Consumer medicine information

Tykerb

Lapatinib

BRAND INFORMATION

Brand name

Tykerb

Active ingredient

Lapatinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tykerb.

SUMMARY CMI

TYKERB®

Consumer Medicine Information (CMI) summary

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

1. Why am I taking TYKERB?

TYKERB contains the active ingredient lapatinib. TYKERB is used to treat breast cancer that may have spread to other parts of your body. For more information, see Section 1. Why am I taking TYKERB? in the full CMI.

2. What should I know before I take TYKERB?

Do not use if you have ever had an allergic reaction to TYKERB or any of the ingredients listed at the end of the CMI. TYKERB may also be used with other medicines including trastuzumab, paclitaxel, capecitabine or other medicines called "aromatase inhibitors" so it is important to read the Consumer Medicine Information (CMI) for these medicines as well.
Talk to your doctor if you have any other medical conditions affecting your heart, lungs, or liver. Your doctor will want to monitor these closely and will send you for regular blood tests to check how you are responding to treatment. Tell your doctor if you 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 take TYKERB? in the full CMI.

3. What if I am taking other medicines?

Some medicines interfere with TYKERB and affect how it works. Grapefruit in any form will also affect how well TYKERB 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 take TYKERB?

  • Your doctor will decide how much TYKERB you will need to take. This may change depending on how your body responds or whether you are taking any additional medicines for your breast cancer.
  • TYKERB must be taken on an empty stomach at least 1 hour before or 1 hour after eating.

More instructions can be found in Section 4. How do I take TYKERB? in the full CMI.

5. What should I know while taking TYKERB?

Things you should do
  • Remind any doctor, dentist, or pharmacist you visit that you are taking TYKERB.
  • Use effective contraception to avoid becoming pregnant.
  • Tell your doctor immediately if you are pregnant or think you are pregnant.
Things you should not do
  • Do not stop taking this medicine suddenly.
  • Do not take TYKERB with grapefruit or grapefruit juice of any kind
Driving or using machines
  • Tykerb can cause tiredness and may make you unfit to drive. Talk to your doctor.
Looking after your medicine
  • Keep TYKERB tablets in its original packaging until it is time to take them.
  • Store in a cool, dry place below 30°C.

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

6. Are there any side effects?

Common side effects include feeling sick, dizzy, or tired, weight loss, diarrhoea, tummy pain, sore throat, dry, cracked skin/nails, hair loss, nose bleeds, feeling sore, sore/red mouth, back pain, trouble sleeping, rash, red/irritated and itchy skin. More serious side effects include trouble breathing, wheezing, fainting, chest pain, blue lips or skin, yellowing of skin or eyes, blistering or swelling of skin, eyes, lips or tongue, changes to heart rate, severe tummy pain/diarrhoea, tingling or numbness in hands, feet or limbs, trouble doing a wee; cracked lips and skin while feeling very thirsty, weakness, chills, pale skin, being more sick than usual.
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

TYKERB® (TIE-curb)

Active ingredient(s): lapatinib (La·pa·tee-nib)

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I taking TYKERB?

TYKERB contains the active ingredient lapatinib. TYKERB is a medicine known as a 'protein kinase inhibitor' meaning when used with other medicines, it may slow or stop the spread of cancer cells that have originated from your breast.

TYKERB is used with other medicines to treat breast cancer that may or may not yet have spread to other parts of your body. When cancer cells spread to other parts of your body (a process called "metastasis") they may be growing because of hormones (chemicals) that are naturally produced in your body such as oestrogen and progesterone.

2. What should I know before I take TYKERB?

Warnings

Do not take TYKERB if:

  • You are allergic to lapatinib, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • The expiry date has passed on the packaging or shows evidence of tampering.
  • You are under 18 years of age

Some signs of an allergic reaction may include difficulty breathing or shortness of breath leading to pale or blue lips/skin. Other signs can include swelling of the lips, face, or tongue as well as skin problems including rash, hives or painful and itchy red skin that are sudden and spreading.

Check with your doctor if you:

  • have a heart condition for example an irregular heartbeat
  • have any lung problems or breathing difficulties
  • have a liver condition
  • are taking other medicines to treat infections (such as ketoconazole, itraconazole, rifampin) or epilepsy (carbamazepine, phenytoin). See section "what if I am taking other medicines"
  • have any allergies to food, preservatives, dyes or other medicines

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?

Monitoring

Your doctor may want to monitor your heart and lungs while you are on treatment with TYKERB.

Your doctor may also send you for blood tests before starting treatment or once you have started treatment to monitor your liver function.

These blood tests may also be looking for the number of white blood cells in your body as TYKERB when used with some medicines may reduce the number of white blood cells in your body. This can make you more likely to get sick.

Your doctor may alter your treatment plan depending on your results.

Changes to toilet habits

Tell your doctor immediately if you have noticeable changes to your toilet habits including severe diarrhoea or if you are unable to go to the toilet at all. Your doctor may choose to stop TYKERB treatment if the problem persists or prescribe you with additional medicines to treat diarrhoea.

Skin reactions

Tell your doctor immediately if you have a rash on your skin that is spreading/getting worse. Your doctor may choose to stop treatment with TYKERB based on this.

Birth control

You should avoid becoming pregnant while taking TYKERB. TYKERB may harm your unborn baby.

You must use a reliable form of birth control (contraception) during treatment with TYKERB and for at least 5 days after your last dose. Your doctor can provide you advice on the most effective method.

Taking TYKERB with other medicines

TYKERB is generally taken with other medicines for cancer including trastuzumab, paclitaxel, capecitabine or other medicines called "aromatase inhibitors" (see section "What if I am taking other medicines"). You should also read the "Consumer Medicine Information" for these medicines carefully.

Taking TYKERB with food

TYKERB must be taken on an empty stomach at least 1 hour before OR 1 hour after eating.

You should not drink grapefruit juice or eat grapefruit during your treatment with TYKERB. It may make this medicine less effective and possibly increase the chance of side effects.

Pregnancy and breastfeeding

Tell your doctor straight away if you are pregnant or think you may be pregnant. Talk to your doctor before starting treatment with TYKERB if you intend to become pregnant.

Do not breastfeed while taking TYKERB and for at least 5 days after stopping treatment with TYKERB as it may harm your baby.

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.

Taking TYKERB with a medicine called 'trastuzumab'

Trastuzumab is given to you in a hospital and can also be used to treat breast cancer where the cancer may have spread to other parts of your body. Your doctor may consider your dose of TYKERB carefully if you are taking trastuzumab.

Taking TYKERB with a medicine called 'paclitaxel'

Paclitaxel is given to you in a hospital and can also be used to treat breast cancer where the cancer may have spread to other parts of your body. TYKERB may increase the effect of paclitaxel on your body. When taken together, it may cause more severe diarrhoea and changes to your blood test results.

Your doctor may consider your dose of TYKERB carefully if you are also taking paclitaxel.

Taking TYKERB with a medicine called 'capecitabine'

Capecitabine can also be used to treat breast cancer where the cancer may have spread to other parts of your body. Your doctor may consider your dose of TYKERB carefully if you are also taking capecitabine.

Taking TYKERB with medicines called 'aromatase inhibitors'

Aromatase inhibitors (such as medicines containing 'letrozole') can also be used to treat breast cancer that may have spread to other parts of your body. Your doctor may consider your dose of TYKERB carefully if you are also taking letrozole or any other similar medicine.

Other medicines that may affect how well TYKERB works

  • Erythromycin, ketoconazole, itraconazole, posaconazole, voriconazole, rifabutin, rifampicin, telithromycin (used to treat infections).
  • Ritonavir, saquinavir (used to treat HIV).
  • Cisapride (used to treat digestive system problems).
  • Esomeprazole or other drugs that decrease stomach acidity (used to treat stomach ulcers or indigestion).
  • Medicines used for sedation before surgery (anaesthesia), such as midazolam.
  • Quinidine, digoxin (used to treat heart problems)
  • Verapamil (used to treat high blood pressure or angina)
  • Rosuvastatin (used to treat high cholesterol)
  • Repaglinide (used to treat diabetes)
  • Phenytoin, carbamazepine (used to treat seizures)
  • Pimozide (used to treat mental health problems)
  • Nefazodone (used to treat depression)
  • St John's Wort (herb extract used to treat depression)
  • Cyclosporin (used to prevent the rejection of transplanted organs)
  • Topotecan, irinotecan, docetaxel (used to treat cancer).

