with HER2 inhibition. Nerlynx has not been studied in patients with less than lower limit of normal left ventricular ejection fraction (LVEF) or with significant cardiac history. In patients with known cardiac risk factors, conduct cardiac monitoring, including assessment of LVEF, as clinically indicated.

Skin and subcutaneous tissue disorders.

Nerlynx is associated with skin and subcutaneous tissue disorders. Patients with symptomatic skin and subcutaneous tissue disorders should be carefully monitored.

Use in hepatic impairment.

In patients with severe hepatic impairment (Child-Pugh C) there is a 2.8-fold increase of exposure to neratinib (see Section 5.2 Pharmacokinetic Properties).
Hepatotoxicity has been reported in patients treated with Nerlynx. Liver function tests including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin should be monitored at 1 week, then monthly for the first 3 months and every 6 weeks thereafter while on treatment or as clinically indicated (see Section 4.2 Dose and Method of Administration).

Use in renal impairment.

Patients with renal impairment are at a higher risk of complications of dehydration if they develop diarrhoea, and these patients should be carefully monitored (see Section 4.2 Dose and Method of Administration).
Nerlynx has not been studied in patients with severe renal impairment including patients on dialysis. Treatment of patients with severe renal impairment or on dialysis is not recommended (see Section 5.2 Pharmacokinetic Properties).

Proton pump inhibitors, H2-receptor antagonists and antacids.

Treatments that increase gastrointestinal pH may lower the absorption of neratinib, thus decreasing systemic exposure. Co-administration with proton pump inhibitors (PPIs) is not recommended (see Section 4.5; Section 5.2).
In case of H2-receptor antagonists or antacids, modalities of administration should be adapted (see Section 4.2; Section 4.5; Section 5.2).

Concomitant treatment with inhibitors of CYP3A4 and P-gp.

Concomitant treatment with strong or moderate CYP3A4 and P-gp inhibitors is not recommended due to risk of increased exposure to neratinib. If the inhibitor cannot be avoided, Nerlynx dose adjustment should be applied (see Section 4.2; Section 4.5; Section 5.2).

Grapefruit or pomegranate juice should be avoided during treatment with Nerlynx.

(See Section 4.2; Section 4.5).

Concomitant treatment with moderate inducers of CYP3A4 and P-gp.

Concomitant treatment with moderate CYP3A4 and P-gp inducers is not recommended as it may lead to a loss of neratinib efficacy (see Section 4.5; Section 5.2).

Concomitant treatment with substrates of P-gp.

Patients who are treated concomitantly with therapeutic agents with a narrow therapeutic window whose absorption involves P-gp transporters in the gastrointestinal tract should be carefully monitored (see Section 4.5; Section 5.2).

Use in the elderly.

Elderly patients (≥ 65 years of age) are at a higher risk of renal insufficiency and dehydration which may be a complication of diarrhoea and these patients should be carefully monitored.

Paediatric use.

The safety and efficacy of Nerlynx in the paediatric population has not been studied in breast cancer.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of other substances on neratinib.

CYP3A4 inhibitors/P-gp inhibitors.

A clinical study and model-based predictions have demonstrated that concomitant use of strong or moderate CYP3A4/P-gp inhibitors significantly increased neratinib systemic exposure, therefore, concomitant use of neratinib with strong and moderate CYP3A4/P-gp inhibitors is not recommended (e.g. strong inhibitors: atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, lopinavir, ketoconazole, itraconazole, clarithromycin, troleandomycin, voriconazole, and cobicistat; moderate inhibitors: ciprofloxacin, cyclosporin, diltiazem, fluconazole, erythromycin, fluvoxamine and verapamil). If the inhibitor cannot be avoided, Nerlynx dose adjustment should be applied (see Section 4.2; Section 4.4; Section 5.2).
Grapefruit, grapefruit juice, grapefruit hybrids, pomegranate, pomegranate juice, pomelos, starfruit, and Seville oranges may also increase neratinib plasma concentrations and should be avoided.
Co-administration of a single oral dose of 240 mg of neratinib in the presence of ketoconazole (400 mg once daily for 5 days), a strong CYP3A4/P-gp inhibitor, increased neratinib systemic exposure by 3.2- and 4.8-fold for Cmax and AUC, respectively, compared with neratinib administered alone.
Model-based predictions suggested that co-administration of a single oral dose of 240 mg of neratinib in the presence of fluconazole (200 mg once daily for 8 days), a moderate CYP3A4 inhibitor, increased neratinib systemic exposure by 1.3- and 1.7-fold for Cmax and AUC, compared with neratinib administered alone.
Model-based predictions suggested that co-administration of a single oral dose of 240 mg of neratinib in the presence of verapamil (120 mg twice daily for 8 days), a moderate CYP3A4/strong P-gp inhibitor, increased neratinib systemic exposure by 3.0- and 4.0-fold for Cmax and AUC, compared with neratinib administered alone (see Section 4.2; Section 4.4; Section 4.5).