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

4. How do I take TYKERB?

How much TYKERB to take

  • Follow all instructions from your doctor.
  • Your doctor will decide how much TYKERB you need to take. Depending on how well you respond to treatment or if you have any side effects, your doctor may change your dose or stop treatment.
  • You may be taking other medicines for your breast cancer in addition to TYKERB. See below for the usual amount of TYKERB you would be taking in those settings.

Taking TYKERB with a medicine called 'trastuzumab'

  • The usual amount is 4 (four) TYKERB tablets taken once a day continuously (a total daily dose of 4 x 250 mg tablets is 1000 mg a day) along with the amount of trastuzumab your doctor tells you to.

Taking TYKERB with a medicine called 'paclitaxel'

  • The usual amount is 6 (six) TYKERB tablets taken once a day continuously (a total daily dose of 6 x 250 mg tablets is 1500 mg each day) along with the amount of paclitaxel your doctor tells you to.

Taking TYKERB with a medicine called 'capecitabine'

  • The usual amount is 5 (five) TYKERB tablets taken once a day continuously (a total daily dose of 5 x 250 mg tablets which is 1250 mg each day) along with the amount of capecitabine your doctor tells you to.

Taking TYKERB with other medicines known as 'aromatase inhibitors'

  • The usual amount is 6 (six) TYKERB tablets taken once a day continuously (a total daily dose of 6 x 250 mg tablets is 1500 mg each day) along with the amount of aromatase inhibitor your doctor tells you to.

Your doctor will tell you how much trastuzumab, paclitaxel, capecitabine, or aromatase inhibitor you should take and when you should take it. These medicines may have a different schedule to TYKERB that you will also need to follow.

How to take TYKERB

  • TYKERB must be taken on an empty stomach at least 1 hour before OR 1 hour after eating.
  • TYKERB tablets need to be swallowed whole with a glass of water. You must not chew, crush, or split the tablets before you swallow it.

When to take TYKERB

  • Take TYKERB at the same time every day to help you remember to take it regularly.
  • TYKERB must be taken at least one hour before or after you eat.

How long to take TYKERB

  • Keep taking TYKERB until your doctor tells you to stop.

If you forget to take TYKERB

If it is almost time for your next 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 you missed.

If you take too much TYKERB

If you think that you have used too much TYKERB, 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 taking TYKERB?

Things you should do

  • Attend all your appointments with your doctor as well as any other ones where your heart, lungs or kidneys are being checked.
  • Get your blood tests done promptly so your doctor can check how your body is responding to TYKERB.
  • Continue taking TYKERB as well as any other medicines you may be taking as directed by your doctor for as long as they tell you to.
  • Use effective birth control to avoid becoming pregnant (see section on "Pregnancy and breastfeeding").
  • Make sure you take TYKERB on an empty stomach. At least one hour before OR 1 hour after eating.

Call your doctor straight away if you:

  • Are pregnant or think you may be pregnant.
  • Are experiencing a sudden angry-looking rash, hives or blisters on your skin that is spreading.
  • Are experiencing check pain, trouble breathing or shortness of breath.
  • Are experiencing noticeable changes to your toilet habits.
  • Are experience swelling of your lips, tongue or face

Remind any doctor, dentist, or pharmacist you visit that you are taking TYKERB.

Things you should not do

  • Do not drink grapefruit juice or eat grapefruits while you are taking TYKERB.
  • Do not give this medicine to someone else.
  • Do not stop taking this medicine suddenly.

Driving or using machines

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

TYKERB can cause tiredness and may make you unfit to drive.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Keep TYKERB tablets in its original packaging until it is time to use it.
  • Store in a cool, dry place below 30°C.

Do not store TYKERB in the bathroom or near a sink. Do not store in the car or on a windowsill.

Keep it where young children cannot reach it.

When to discard your medicine

You must only discard this medicine if your Doctor tells you to stop taking TYKERB or if the expiry date on the packaging has passed.

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
Tummy problems:
  • Tummy discomfort/indigestion
  • Loss of appetite
  • Constipation (unable to poo)
General well-being:
  • Feeling tired
  • Feeling dizzy
  • Feeling or being sick (vomiting)
  • Trouble sleeping
  • Nose bleeds
  • Headaches
  • Mouth sores (ulcer) or redness
  • Hair loss
  • Weight loss
Muscle problems
  • Sore muscles
  • Back pain
  • Pain in limbs
Skin and nail problems:
  • Dry or cracked skin
  • Dry nails
  • Infected nails or swelling of nails
  • Itchy skin
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
Breathing problems
  • Shortness of breath or wheezing
  • Blue lips or tongue
  • Feeling faint, weak, light-headed, or fainting
Heart problems:
  • Irregular heartbeat or chest pain
  • Changes to your heart's electrical rhythm
  • Tingling ('pins and needles') numbness of the arms and legs
Liver problems:
  • Yellow eyes
Tummy problems:
  • Severe/uncontrolled diarrhoea
  • Severe tummy pain
Kidney problems:
  • Very dark wee, pain when going to the toilet, unable to go to the toilet.
Skin problems:
  • Yellow skin
  • Blistering (especially on the lips, eyes, or mouth) or hives
  • Red itchy rash that is spreading or skin peeling.
  • Tingling, pain, swelling or redness on your hands and feet, your lips, tongue, eyes, or face.
Infections and blood problems:
  • Feeling sick or weak constantly
  • Fever, chills, sore throat
  • Pale skin
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
As you will likely be taking TYKERB with another medicine you may experience effects related to TYKERB or one of these other medicines.

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. 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.

Each TYKERB tablet contains the active ingredient lapatinib ditosilate monohydrate, equivalent to 250 mg of lapatinib.

What TYKERB contains

Active ingredient
(main ingredient)		Lapatinib ditosilate monohydrate (lapatinib)
Other ingredients
(inactive ingredients)
  • Microcrystalline cellulose (E460)
  • Povidone (E1201)
  • Sodium starch glycollate type A
  • Magnesium stearate (E572) (vegetable origin)
  • Hypromellose (E464)
  • Titanium dioxide (E171)
  • Macrogol (E1521)
  • Polysorbate (E433)
  • Iron oxide yellow (E172)
  • Iron oxide red (E172)
Potential allergensTYKERB tablets do not contain lactose, sucrose, tartrazine, or any other azo dyes.

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

What TYKERB looks like

TYKERB is supplied in plastic bottles containing 70 tablets.

TYKERB 250 mg tablets are oval, rounded on both sides, yellow film-coated, and with GS XJG imprinted on one side (AUST R 185997).

Who distributes TYKERB

Tykerb is supplied in Australia by:
Novartis Pharmaceuticals Australia Pty Limited
54 Waterloo Road,
Macquarie Park, NSW 2113, Australia
Telephone 1 800 671 203
ABN 18 004 244 160
www.novartis.com.au

® = Registered Trademark

This leaflet was prepared in November 2023.

Internal document code:
tyk270522c_v2 based on PI tyk270522i.

Published by MIMS December 2023

BRAND INFORMATION

Brand name

Tykerb

Active ingredient

Lapatinib

Schedule

S4

 

1 Name of Medicine

Lapatinib (as ditosilate monohydrate).

2 Qualitative and Quantitative Composition

Active substance.

Each Tykerb tablet contains 405 mg of lapatinib ditosilate monohydrate, which is equivalent to 250 mg of lapatinib free base. Lapatinib is a member of 4-anilinoquinazoline class of kinase inhibitors.

Excipients.

For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Yellow, oval, biconvex, film-coated tablet, with GS XJG debossed on one face of the tablet and a plain reverse face.

4 Clinical Particulars

4.1 Therapeutic Indications

Human epidermal growth factor receptor 2 positive (HER2+) over expressing advanced or metastatic breast cancer.

Tykerb is indicated in combination with:
An aromatase inhibitor for the treatment of post-menopausal women with hormone receptor-positive metastatic breast cancer whose tumours overexpress HER2 (ErbB2) (epidermal growth factor receptor 2) and for whom hormonal therapy is indicated.
Capecitabine for the treatment of patients with advanced/metastatic breast cancer whose tumours overexpress HER2 (ErbB2) and whose tumours have progressed after treatment with an anthracycline and a taxane, and who have progressed on prior trastuzumab therapy in the metastatic setting.
Paclitaxel for the first-line treatment of patients with metastatic breast cancer whose tumours overexpress HER2 (ErbB2) and for whom trastuzumab is not appropriate (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Tykerb should only be initiated by a physician experienced in the administration of anticancer agents.
Prior to the initiation of treatment, left ventricular ejection fraction (LVEF) must be evaluated in all patients, using echocardiogram or multigated acquisition (MUGA), to ensure that baseline LVEF is within the institutional limits of normal (see Section 4.4 Special Warnings and Precautions for Use). LVEF must continue to be monitored during treatment with Tykerb to ensure that LVEF does not decline below the institutional lower limit of normal (LLN) (see Section 4.2 Dose and Method of Administration, Dose delay and dose reduction (all indications), Cardiac events).
HER2 protein overexpression or gene amplification is necessary for the selection of patients for whom Tykerb therapy is appropriate. Evidence of a previous positive test result for HER2 overexpression or gene amplification should be confirmed before initiating therapy with Tykerb. If historical results are not available, repeat HER2 testing should be considered.
Assessment of HER2 overexpression and/or of HER2 gene amplification should be performed by laboratories with accreditation or demonstrated proficiency. HER2 overexpressing tumours are defined by a score of 3+ using an immunohistochemistry (IHC)-based assessment, or IHC2+ and gene amplification or gene amplification alone.
Treatment with Tykerb should be continued until disease progression or unacceptable toxicity occurs.

Dosage.

HER2+ over expressing advanced or metastatic breast cancer.

General target population.

Tykerb in combination with capecitabine.

The recommended dose of Tykerb is 1250 mg (i.e. five tablets) once daily continuously when taken in combination with capecitabine.
The recommended dose of capecitabine is 2000 mg/m2/day taken in 2 doses 12 hours apart on days 1-14 in a 21 day cycle (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Capecitabine should be taken with food or within 30 minutes after food.

Tykerb in combination with paclitaxel.

The recommended dose of Tykerb is 1500 mg (i.e. six tablets) once daily continuously in combination with paclitaxel. When coadministered with Tykerb, the recommended dose of paclitaxel is 80 mg/m2 on days 1, 8, and 15 of a 28 day schedule. Alternatively, paclitaxel may be given at a dose of 175 mg/m2 every 21 days (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Tykerb in combination with an aromatase inhibitor.

The recommended dose of Tykerb is 1500 mg (i.e. six tablets) once daily continuously when taken in combination with an aromatase inhibitor.
When Tykerb is coadministered with the aromatase inhibitor letrozole, the recommended dose of letrozole is 2.5 mg once daily. If Tykerb is coadministered with an alternative aromatase inhibitor, please refer to the product information of the medicinal product for dosing details.
Special populations.

Use in hepatic impairment.

Patients with severe hepatic impairment (Child-Pugh class C) should have their dose of Tykerb reduced. A dose reduction from 1250 mg/day to 750 mg/day or from 1500 mg/day to 1000 mg/day in patients with severe hepatic impairment is predicted to adjust the area under the curve (AUC) to the normal range. However, there are no clinical data with this dose adjustment in patients with severe hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Special populations, Hepatic impairment).

Use in renal impairment.

See Section 5.2 Pharmacokinetic Properties, Special populations.

Use in the elderly.

There are limited data on the use of lapatinib in patients aged 65 years and older. See Table 1.
No age based differences in the safety or efficacy of these regimens were observed. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Greater sensitivity of elderly individuals cannot be ruled out.

Paediatric use.

The safety and efficacy of Tykerb in patients below 18 years of age has not been established.
Dose delay and dose reduction (all indications).

Cardiac events.

Tykerb should be interrupted in patients with symptoms associated with decreased LVEF that are National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade 3 or greater or if their LVEF drops below the institution's lower limit of normal. Tykerb may be restarted at a reduced dose (1000 mg/day when administered with capecitabine and 1250 mg/day when administered with paclitaxel or an aromatase inhibitor) after a minimum of 2 weeks and if the LVEF recovers to normal and the patient is asymptomatic. Based on current data, the majority of LVEF decreases occur within the first 12 weeks of treatment, however, there is limited data on long term exposure. Also see Section 4.4 Special Warnings and Precautions for Use.

Interstitial lung disease/pneumonitis.

Tykerb should be discontinued in patients who experience pulmonary symptoms indicative of interstitial lung disease/pneumonitis, which are NCI CTCAE grade 3 or greater. See Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects).

Diarrhoea.

Tykerb dosing should be interrupted in patients with diarrhoea which is NCI CTCAE grade 3 or grade 1 or 2 with complicating features (moderate to severe abdominal cramping, nausea or vomiting greater than or equal to NCI CTCAE grade 2, decreased performance status, fever, sepsis, neutropenia, frank bleeding or dehydration). Tykerb may be reintroduced at a lower dose (reduced from 1000 mg/day to 750 mg/day, from 1250 mg/day to 1000 mg/day or from 1500 mg/day to 1250 mg/day) when diarrhoea resolves to grade 1 or less. Tykerb dosing should be permanently discontinued in patients with diarrhoea which is NCI CTCAE grade 4. See Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects).

Severe cutaneous reactions.

Lapatinib should be discontinued in patients who experience severe progressive skin rash with blisters or mucosal lesions. See Section 4.4 Special Warnings and Precautions for Use.

Other toxicities.

Discontinuation or interruption of Tykerb may be considered when a patient develops toxicity greater than or equal to NCI CTCAE grade 2. Dosing can be restarted at either, 1250 mg/day when administered with capecitabine or 1500 mg/day when administered with paclitaxel or an aromatase inhibitor, when the toxicity improves to grade 1 or lower. If the toxicity recurs, Tykerb should be restarted at a lower dose (1000 mg/day when administered with capecitabine and 1250 mg/day when administered with paclitaxel or an aromatase inhibitor).

Dose delay and dose reduction (administration with paclitaxel).

Discontinuation or interruption of dosing with Tykerb may be considered when a patient develops toxicity greater than or equal to grade 2 on the NCI CTCAE. Dosing can be restarted at 1500 mg/day when toxicity improves to grade 1 or less. If the toxicity recurs, then Tykerb should be restarted at 1250 mg/day.
Taxanes are also associated with bone marrow suppression and other toxicities. The full prescribing information for paclitaxel should be referred to for advice on dose delay and dose reduction of paclitaxel.

Administration.

Tykerb should be taken at least one hour before, or at least one hour after food (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.2 Pharmacokinetic Properties, Absorption). The recommended daily Tykerb dose should not be divided. Missed doses should not be replaced and the dosing should resume with the next scheduled daily dose (see Section 4.9 Overdose).
Consult the product information of the co-administered medicinal product for relevant details of their dosage, contraindications and safety information.

4.3 Contraindications

Tykerb is contraindicated in patients with hypersensitivity to any of the ingredients (see Section 6.1 List of Excipients; Section 4.8 Adverse Effects (Undesirable Effects)).

4.4 Special Warnings and Precautions for Use

Cardiac toxicity.