Antidiarrhoeal loperamide.

A clinical study has demonstrated that there were no clinically significant differences in the exposure of subjects to neratinib with or without concurrent dosing with loperamide (see Section 5.2).

Effects of other treatment on neratinib.

There were no apparent clinically relevant drug-drug interactions observed for neratinib when administered concomitantly with capecitabine, paclitaxel, trastuzumab, vinorelbine, or antidiarrhoeals (loperamide) (see Section 4.5).

Proton pump inhibitors, H2-receptor antagonists and antacids.

Co-administration with proton pump inhibitors (PPIs) is not recommended (e.g. omeprazole or lansoprazole) (see Section 4.4; Section 5.2).
Nerlynx should be taken at least 2 hours before or 10 hours after the intake of the H2-receptor antagonist (see Section 4.2; Section 4.4; Section 5.2). Separate dosing of Nerlynx and antacids by at least 3 hours (see Section 4.2; Section 4.4; Section 5.2).
Neratinib solubility decreases with increasing pH. Drugs that alter the pH of the upper GI tract may alter the solubility of neratinib and hence its bioavailability. Co-administration of lansoprazole or ranitidine (1 x 300 mg) with a 240 mg single dose of neratinib in healthy volunteers resulted in a decreased neratinib exposure by around 70% or 50%, respectively. The magnitude of ranitidine interaction on neratinib AUC was reduced by around 25% by staggering the administration of ranitidine (2 x 150 mg) 2 hours after neratinib administration (see Section 4.2; Section 4.4; Section 4.5). Increasing the dose of Nerlynx when co-administered with gastric acid reducing agents is not likely to compensate for this loss of exposure (see Section 4.2 Dose and Method of Administration).

CYP3A4/P-gp inducers.

A clinical study demonstrated that concomitant use of strong CYP3A4/P-gp inducers significantly decreased neratinib exposure, therefore, concurrent use of neratinib with strong CYP3A4/P-gp inducers is contraindicated (e.g. strong inducers: phenytoin, carbamazepine, rifampicin, or herbal preparations containing St John's wort (Hypericum perforatum). Concurrent use of neratinib with moderate CYP3A4/P-gp inducers is not recommended as it may also lead to loss of efficacy (e.g. moderate inducers: bosentan, efavirenz, etravirine, phenobarbital, primidone, dexamethasone) (see Section 4.3; Section 5.2).
Following concomitant administration of 240 mg neratinib with repeated doses of 600 mg rifampicin, a strong CYP3A4/P-gp inducer, neratinib exposures were significantly decreased by 76% and 87% for Cmax and AUC, respectively, compared with neratinib administration alone (see Section 4.3; Section 4.5).

Effects of neratinib on other substances.

Hormonal contraceptives.

It is currently unknown whether Nerlynx reduces the effectiveness of systemically acting hormonal contraceptives. Therefore, women using systemically acting hormonal contraceptives should add a barrier method (see Section 4.6 Fertility, Pregnancy and Lactation).

Breast cancer resistance protein inhibitors.

Neratinib may inhibit breast cancer resistance protein (BCRP) moderately as suggested by in vitro studies. Clinical studies with BCRP substrates have not been conducted. Patients who are treated with BCRP substrates (e.g. rosuvastatin and sulfasalazine) should be monitored carefully.

P-glycoprotein transporters.

In in-vitro studies, neratinib is an inhibitor of P-glycoprotein (P-gp) substrates. In healthy subjects, digoxin increased Cmax by 54% and AUC increased by 32% when co-administered with multiple oral doses of neratinib 240 mg compared with exposures of digoxin alone. The clearance values of digoxin were equivalent following digoxin and digoxin plus neratinib. It appeared that the inhibitory effect of neratinib was primarily on P-gp activity in the gastrointestinal tract as a result of pre-systemic inhibition. This pre-systemic interaction of neratinib with digoxin might be clinically relevant for P-gp substrates with a narrow therapeutic window (e.g. dabigatran, digoxin, and fexofenadine). Patients who are treated concomitantly with therapeutic agents whose metabolism involves P-gp substrates in the gastrointestinal tract should be monitored carefully.

Other transporters.

There was no clinically relevant inhibition of human BSEP efflux transporter activity in vitro, with a reported IC50 value of > 10 microM. Neratinib at 10 microM appeared to inhibit the BCRP efflux transporter which could be clinically relevant at intestinal level (see Section 4.5).
In in vitro studies, neratinib was an inhibitor of P-glycoprotein (P-gp) efflux transporters, which was further confirmed in a clinical study. Multiple oral doses of neratinib 240 mg increased digoxin exposures (54 and 32% increase in Cmax and AUC, respectively) with no impact on its renal clearance level (see Section 4.4; Section 4.5).
Neratinib produced no inhibitory activity towards the uptake transporters, OATP1B1*1a, OATP1B3, OAT1, OAT3 and OCT2, with reported IC50 values were > 10 microM. Neratinib produced inhibitory activity in OCT1 uptake transporter, with an IC50 of 2.9 microM.

CYP substrates.

Neratinib and metabolite M6 were not potent direct inhibitors of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, or 3A4. Time-dependent inhibition of CYP3A4 and CYP2B6 by neratinib and M6 could not be excluded.
Neratinib did not induce CYP1A2, 1B6, 2C9, or 3A4.

4.6 Fertility, Pregnancy and Lactation

Women of childbearing potential/contraception in females and males.

Based on findings in animals, neratinib may cause fetal harm when administered to pregnant women. Women should avoid becoming pregnant while taking Nerlynx and for up to 1 month after ending treatment. Therefore, women of child-bearing potential must use highly effective contraceptive measures while taking Nerlynx and for 1 month after stopping treatment.
It is currently unknown whether neratinib may reduce the effectiveness of systemically acting hormonal contraceptives, and therefore women using systemically acting hormonal contraceptives should add a barrier method.
Men should use a barrier method of contraception during treatment and for 3 months after stopping treatment.

Effects on fertility.

No fertility studies in women or men have been conducted. No significant changes in fertility parameters in male and female rats were detected following oral dosing up to 12 mg/kg/day resulting in estimated exposures 22 times the clinical AUC.
(Category D)
There are no data from the use of Nerlynx in pregnant women. Studies in animals have shown embryofetal lethality and fetal morphological anomalies. In rabbits, an increased incidence of fetal skeletal variations/ abnormalities (fetal gross external (domed head), soft tissue (dilation of the brain ventricles and a ventricular septal defect), skeletal (misshapen anterior fontanelles and enlarged anterior and/or posterior fontanelles) abnormalities, ventricular septum defect of heart) were observed at an oral dose of ≥ 6 mg/kg/day, with exposures below (based on AUC) the clinical exposure.
The potential risk for humans is unknown. Nerlynx is not recommended during pregnancy and in women of childbearing potential not using contraception.
If neratinib is used during pregnancy, or if the patient becomes pregnant while taking Nerlynx, the patient should be informed of the potential hazard to the fetus.
 It is not known whether neratinib is excreted in human milk. A risk to the breast-fed infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Nerlynx, taking into account the importance of Nerlynx to the mother and the benefit of breast-feeding to the child.