Left ventricular ejection fraction (LVEF). Tykerb has been associated with decreases in LVEF. In clinical studies cardiac events, including LVEF decreases, were observed in patients who received Tykerb (see Section 4.8 Adverse Effects (Undesirable Effects)). Caution should be taken if Tykerb is to be administered to patients with conditions that could impair left ventricular function. LVEF should be evaluated in all patients prior to initiation of treatment with Tykerb to ensure that it is within the institution's normal limits. LVEF should continue to be evaluated during treatment with Tykerb at approximately 8-12 week intervals to ensure that LVEF does not decline to an unacceptable level (see Section 4.2 Dose and Method of Administration, Dose delay and dose reduction (all indications), Cardiac events; Section 5.1 Pharmacodynamic Properties, Clinical trials).
QT prolongation. A concentration dependent QTc interval increase has been observed in a dedicated placebo-controlled crossover study in subjects with advanced solid tumours. Electrocardiograms with QT measurement should be considered prior to administration of Tykerb and throughout treatment.

Study EGF114271.

The effect of lapatinib on the QT-interval was evaluated in a single-blind, placebo-controlled, single sequence (placebo and active treatment) crossover study in patients with advanced solid tumours (N = 58). Patients with cardiac conduction abnormalities and abnormal baseline ECG findings (including of QTcF interval > 480 ms) were excluded from the study. During the 4-day treatment period, three doses of matching placebo were administered 12 hours apart in the morning and evening on day 1 and in the morning on day 2. This was followed by three doses of lapatinib 2000 mg administered in the same way. Measurements, including ECGs and pharmacokinetic samples were done at baseline and at the same time points on day 2 and day 4.
In the evaluable population (N = 37), the maximum mean ΔΔQTcF (90% CI) of 8.75 ms (4.08, 13.42) was observed 10 hours after ingestion of the third dose of lapatinib 2000 mg. The ΔΔQTcF exceeded the 5 ms threshold and the upper bound 90% CIs exceeded the 10 ms threshold at multiple time points. The results for the PD population (n = 52) were consistent with those from the evaluable population (maximum ΔΔQTcF (90% CI) of 7.91 ms (4.13, 11.68) observed 10 hours after ingestion of the third dose of lapatinib. The PK/PD analyses confirmed the presence of a positive relationship between lapatinib plasma concentrations and ΔΔQTcF.
Caution should be taken if Tykerb is administered to patients who have or may develop prolongation of QTc. These conditions include patients with hypokalaemia or hypomagnesemia, congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products that lead to QT prolongation. Hypokalaemia, hypocalcaemia or hypomagnesemia should be corrected prior to Tykerb administration.

Interstitial lung disease and pneumonitis.

Tykerb has been associated with reports of interstitial lung disease and pneumonitis (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease/pneumonitis (see Section 4.2 Dose and Method of Administration).

Hepatotoxicity.

Hepatotoxicity (ALT or AST > 3 times the upper limit of normal (ULN) and total bilirubin > 1.5 times the ULN) has been observed in clinical trials (< 1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported, although the relationship to Tykerb is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment.
Liver function tests (transaminases, bilirubin and alkaline phosphatase) should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with Tykerb should be discontinued permanently (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients who carry the HLA alleles DQA1*02:01 and DRB1*07:01 have increased risk of Tykerb associated hepatotoxicity. In a large, randomised clinical trial of Tykerb monotherapy (n = 1,194), the overall risk of severe liver injury (ALT > 5 times the upper limit of normal, NCI CTCAE grade 3) was 2% (1:50), the risk in DQA1*02:01 and DRB1*07:01 allele carriers was 8% (1:12) and the risk in noncarriers was 0.5% (1:200). Carriage of the HLA risk alleles is common (15% to 25%) in Caucasian, Asian, African and Hispanic populations but lower (1%) in Japanese populations.

Diarrhoea.

Diarrhoea, including severe diarrhoea, has been reported with Tykerb treatment (see Section 4.8 Adverse Effects (Undesirable Effects)). Diarrhoea may be severe, and deaths have been reported. Diarrhoea generally occurs early during Tykerb treatment, with almost half of those patients with diarrhoea first experiencing it within 6 days. This usually lasts 4-5 days. Tykerb induced diarrhoea is usually low grade, with severe diarrhoea of NCI CTCAE grades 3 and 4 occurring in < 10% and < 1% of patients, respectively. Early identification and intervention is critical for the optimal management of diarrhoea. Patients should be instructed to report any change in bowel patterns immediately. Prompt treatment of diarrhoea with antidiarrhoeal agents (such as loperamide) after the first unformed stool is recommended. Severe cases of diarrhoea may require administration of oral or intravenous electrolytes and fluids, use of antibiotics such as fluoroquinolones (especially if diarrhoea is persistent beyond 24 hours, there is fever, or grade 3 or 4 neutropenia) and interruption or discontinuation of Tykerb therapy (see Section 4.2 Dose and Method of Administration, Dose delay and dose reduction (all indications), Diarrhoea).

Neutropenia.

Neutropenia has been reported with Tykerb administered in combination with paclitaxel (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Complete blood counts should be monitored regularly during treatment with this combination (see Section 4.2 Dose and Method of Administration, Dose delay and dose reduction (administration with paclitaxel)).

Severe cutaneous reactions.

Severe cutaneous reactions have been reported with lapatinib. If erythema multiforme or life threatening reactions such as Stevens-Johnson syndrome, or toxic epidermal necrolysis (e.g. progressive skin rash often with blisters or mucosal lesions) are suspected, discontinue treatment with lapatinib (see Section 4.2 Dose and Method of Administration).

Concomitant treatment with inhibitors or inducers of CYP3A4.

Concomitant treatment with inhibitors or inducers of CYP3A4 should proceed with caution due to risk of increased or decreased exposure to Tykerb, respectively (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Special populations.

Use in hepatic impairment.

If Tykerb is to be administered to patients with severe pre-existing hepatic impairment, dose reduction is recommended. In patients who develop severe hepatotoxicity while on therapy, Tykerb should be discontinued and patients should not be retreated with Tykerb (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Hepatic impairment).

Use in renal impairment.

Less than 2% of an administered dose is eliminated by the kidneys as unchanged lapatinib and metabolites. Lapatinib pharmacokinetics have not been specifically studied in patients with renal impairment or in patients undergoing haemodialysis. Please see Section 5.2 Pharmacokinetic Properties.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

See Section 4.2 Dose and Method of Administration.

Use in patients for whom trastuzumab is not appropriate.

Limited data suggest that Tykerb in combination with paclitaxel is less effective and not as tolerable as trastuzumab in combination with paclitaxel for the first line treatment of patients with metastatic breast cancer whose tumours overexpress HER2 (ErbB2). Therefore lapatinib-paclitaxel should be used in patients for whom trastuzumab is not appropriate (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Effects on laboratory tests.

Please see Section 4.8 Adverse Effects (Undesirable Effects).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Tykerb is predominantly metabolised by CYP3A (see Section 5.2 Pharmacokinetic Properties). Therefore, inhibitors or inducers of these enzymes may alter the pharmacokinetics of Tykerb.

Interactions with CYP3A4-inhibitors.

Coadministration of Tykerb with known inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole or grapefruit juice) should proceed with caution and clinical response and adverse events should be carefully monitored (see Section 4.4 Special Warnings and Precautions for Use).
If patients must be coadministered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, a dose reduction to 500 mg/day of Tykerb is predicted to adjust the Tykerb AUC to the range observed without inhibitors and should be considered. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the Tykerb dose is adjusted upward to the indicated dose.

Interactions with CYP3A4-inducers.

Coadministration of Tykerb with known inducers of CYP3A4 (e.g. rifampicin, carbamazepine, phenytoin or Hypericum perforatum (St. John's wort)) should proceed with caution and clinical response and adverse events should be carefully monitored (see Section 4.4 Special Warnings and Precautions for Use). If patients must be coadministered a strong CYP3A4 inducer, the dose of Tykerb should be titrated gradually, based on tolerability. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued the Tykerb dose should be reduced over approximately 2 weeks to the indicated dose.