4.7 Effects on Ability to Drive and Use Machines

Nerlynx has minor or moderate influence on the ability to drive and use machines. Fatigue, dizziness, dehydration, and syncope have been reported as adverse reactions with neratinib. The clinical status of the patient should be considered when assessing the patient's ability to perform tasks that require judgment, motor, or cognitive skills.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The most common adverse reactions of any grade in the pooled data from 1,710 patients were diarrhoea (93.6%), nausea (42.5%), fatigue (27.3%), vomiting (26.8%), abdominal pain (22.7%), rash (15.4%), decreased appetite (13.7%), abdominal pain upper (13.2%), stomatitis (11.2%), and muscle spasms (10.0%).
The most common Grade 3-4 adverse reactions in the pooled data from 1,710 patients were diarrhoea (Grade 3, 36.9% and Grade 4, 0.2%) and vomiting (Grade 3, 3.4% and Grade 4, 0.1%). Patients who received Nerlynx in the pivotal Phase ExteNET trial were not required to receive prophylaxis with anti-diarrhoeal agents to prevent diarrhoea.
Adverse reactions reported as serious included diarrhoea (1.9%), vomiting (1.3%), dehydration (1.1%), nausea (0.5%), alanine aminotransferase increased (0.4%), aspartate aminotransferase increased (0.4%), abdominal pain (0.3%), fatigue (0.3%) and decreased appetite (0.2%).

Tabulated list of adverse reactions.

Table 7 lists adverse reactions observed with Nerlynx based on the assessment of pooled data from 1,710 patients.
The following convention has been utilised for the classification of frequency: very common ≥ 1/10, common ≥ 1/100 but < 1/10, uncommon ≥ 1/1,000 but < 1/100, rare ≥ 1/10,000 but < 1/1,000, very rare < 1/10,000.
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Description of selected adverse reactions.

Diarrhoea. Of the 1,660 patients treated with Nerlynx monotherapy without loperamide prophylaxis, 94.6% experienced at least 1 episode of diarrhoea. 2.0% of patients experienced serious diarrhoea. Grade 3 diarrhoea was reported in 37.5% of Nerlynx patients. 0.2% of patients had diarrhoea classified as Grade 4. Diarrhoea led to hospitalisation in 1.9% of Nerlynx-treated patients.
Diarrhoea generally occurred in the first month, with 83.6% of patients reporting this toxicity in the first week, 46.9% in the second week, 40.2% in the third week and 43.2% in the fourth week (median time to first onset was 2 days). Thereafter, the incidence of diarrhoea remained relatively stable through month 12.
The median duration of a single episode of any grade diarrhoea was 2 days. The median cumulative duration of any grade diarrhoea was 59 days and the median cumulative duration of Grade 3 diarrhoea was 5 days.
Diarrhoea was also the most common adverse reaction leading to discontinuation, 14.4% of patients treated with Nerlynx without loperamide prophylaxis discontinued treatment due to diarrhoea.
Dose reductions occurred in 24.7% of Nerlynx-treated patients.
Management of diarrhoea.

CONTROL study.

The CONTROL (NCT02400476) study was a multicentre, open-label, multi-cohort trial evaluating patients with early stage HER2-positive breast cancer treated with Nerlynx 240 mg daily for up to one year receiving loperamide prophylaxis with additional anti-diarrhoeal treatment as needed or Nerlynx dose escalation with loperamide as needed. All patients in the prophylaxis cohort received loperamide 4 mg loading dose, followed by 4 mg three times a day from days 1-14, followed by 4 mg twice a day on days 15-56, followed by loperamide as needed through 1 year of treatment with Nerlynx (see Section 4.2 Dose and Method of Administration). All patients in the dose escalation cohort received Nerlynx 120 mg for Week 1, followed by Nerlynx 160 mg for Week 2, followed by Nerlynx 240 mg for Week 3 and thereafter (see Section 4.2 Dose and Method of Administration).
The diarrhoea adverse reactions for Nerlynx with loperamide prophylaxis and Nerlynx dose escalation is summarised in Table 8.
Rash. In the Nerlynx monotherapy group, 16.7% of patients experienced rash. The incidence of Grade 1 and Grade 2 was 13.3% and 2.9% respectively; 0.4% of Nerlynx-treated patients experienced Grade 3 rash.
Nail disorders. In the Nerlynx monotherapy group, 7.8% patients experience nail disorders. The incidence of Grade 1 and Grade 2 was 6.2% and 1.4% respectively. There were 0.2% of Nerlynx treated patients who experienced Grade 3 nail disorder.
Both rash and nail disorders led to treatment discontinuation in 0.6% of Nerlynx-treated patients.
Hepatotoxicity. Hepatic-associated adverse reactions in the pivotal phase III study, ExteNET (3004), were reported more frequently in the Nerlynx arm compared to the placebo arm (12.4% vs. 6.6%), due primarily to alanine aminotransferase (ALT) increased (8.5% vs. 3.2%), aspartate aminotransferase (AST) increased (7.4 vs 3.3%) and blood alkaline phosphatase increased (2.1% vs. 1.1%). Grade 3 adverse reactions were reported in 1.6% vs 0.5% and Grade 4 adverse reactions were reported in 0.2% vs. 0.1%, Nerlynx- and placebo-treated patients, respectively. Grade 3 ALT increased was reported in 1.1% vs 0.2% and Grade 4 ALT increased was reported in 0.2% vs 0.0% of Nerlynx- vs placebo-treated patients. Grade 3 AST increased was reported in 0.5% vs 0.3% and Grade 4 AST increased was reported in 0.2% vs 0.0%, of Nerlynx- vs placebo-treated patients. There was no Grade 3 or 4 adverse reactions of blood bilirubin increased.

Other special populations.

Elderly.

In the pivotal phase III study, ExteNET (3004), the mean age was 52 years in the Nerlynx arm, 1236 patients were < 65 years, 172 were ≥ 65 years, of whom 25 were 75 years or older.
There was a higher frequency of treatment discontinuations due to adverse reactions in the ≥ 65 years age group than < 65 years age group; in the Nerlynx arm, the respective percentages were 44.8% compared with 25.2%, respectively.
The incidence of serious adverse reactions in the Nerlynx arm vs placebo arm was 7.0% vs. 5.7% (< 65 years-old) and 9.9% vs. 8.1% (≥ 65 years-old). The serious adverse reactions most frequently reported in the ≥ 65 years-old group were vomiting (2.3%), diarrhoea (1.7%), dehydration (1.2%), and renal failure (1.2%).
Treatment-emergent adverse reactions leading to hospitalisation in the Nerlynx arms versus the placebo arm was 6.3% vs 4.9% in the < 65 years-old group and 8.7% vs. 8.1% in the ≥ 65 years-old group.

Effect of race.

In the pivotal phase III study, ExteNET (3004), the frequency of Treatment Emergent Adverse Events (TEAEs) in the Skin and Subcutaneous Disorders System Organ Class (SOC) in Asian patients treated with Nerlynx was higher than in Caucasian patients (56.4% vs. 34.5%) but comparable in placebo patients (24.9% vs. 22.8%). Pooled safety data of 1710 patients treated with Nerlynx monotherapy showed a higher incidence of dermatologic toxicities in Asian patients (57.1%) versus Caucasian patients (34.6%).
In the analysis of pooled safety data, the majority of TEAEs in the Skin and Subcutaneous Disorders SOC in Asians were Grade 1 (43.3%) and Grade 2 (12.3%); in Caucasians, the incidence of Grade 1 and Grade 2 events was 25.6% and 7.8%, respectively. The frequency of Grade 3 events was similar between Asians and Caucasians (1.6% vs. 1.0%). There was no difference in frequency of SAEs in the Skin SOC between Asian and Caucasian subgroups. The most common TEAEs in the Skin SOC that occurred more frequently in Asian patients than in Caucasian patients were rash (29.4% vs. 13.5%), Palmar-plantar erythrodysaesthesia syndrome (9.9% vs. 1.0%), and dermatitis acneiform (6.0 vs. 1.0%).