Drugs that affect gastric pH.

The solubility of Tykerb is pH dependent. Concomitant treatment with substances that increase gastric pH should be avoided since Tykerb solubility and absorption may decrease. Pretreatment with a proton pump inhibitor (esomeprazole) decreased Tykerb exposure by an average of 27% (range: 6% to 49%). This effect decreases with increasing age from approximately 40 to 60 years. Therefore, caution should be used when Tykerb is used in patients pretreated with a proton pump inhibitor.

Effect of Tykerb on other drugs.

Tykerb inhibits CYP3A4 in vitro at clinically relevant concentrations. Coadministration of lapatinib with orally administered midazolam resulted in an approximate 45% increase in the AUC of midazolam. There was no clinically meaningful increase in AUC when midazolam was dosed intravenously. Caution should be exercised when dosing Tykerb concurrently with orally administered medications with narrow therapeutic windows that are substrates of CYP3A4 (see Section 5.2 Pharmacokinetic Properties).
Tykerb inhibits CYP2C8 at clinically relevant concentrations. Caution should be exercised (see Section 5.2 Pharmacokinetic Properties) when dosing lapatinib concurrently with medications with narrow therapeutic windows that are substrates of CYP2C8 (see Section 5.2 Pharmacokinetic Properties).

Combination therapy and non-fixed dose combination therapy.

Coadministration of lapatinib with intravenous paclitaxel increased the exposure of paclitaxel by 23%, due to lapatinib inhibition of CYP2C8 and/or P-glycoprotein (Pgp). An increase in the incidence and severity of diarrhoea and neutropenia has been observed with this combination in clinical trials. Caution is advised when lapatinib is coadministered with paclitaxel.

Effect of Tykerb on transport proteins.

Tykerb is a substrate for the transport proteins P-glycoprotein and BCRP (breast cancer resistance protein). Inhibitors and inducers of these proteins may alter the exposure and/or distribution of lapatinib.
Tykerb inhibits the transport protein P-glycoprotein in vitro at clinically relevant concentrations. Coadministration of lapatinib with orally administered digoxin resulted in an approximate 98% increase in the AUC of digoxin. Caution should be exercised when dosing lapatinib concurrently with medications with narrow therapeutic windows that are substrates of Pgp.
Lapatinib inhibits the transport proteins BCRP and OATP1B1 in vitro. The clinical relevance of this effect has not been evaluated. It cannot be excluded that lapatinib will affect the pharmacokinetics of substrates of BCRP (e.g. topotecan) and OATP1B1 (e.g. rosuvastatin).
Concomitant administration of Tykerb with capecitabine, letrozole or trastuzumab did not meaningfully alter the pharmacokinetics of these agents (or the metabolites of capecitabine) or Tykerb.

Drug-food/drink interactions.

The bioavailability of Tykerb is affected by food (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties). Grapefruit juice may increase the bioavailability of lapatinib and should be avoided during treatment with Tykerb (see earlier section: Interactions with CYP3A4-inhibitors above).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Rat fertility was unaffected by lapatinib at doses (as free base) of up to 180 mg/kg/day (males) and 120 mg/kg/day (females), which correspond to exposures (AUC) that were approximately 2 and 8 times the expected clinical exposure, respectively. There was an increase in postimplantation loss in the female fertility study at > 60 mg/kg/day (relative exposure approximately 4). The effect on human fertility is unknown.
(Category C)
There are no adequate and well-controlled studies of Tykerb in pregnant women. The effect of Tykerb on human pregnancy is unknown. Tykerb should not be used in pregnancy.
Lapatinib was studied in pregnant rats and rabbits given oral doses of 30, 60 and 120 mg/kg/day. There were no treatment related malformations, however, alterations (left sided umbilical artery, cervical rib) were observed in rats in the presence of maternal toxicity at 120 mg/kg/day (approximately 6 times the clinical exposure based on AUC). An increased number of early postimplantation losses were also seen in rats treated at 120 mg/kg/day, while precocious ossification was observed in rats in all treatment groups, independent of maternal toxicity or foetal bodyweight changes.
In rabbits, an increased incidence of fetuses and litters with minor skeletal variations was seen at ≥ 60 mg/kg/day, in the presence of decreased maternal bodyweight and clinical signs. Abortions were seen in doses treated at 120 mg/kg/day. Lapatinib exposures at 60 and 120 mg/kg/day in the rabbit study were approximately 10% and 20%, respectively, the clinical exposure (based on AUC).
In the pre- and postnatal development study, a marked decrease in pup survival occurred between birth and postnatal day 21 at doses of ≥ 60 mg/kg/day (approximately 3 times the expected clinical exposure based on AUC). The highest no-effect dose for this study was 20 mg/kg/day, similar to the clinical exposure.

Contraception.

Based on findings in animal studies, lapatinib can cause fetal harm. Females of reproductive potential must be advised to use effective contraception using methods that result in less than 1% pregnancy rates to avoid becoming pregnant while receiving treatment with Tykerb and for at least 5 days after the last dose. If the drug is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be notified that Tykerb may cause harmful effects to the human fetus or neonate.
 There are no data on the presence of lapatinib in human milk, or the effect of lapatinib on the breastfed infant, or on milk production. As many drugs are transferred into human milk and due to the potential for serious ADRs in breast-fed infants from lapatinib, it is advised that women should not breastfeed while receiving therapy with Tykerb and for at least 5 days after the last dose.

4.7 Effects on Ability to Drive and Use Machines

There have been no studies to investigate the effect of Tykerb on driving performance or the ability to operate machinery. A detrimental effect on such activities cannot be predicted from the pharmacology of Tykerb, although in clinical studies, fatigue is a very common adverse event associated with Tykerb treatment. If patients experience fatigue, weakness or tiredness, they should be advised not to drive or operate machinery (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

The safety of Tykerb has been evaluated as monotherapy or in combination with other chemotherapies for various cancers in more than 19,000 patients. These included 198 patients who received Tykerb in combination with capecitabine, 222 patients who received Tykerb in combination with paclitaxel (80 mg/m2 weekly), 293 patients who received Tykerb in combination with paclitaxel (175 mg/m2 every 3 weeks), and 654 patients who received Tykerb in combination with letrozole (also see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Adverse effects (undesirable effects) are listed by MedDRA system organ class (SOC) in Tables 2 to 11. The following convention has been utilised for the classification of frequency in all of the AE tables: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000) and very rare (< 1/10,000).

Tykerb monotherapy.

The following adverse reactions have been reported to be associated with Tykerb (Table 2).

Tykerb in combination with capecitabine.

In addition to the adverse reactions observed with Tykerb monotherapy, the following adverse reactions have been reported to be associated with Tykerb in combination with capecitabine with a frequency difference of greater than 5% compared to capecitabine alone (Table 3). These data are based on exposure to this combination in 198 patients (see Tables 4, 5 and 6).

Tykerb in combination with paclitaxel.

The following additional adverse reactions have been reported to be associated with Tykerb in combination with paclitaxel (80 mg/m2 weekly) with a frequency of greater than 5% compared to paclitaxel alone (see Table 7). These data are based on exposure to this combination in 222 patients (see Table 8).

Tykerb in combination with letrozole.

In addition to the adverse reactions observed with Tykerb monotherapy, the following adverse reactions have been reported to be associated with Tykerb in combination with letrozole with a frequency difference of greater than 5% compared to letrozole alone. These data are based on exposure to this combination in 654 patients (see Table 9).
In the Tykerb plus letrozole treatment group, the most commonly observed study medication related serious adverse events were decreased left ventricular ejection fraction (LVEF) (2% of patients, compared to 1% for letrozole plus placebo) and diarrhoea (2% of patients, compared to < 1% for letrozole plus placebo). Other study medication related serious adverse events, including skin rash, hepatotoxicity and pneumonitis, were observed in < 1% of patients. The most common adverse events leading to discontinuation of treatment in the Tykerb plus letrozole treatment group were diarrhoea (4%) and vomiting (2%) (see Table 10).