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 and [email protected].

4.9 Overdose

There is no specific antidote, and the benefit of haemodialysis in the treatment of Nerlynx overdose is unknown. In the event of an overdose, administration should be withheld and general supportive measures undertaken.
In the clinical trial setting, a limited number of patients reported adverse reactions associated with overdose. The adverse reactions most commonly reported were diarrhoea, with or without nausea, vomiting and dehydration.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic agent, other antineoplastic agents, protein kinase inhibitor, ATC code: L01XE45.

Mechanism of action.

Neratinib is an irreversible inhibitor of 3 epidermal growth factor receptors (EGFRs): EGFR (encoded by ERBB1), HER2 (encoded by ERBB2), and HER4 (encoded by ERBB4). Neratinib binds to the HER2 receptor, reduces EGFR and HER2 autophosphorylation, downstream MAPK and AKT signalling pathways, and inhibits tumour cell proliferation in vitro. In vivo, oral administration of neratinib inhibited tumour growth in mouse xenograft models with tumour cell lines expressing HER2 and EGFR.

Clinical trials.

In the multicentre, randomised, double-blind, placebo-controlled, pivotal phase III study, ExteNET (3004), 2,840 women with early-stage HER2-positive breast cancer (as confirmed locally by assay) who had completed adjuvant treatment with trastuzumab were randomised 1:1 to receive either Nerlynx or placebo daily for one year. The median age in the intention-to-treat (ITT) population was 52.3 years (59.9% was ≥ 50 years old, 12.3% was ≥ 65 years old); 81.0% were Caucasian, 2.6% black or African American, 13.6% Asian and 2.9% other. At baseline, 57.4% had hormone receptor positive disease (defined as ER-positive and/or PgR-positive), 23.6% were node negative, 46.8% had one to three positive nodes and 29.6% had four or more positive nodes. Approximately 10% of patients had Stage I tumours, approximately 40% had Stage II tumours and approximately 30% had Stage III tumours. Median time from the last adjuvant trastuzumab treatment to randomisation was 4.5 months.
The primary endpoint of the study was invasive disease-free survival (iDFS). Secondary endpoints of the study included disease-free survival (DFS) including ductal carcinoma in situ (DFS-DCIS), time to distant recurrence (TTDR), distant disease-free survival (DDFS), cumulative incidence of central nervous system recurrence and overall survival (OS).
The primary analysis of the study 2 years post-randomisation demonstrated that Nerlynx significantly reduced the risk of invasive disease recurrence or death by 34% (HR=0.66 with 95% CI (0.49, 0.90), two-sided p = 0.008) in the ITT population.
The results for the primary and secondary endpoints are shown in Table 9.
Figure 1 shows the Kaplan-Meier plots for iDFS for the ITT population of study ExteNET (3004).
Figure 2 shows the Forrest Plot for iDFS by pre-specified patient subgroup.
Approximately 75% of patients were re-consented for extended follow-up beyond 24 months. This exploratory analysis confirms that the iDFS results at 5 years are durable and consistent with the 2-year iDFS results.
Figure 3 shows a descriptive analysis of the 5-year iDFS that demonstrated the durability of the treatment effect on efficacy. The Hazard Ratio is 0.73 (95% CI 0.57, 0.92) for the ITT population.
Of the 2840 women in the ITT population (Nerlynx, n = 1420; placebo, n = 1420), 1334 had HR+ tumours and were randomised to start study treatment within 1 year of completing trastuzumab (Nerlynx, n = 670; placebo, n = 664).
Among patients with HR+ tumours who started Nerlynx within 1 year of completing trastuzumab, there was an absolute iDFS benefit of 4.5% with Nerlynx after 2 years' follow-up [hazard ratio 0.49; 95% CI 0.30-0.78; p = 0.002].
In the subgroup of patients with HR+ disease who commenced Nerlynx less than one year after completing trastuzumab therapy:
An absolute DDFS benefit of 3.2% was evident with Nerlynx after 2 years [hazard ratio 0.53; 95% CI 0.31-0.88; p = 0.015].
The number of CNS recurrence events was low at 2 years (Nerlynx, n = 2; placebo, n = 6); the cumulative incidence of CNS recurrences at 2 years was 0.34% with Nerlynx and 1.01% with placebo (p = 0.187).
The median OS follow-up time for the ITT population was 8.06 years, 8.03 years in the neratinib arm and 8.10 years in the placebo arm, with a total of 1542 (54.3%) patients followed up for survival for 8 or more years, 746 (52.5%) in the neratinib arm and 796 (56.1%) in the placebo arm. The number of deaths was 264 (9.3%), with 127 (8.9%) in the patients treated with neratinib and 137 (9.6%) in the patients treated with placebo. There was no statistically significant difference in overall survival between the Nerlynx and the placebo arm [HR 0.96 (95% CI: 0.75, 1.22)] in the ITT population at a median follow-up of 8.06 years.
In the hormone receptor positive population who were less than one year from completion of trastuzumab therapy, after a median follow-up of 8.0 years, 53 (7.9%) of 670 patients in the neratinib group and 68 (10.2%) of 664 patients in the placebo group had died. The hazard ratio of OS was 0.79 (95% CI, 0.55-1.13), and the estimated 8-year OS rates were 91.5% (95% CI, 88.9%-93.5%) in the neratinib group and 89.4% (95% CI, 86.6%-91.6%) in the placebo group.

5.2 Pharmacokinetic Properties

The mass balance after administration of a single oral dose of 200 mg of neratinib was studied in six healthy subjects.

Absorption.

Following oral administration of 240 mg neratinib, absorption was slow and peak plasma concentrations of neratinib occurred around 7 hours after administration. A single dose of 240 mg neratinib taken with food increased Cmax and AUC by approximately 17% and 13%, respectively, compared with administration in the fasting state. A single oral dose of 240 mg neratinib taken with a meal high in fat increased both Cmax and AUC by approximately 100%. In a mass balance study, the total recovery (urinary and fecal excretion) of intact neratinib and metabolites demonstrates that the fraction absorbed for neratinib is at least 10% and likely more than 20%. Moreover, model-based predictions suggested an overall absorbed fraction from the gut (fa) of 26%.
In vitro neratinib solubility is pH-dependent. Treatments that increase gastrointestinal pH may lower the absorption of neratinib, thus decreasing systemic exposure.

Distribution.

Binding of neratinib to human plasma proteins, including covalent binding to human serum albumin (HSA), was greater than 98% and independent of concentration. Neratinib bound predominantly to HSA and human alpha-1 acid glycoprotein (AAG). In vitro, neratinib inhibited P-gp and BCRP at concentrations similar to the expected intestinal concentrations of neratinib. Neratinib produced no clinically-relevant inhibitory activity towards the transporters, BSEP, OATP1B1*1a, OATP1B3, OAT1, OAT3, OCT1 and OCT2.

Metabolism.

Neratinib is metabolised primarily in liver microsomes by CYP3A4 and to a lesser extent by flavin-containing monooxygenase (FMO).
Metabolite profiling in human plasma indicates that after oral administration, neratinib undergoes oxidative metabolism through CYP3A4. Circulating metabolites include neratinib pyridine N-oxide (M3), N-desmethyl neratinib (M6), neratinib dimethylamine N-oxide (M7) and traces of hydroxyl neratinib N-oxide and neratinib bis-N-oxide (M11). Neratinib represents the most prominent component in plasma and systemic exposure to the metabolites (M3, M6, M7 and M11) after oral administration of neratinib is between 10% and 33% lower than parent in healthy subjects. The neratinib metabolites M3, M6, M7 and M11 were shown to have similar or lower potencies to neratinib in either in vitro enzyme (binding assays) or cell based assays against cells expressing ERBB1, ERBB2 (HER2) and ERBB4.
Based on steady-state exposures, neratinib provides the majority of pharmacological activity (73%), with 20% provided by exposure to M6, 6% provided by M3, and negligible contribution (< 1%) from M7 and M11 AUC.