Post marketing data.

The following adverse drug reactions have been derived from post-marketing experience with Tykerb via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness (see Table 11).

Reporting suspected adverse events.

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

The maximum oral dose of Tykerb that has been administered in clinical trials is 1800 mg once daily.
More frequent ingestion of Tykerb could result in serum concentrations exceeding those observed in clinical trials, therefore, missed doses should not be replaced and dosing should resume with the next scheduled daily dose (see Section 4.2 Dose and Method of Administration).

Symptoms and signs.

Asymptomatic and symptomatic cases of overdose have been reported in patients being treated with lapatinib. Symptoms observed include known lapatinib associated events (see Section 4.8 Adverse Effects (Undesirable Effects)) and in some cases sore scalp, sinus tachycardia (with otherwise normal ECG) and/or mucosal inflammation.
Tykerb is not significantly renally excreted and is highly bound to plasma proteins, therefore, haemodialysis would not be expected to be an effective method to enhance the elimination of lapatinib.

Treatment.

There is no specific antidote for the inhibition of ErbB1 (EGFR) and/or HER2 tyrosine phosphorylation.
Further management should be as clinically indicated. For information on the management of overdose contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

Pharmacotherapeutic group: Antineoplastic agent, other antineoplastic agents, human epidermal growth factor receptor 2 (HER)2 tyrosine kinase inhibitor.
ATC code: L01EH01.

5.1 Pharmacodynamic Properties

Mechanism of action.

Lapatinib is a potent, reversible and selective inhibitor of the intracellular tyrosine kinase domains of both ErbB1 (EGFR) and HER2 (ErbB2) receptors (estimated Kiapp values of 3 nanoM and 13 nanoM, respectively) with a slow off rate from these receptors (half-life greater than or equal to 300 minutes). This dissociation rate from ErbB1 (EGFR) was found to be slower for lapatinib than for erlotinib and gefitinib. Lapatinib inhibits tumour cell proliferation in vitro and inhibits the growth of ErbB1 (EGFR) and HER2 overexpressing xenograft tumours in mice. Inhibition of tumour growth was associated with decreased phosphorylation of ErbB1 (EGFR) and HER2 in tumour tissue.
The growth inhibitory effects of lapatinib were evaluated in trastuzumab conditioned cell lines. Lapatinib retained significant activity against breast cancer cell lines selected for resistance to trastuzumab by long-term growth in trastuzumab containing medium in vitro. These findings suggest non-cross resistance between these two HER2 directed agents.
Hormone sensitive breast cancer cells (estrogen receptor [ER] positive and/or progesterone receptor [PgR] positive) that coexpress HER2 tend to be resistant to established endocrine therapies. Hormone sensitive breast cancer cells that initially lack overexpression of EGFR or HER2 will up regulate these receptors as the tumour becomes resistant to endocrine therapy.

Clinical trials.

Data in two randomised metastatic settings have shown that Tykerb combined with chemotherapy is less effective than trastuzumab when combined with chemotherapy (see studies EGF111438 and EGF108919 in this section). Lapatinib is not indicated in the adjuvant setting.

Combination treatment with Tykerb and capecitabine.

Open label studies.

Phase III study EGF100151.

The efficacy and safety of Tykerb in combination with capecitabine in breast cancer was evaluated in this randomised, open label, multicentre phase III trial. Patients eligible for enrollment had HER2 overexpressing, locally advanced or metastatic breast cancer, after prior treatment that included taxanes, anthracyclines and trastuzumab. Left ventricular ejection fraction (LVEF) was evaluated in all patients (using echocardiogram or multigated acquisition (MUGA) scans) prior to initiation of treatment with Tykerb to ensure baseline LVEF was within the institution's normal limits.
In clinical trials, LVEF was monitored at approximately 8 week intervals during treatment with Tykerb to ensure it did not decline to below the institution's lower limit of normal. The majority of LVEF decreases (greater than 60%) were observed during the first nine weeks of treatment, however, limited data was available for long-term exposure.
Patients were randomised to receive either Tykerb 1250 mg once daily (continuously) plus capecitabine (2000 mg/m2/day on days 1-14 every 21 days) or to receive capecitabine alone (2500 mg/m2/day on days 1-14 every 21 days). The primary efficacy endpoint was time to tumour progression (TTP) as assessed by an independent review panel. TTP was defined as the time from randomisation to tumour progression or death related to breast cancer.
At the data cut off date for the prespecified interim analysis (15 November 2005), 324 patients were enrolled (163 in the combination arm, 161 in the monotherapy arm). The efficacy results showed a statistically significant improvement in TTP (51% reduction in the hazard of disease progression) for patients receiving Tykerb plus capecitabine with a median TTP of 8.5 months in the combination arm versus 4.5 months in the monotherapy arm (p = 0.00008). See Table 12. The TTP data are represented graphically in Figure 1.
Progression free survival (PFS) is defined as time from randomisation until disease progression or death due to any cause. At the interim analysis, Tykerb, when given in combination with capecitabine significantly prolonged PFS compared to capecitabine alone (8.5 months versus 4.1 months, p = 0.000023).
The response rate (complete or partial response) independently assessed was 22% in the Tykerb plus capecitabine group compared with 14% in the capecitabine group (p = 0.091); similar results were observed for the clinical benefit response rate (complete response + partial response + stable disease for at least 6 months), which was 27% vs 18% (p = 0.069) in the combination versus the monotherapy arm, respectively.
At the time of interim analysis, the survival data were not sufficiently mature to detect a difference in overall survival between the treatment groups, 36 subjects (22%) in the Tykerb plus capecitabine group and 35 subjects (22%) in the capecitabine group had died. An exploratory analysis of patients with central nervous system (CNS) metastases showed four (2%) patients in the combination therapy group had symptomatic CNS progression as part of their first progression event as compared to 11 (7%) patients in the monotherapy group (p = 0.068).
An independent data monitoring committee (IDMC) initially reviewed the results of the interim analysis (which included data from 321 of the 324 patients) and recommended that further enrollment into the study be halted due to a statistically significant and clinically relevant increase in TTP for the combination of Tykerb and capecitabine over capecitabine alone, which crossed a predefined statistical stopping boundary for superiority. At the time enrollment was halted (3 April, 2006), a total of 399 patients had been randomised to study treatment.
A subsequent updated analysis was conducted with a data cut off of 3 April, 2006 when enrollment was halted. An additional 75 subjects had been enrolled into the study between the interim analysis clinical cut off date and halting enrollment into the study (n = 198 combination arm vs n = 201 control arm). This analysis revealed maintenance of a highly statistically significant improvement in TTP for subjects enrolled in the combination arm conferring a 43% reduction in hazard of disease progression (p = 0.00013). The median TTP by independent review for the combination arm versus the control arm was 6.3 versus 4.3 months, respectively.
The overall response rate, as assessed by an independent review panel was 23.7% for patients receiving lapatinib plus capecitabine and 13.9% for patients receiving capecitabine (p = 0.017). Median duration of response was 7.4 months and 7 months respectively. On the combination arm, there were 4 (2%) progressions in the central nervous system as compared with the 13 (6%) progressions on the capecitabine alone arm, as assessed by an independent review panel (p = 0.045).
At the time that enrollment into study EGF100151 was halted, 399 patients were randomised to study therapy and 9 other patients were being screened. All 9 patients in screening, and all those already receiving capecitabine monotherapy, were offered combination treatment. In total, 207 patients were assigned to the combination therapy and 201 patients were assigned to capecitabine monotherapy. An analysis of overall survival (OS) data to 1 October, 2008 is summarised in Table 13.
After the study was halted, 36 patients crossed over from capecitabine to Tykerb + capecitabine, of whom 26 crossed over prior to disease progression while on capecitabine alone.
To isolate the treatment effect in the presence of crossover, Cox regression analysis considering crossover as a time dependent covariate and treatment effect was performed. The results from this analysis suggest a clinically relevant reduction in risk of death by 20%, with a treatment effect hazard ratio of 0.80 (95% confidence interval [CI]: 0.64, 0.99; p = 0.043).

Phase III study EGF111438.

A randomised phase III open label study (EGF111438) (N = 540) compared the effect of Tykerb in combination with capecitabine relative to trastuzumab in combination with capecitabine on the incidence of CNS as site of first relapse in women with HER2 overexpressing metastatic breast cancer. Patients were randomised to either Tykerb 1250 mg once daily (continuously) plus capecitabine (2000 mg/m2/day on days 1-14 every 21 days), or trastuzumab (loading dose of 8 mg/kg followed by 6 mg/kg infusions every 3 weeks) plus capecitabine (2500 mg/m2/day, days 1-14, every 21 days). Randomisation was stratified by prior trastuzumab treatment and number of prior treatments for metastatic disease (none versus ≥ 1st line). The study was stopped early when a preplanned interim analysis (N = 475) showed superior efficacy of the trastuzumab plus capecitabine arm and a low incidence of CNS events.
The final analysis confirmed that the results of the primary endpoint were inconclusive due to a low number of CNS events [8 patients (3.2%) in the Tykerb plus capecitabine arm experienced CNS metastasis as site of first progression, compared with 12 patients (4.8%) in the trastuzumab plus capecitabine arm]. The final results of progression free survival and overall survival (the key secondary endpoints) are shown in Table 14, as well as the subgroup analyses based on the stratification factors. At the time of final analysis the median overall survival (OS) was not reached. The final analysis confirmed the superior efficacy of trastuzumab plus capecitabine arm.

Combination treatment with Tykerb and paclitaxel.

Double-blind, placebo-controlled studies.

Phase III study EGF104535.

The efficacy and safety of Tykerb in combination with paclitaxel in breast cancer were evaluated in a randomised double-blind, placebo-controlled trial, EGF104535. Patients had histologically confirmed invasive breast cancer (stage IV disease) that overexpressed HER2, and had not received prior therapy for metastatic disease.
Patients were randomly assigned to paclitaxel (80 mg/m2 intravenous on days 1, 8, and 15 of a 28 day schedule) and either Tykerb 1500 mg/day or placebo once daily. Patients received a minimum of 6 cycles of Tykerb or placebo plus paclitaxel. After the 6 cycles of combination with paclitaxel were completed, patients continued on Tykerb or placebo until disease progression or an unacceptable toxicity occurred. The primary endpoint was overall survival (OS). Four hundred forty four (444) patients were enrolled in this study. Of the 222 patients who were on paclitaxel plus placebo, 149 patients (67%) with disease progression entered the open label extension phase of the study and received Tykerb monotherapy. The median age was 50 years and 7% were older than 65 years. Eighty six percent (86%) were Asian, 8% Hispanic, and 5% Caucasian. The overall survival data are summarised in Table 15 and represented graphically in Figure 2. A summary of other key efficacy endpoints are provided in Table 16.

Phase III study EGF30001.

Another randomised, double blind, placebo-controlled study evaluated Tykerb and paclitaxel as first line therapy for metastatic breast cancer in patients with negative or untested HER2 status and previously untreated in the metastatic setting (EGF30001). Patients (N = 579) were randomly assigned 1:1 to paclitaxel (175 mg/m2 intravenously over 3 hours on day 1, every 3 weeks) and either Tykerb 1500 mg/day or placebo once daily. Sixty four percent (64%) were Caucasian, 18% Hispanic, and 11% Asian. There were 91 patients (16%) with HER2 positive disease.
The primary endpoint was time to progression (TTP); secondary endpoints included PFS, tumour response rate (RR), clinical benefit rate (CBR), OS and safety. No significant differences in TTP or PFS were observed between treatment arms in the unselected ITT population. In the HER2 positive subgroup, statistically significant and clinically relevant benefit was observed in TTP and PFS in favour of the Tykerb plus paclitaxel group. The median TTP in the HER2 positive subgroup was 35.1 weeks in the Tykerb plus paclitaxel group compared to 23.1 weeks in the paclitaxel plus placebo group (hazard ratio of 0.57; 95% CI: 0.34, 0.93; p = 0.011). The median PFS in the HER2 positive subgroup was 34.4 weeks (95% CI: 32.1, 41.6) in the Tykerb plus paclitaxel combination compared to 22.6 weeks (95% CI: 20.1, 32.9) in the paclitaxel plus placebo group (hazard ratio of 0.56; 95% CI: 0.34, 0.90; p = 0.007). The overall survival analysis of the ITT population and HER2 positive subgroup are presented in Table 17.
Open label studies.

Phase III study EGF108919.

A randomised phase III open label study (EGF108919) (N = 652) compared the efficacy and safety of Tykerb plus a taxane followed by Tykerb alone versus trastuzumab plus a taxane followed by trastuzumab alone as first line therapy for women with HER2 positive metastatic breast cancer. Patients were randomised to either Tykerb 1250 mg once daily plus paclitaxel: 80 mg/m2 once weekly (days 1, 8 and 15 of a 4 week cycle) or docetaxel 75 mg/m2 once every 3 weeks (days 1 of a 3 week cycle) for 24 weeks followed by Tykerb 1500 mg once daily, or trastuzumab once weekly (loading dose 4 mg/kg followed by 2 mg/kg weekly infusions) plus paclitaxel: 80 mg/m2 once weekly (days 1, 8 and 15 of a 4 week cycle) or docetaxel 75 mg/m2 once every 3 weeks (days 1 of a 3 week cycle) for 24 weeks followed by trastuzumab: 6 mg/kg once every 3 weeks. The study was stopped early when a preplanned interim analysis showed superior efficacy of the combination trastuzumab plus taxane arm in terms of progression free survival (primary endpoint). This was confirmed by the final analysis. At the clinical cut off date for final analysis, 28% of subjects had died, and therefore the median OS for this study was not reached (see Table 18).
The TTax/T regimen was better tolerated than the LTax/L regimen with the exception of slightly higher incidence of LV dysfunction observed in the trastuzumab arm. Across both the combination and monotherapy study phases, the incidences of AEs leading to permanent discontinuation of study treatment, SAEs, and drug related SAEs were higher in the LTax/L treatment arm.

Combination treatment with Tykerb and letrozole.

Tykerb has been studied in combination with the aromatase inhibitor letrozole for the treatment of advanced or metastatic breast cancer in hormone receptor positive (estrogen receptor [ER] positive and/or progesterone receptor [PgR] positive) postmenopausal women.
Double-blind controlled trial.

Phase III study EGF30008.

EGF30008 was a phase III, randomised, double blind, controlled trial in patients with hormone receptor positive locally advanced or metastatic breast cancer (MBC), who had not received prior systemic therapy for their metastatic disease. 1286 patients were randomised to letrozole 2.5 mg once daily plus Tykerb 1500 mg once daily or letrozole 2.5 mg with placebo. Randomisation was stratified by sites of disease and prior adjuvant antiestrogen therapy. HER2 receptor status was retrospectively determined by central laboratory testing.
Of all patients randomised to treatment, 219 patients had tumours overexpressing the HER2 receptor (the 'HER2 positive population'), which was the prespecified primary population for the analysis of efficacy. There were 952 HER2 negative patients and a total of 115 patients whose HER2 status was unconfirmed.
In the HER2 positive population, investigator determined PFS was significantly greater with letrozole plus Tykerb compared with letrozole plus placebo (see Table 18). The PFS data in the HER2 positive population is represented graphically in Figure 3.
The benefit of Tykerb + letrozole on PFS in the HER2 positive population was confirmed in a pre-planned Cox regression analysis (HR = 0.65 (95% CI 0.47-0.89) p = 0.008. In addition to a PFS benefit seen in the HER2+ patient population, combination therapy of Tykerb and letrozole was associated with a significant improvement in objective response rate (27.9% and 14.8% respectively) (p = 0.021) compared with treatment with letrozole plus placebo. Although not yet mature, a trend towards a survival benefit was noted for the Tykerb/letrozole combination, HR = 0.74 (95% CI 0.50, 1.1) p = 0.113 (see Table 19).
In the intent to treat (ITT) population, investigator determined PFS was greater between the two treatment arms (see Table 19). Although statistically significant, the difference was not considered clinically relevant.
In the HER2 negative population (n = 952), the Kaplan-Meier analyses for PFS did not show a significant difference between the two treatment arms (see Table 19).