Elimination.

Following single doses of neratinib, the mean apparent plasma half-life of neratinib was 17 hours in patients.

Excretion of neratinib is primarily via the faeces.

Following the administration of a single radiolabelled dose of 240 mg neratinib oral solution, 95.5% and 0.96% of the administered dose was recovered in the faeces and urine, respectively.
The excretion was rapid and complete, with most of the dose recovered in faeces within 48 hours and 96.5% of total radioactivity recovered in excreta after 8 days.
Unchanged neratinib was the most abundant species in excreta accounting for 62.1% of total dose recovered in excreta. The most abundant metabolites in faeces were M6 (19.7% of administered dose), followed by M2, M3 and M7, all below 10% of administered dose.

Pharmacokinetic/pharmacodynamic relationship(s).

Renal impairment.

Pharmacokinetic studies in patients with renal impairment or undergoing dialysis have not been carried out. Population pharmacokinetic modelling revealed that creatinine clearance did not explain the variability between patients, hence, no dose modifications are recommended for patients with mild to moderate renal impairment.

Hepatic impairment.

Neratinib is extensively metabolised in the liver. In subjects with severe pre-existing hepatic impairment (Child Pugh Class C) without cancer, the clearance of neratinib was decreased by 36% and exposure to neratinib increased by about 3-fold as compared to healthy volunteers.

5.3 Preclinical Safety Data

Adverse reactions not observed in clinical studies but seen in animals at exposure levels like clinical exposure levels and with possible relevance to clinical use were as follows:

Genotoxicity.

Nerlynx was not genotoxic in various in vitro and in vivo genotoxicity studies including the bacterial reverse mutation assay, an in vitro mammalian chromosome aberration assay in human peripheral blood lymphocytes and an in vivo bone marrow micronucleus study in mice.
Neratinib metabolites M3, M6, M7 and M11 were negative in the bacterial reverse mutation assay and in vitro mammalian chromosome aberration assay in human peripheral blood lymphocytes. M3 and M11 were negative in a mouse and rat micronucleus test, respectively.

Carcinogenicity.

Neratinib was not carcinogenic in rats up to 10 mg/kg/day (18-30 x the clinical AUC) administered by oral route for 24 months. Neratinib did not show any carcinogenic potential in Tg.rasH2 transgenic mice when administered at oral doses up to ≤ 50 mg/kg/day in males and ≤ 125 mg/kg/day in females, resulting in exposures 9-35 x the clinical AUC.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core.

Mannitol, microcrystalline cellulose, crospovidone, povidone, colloidal anhydrous silica, magnesium stearate.

Tablet coating.

Polyvinyl alcohol, titanium dioxide, macrogol 3350, purified talc, iron oxide red.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions for further information.

6.3 Shelf Life

3 years.

6.4 Special Precautions for Storage

Store below 25°C. Keep the bottle tightly closed in order to protect from moisture.

6.5 Nature and Contents of Container

White, 60 mL high density polyethylene (HDPE) round bottle with child-resistant, polypropylene closure, and foil induction inner seal.
An HDPE desiccant canister with 1 g silica gel is enclosed with the tablets in each bottle.
Each bottle contains either 133 or 180 tablets. Not all presentations may be marketed.

6.6 Special Precautions for Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


Chemical name: (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy) anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate.
Molecular weight: 673.1 (neratinib maleate); 557.1 (neratinib).

CAS number.

915942-22-2 (neratinib maleate); 698387-09-6 (neratinib).
The active ingredient, neratinib maleate, is an off-white to yellow powder. Its solubility decreases as pH increases over the range 1.2 - 9.6; it is insoluble at pH above 5.0 (e.g. in water). The API is slightly soluble in ethanol and sparingly soluble in methanol. The dissociation constant is pKa 7.65 and pKa 4.66. The partition coefficient is logP 4.72 and logP 4.47.

7 Medicine Schedule (Poisons Standard)

S4 / Prescription Medicine.

Summary Table of Changes