5.2 Pharmacokinetic Properties

Absorption.

Absorption following oral administration of lapatinib is highly variable. Serum concentrations appear after a median lag time of 0.25 hours (range 0 to 1.5 hours). Peak plasma concentrations (Cmax) of lapatinib are achieved approximately 4 hours after administration. Daily dosing of 1250 mg produces steady-state geometric mean (95% confidence interval) Cmax values of 2.43 (1.57 to 3.77) microgram/mL and AUC values of 36.2 (23.4 to 56) microgram.hr/mL. The absolute bioavailability of lapatinib has not been determined.
Daily dosing of 1500 mg lapatinib in combination with paclitaxel 175 mg/m2 every three weeks produces steady-state geometric mean (95% confidence interval) Cmax values of 5.31 (3.54 to 7.97) microgram/mL and AUC values of 64.5 (43.3 to 96.2) microgram.hr/mL.
Systemic exposure to lapatinib is increased when administered with food (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Lapatinib AUC values were approximately 3 and 4-fold higher (Cmax approximately 2.5 and 3-fold higher) when administered with a low fat (5% fat [500 calories]) or with a high fat (50% fat [1,000 calories]) meal, respectively.

Distribution.

Lapatinib is highly bound (greater than 99%) to albumin and alpha-1 acid glycoprotein. In vitro studies indicate that lapatinib is a substrate for the transporters BCRP (ABCG2) and P-glycoprotein (ABCB1). Lapatinib has also been shown to inhibit P-glycoprotein (IC50 2.3 microgram/mL), BCRP (IC50 0.015 microgram/mL) and the hepatic uptake transporter OATP1B1 (IC50 2.3 microgram/mL), in vitro at clinically relevant concentrations. The clinical significance of these effects on the pharmacokinetics of other drugs or the pharmacological activity of other anticancer agents is not known. Limited inhibition of the OAT and OCT renal transporters was seen with 17 microgram/mL lapatinib.

Metabolism.

Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8, to a variety of oxidated metabolites, none of which account for more than 14% of the dose recovered in the faeces or 10% of the lapatinib concentration in plasma. Furthermore, it is unlikely that any of these metabolites would contribute to the pharmacological activity of lapatinib.
Lapatinib significantly inhibited the metabolism of the substrates of the recombinant CYP enzymes CYP3A4 and CYP2C8 in vitro at clinically relevant concentrations (approximately 5 microM or 3 microgram/mL). Lapatinib did not significantly inhibit the following enzymes in human liver microsomes: CYP2C9, CYP2C19 and CYP2D6 or UGT enzymes (in vitro IC50 values were greater than or equal to 6.9 microgram/mL). Lapatinib was reported to inhibit the metabolism of substrates of recombinant CYP1A2, however, it did not significantly inhibit CYP1A2 in human liver microsomes.
In healthy volunteers receiving ketoconazole, a CYP3A4 inhibitor, at 200 mg twice daily for 7 days, systemic exposure to lapatinib was increased approximately 3.6-fold and half-life increased 1.7-fold.
In healthy volunteers receiving carbamazepine, a CYP3A4 inducer, at 100 mg twice daily for 3 days and 200 mg twice daily for 17 days, systemic exposure to lapatinib was decreased approximately 72%.

Excretion.

The half-life of lapatinib measured after single doses increases with increasing dose (range 6 to 14 hours). However, daily dosing of lapatinib results in achievement of steady state within 6 to 7 days, indicating an effective half-life of 24 hours. The primary route of elimination for lapatinib and its metabolites is in faeces, with less than 2% of the dose (as lapatinib and metabolites) excreted in urine. Recovery of unchanged lapatinib in faeces accounts for a median 27% (range 3% to 67%) of an oral dose.

Special populations.

Renal impairment.

Lapatinib pharmacokinetics have not been specifically studied in patients with renal impairment or in patients undergoing haemodialysis. However, renal impairment is unlikely to affect the pharmacokinetics of lapatinib given that less than 2% of an administered dose (as unchanged lapatinib and metabolites) is eliminated by the kidneys.

Hepatic impairment.

The pharmacokinetics of lapatinib were examined in subjects with moderate (N = 8) or severe (N = 4) hepatic impairment and in 8 healthy control subjects. Systemic exposure (AUC) to lapatinib after a single oral 100 mg dose increased approximately 56% and 85% in subjects with moderate and severe hepatic impairment, respectively. Administration of lapatinib in patients with hepatic impairment should be undertaken with caution due to increased exposure to the drug. A dose reduction is recommended for patients with severe pre-existing hepatic impairment. In patients who develop severe hepatotoxicity while on therapy, lapatinib should be discontinued and patients should not be retreated with lapatinib (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

5.3 Preclinical Safety Data

Genotoxicity.

Lapatinib was not mutagenic in the bacterial reverse mutation assay (Ames test) or clastogenic in Chinese hamster ovary cells or human lymphocytes in vitro, or an in vivo rat bone marrow chromosome aberration assay. Lapatinib contains an impurity that was genotoxic in vitro and in vivo, however the levels of this impurity in the drug are considered acceptable given the proposed indication.

Carcinogenicity.

In oral carcinogenicity studies with lapatinib, severe skin lesions were seen at the highest doses tested which produced exposures based on AUC up to 2-fold in mice and male rats, and up to 8-fold in female rats, the anticipated clinical AUC. There was no evidence of carcinogenicity in mice. In rats, the incidence of benign haemangioma of the mesenteric lymph nodes was higher in some groups than in concurrent controls, but was within background range. There was also an increase in renal infarcts and papillary necrosis in female rats at exposures 5 and 8-fold the anticipated clinical AUC. The relevance of these findings for humans is uncertain.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tykerb tablet contains microcrystalline cellulose, povidone, sodium starch glycollate type A, magnesium stearate, hypromellose, titanium dioxide, macrogol 400, polysorbate 80, iron oxide red (CI77491) and iron oxide yellow (CI77492) as therapeutically inactive ingredients.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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

Do not store above 30°C.

6.5 Nature and Contents of Container

Packs available.

Tykerb tablets are supplied in HDPE bottles with child resistant closure packs containing 70 tablets in Australia.

Other packs registered.

Bottle packs (HDPE) containing 30*, 84*, 105*, and 140* tablets.
Blister packs (PA/Al/PVC/Al) containing 40*, 70*, 84* and 168* tablets are also registered (not supplied).
*Not all pack sizes may be distributed.

6.6 Special Precautions for Disposal

Any unused product should be returned to a pharmacist for safe disposal. Unused tablets should not be disposed in domestic waste or waste water.

6.7 Physicochemical Properties

Lapatinib ditosilate (monohydrate) has the chemical name: N-(3-chloro-4-{[(3-fluoro phenyl) methyl] oxy}phenyl)-6-[5-({[2-(methyl sulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolin amine bis(4-methyl benzene sulfonate) monohydrate.
It is a yellow crystalline powder at room temperature.
Lapatinib ditosilate (monohydrate) has the molecular formula: C29H26ClFN4O4S(C7H8O3S)2H2O.
The molecular weights are 943.48 g/mole and 581.06 g/mole for the ditosilate and free base respectively.
Lapatinib ditosilate solubility in water and 0.1 N HCl are 0.007 g/L and 0.001 g/L at 25°C respectively.

Chemical structure.


CAS number.

388082-78-8.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription only medicine.

Summary Table of Changes