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.

What is in this leaflet

Please read this leaflet carefully before you take any Tykerb tablets.

This leaflet answers some common questions about Tykerb. It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine.

You can also download the most up to date leaflet from www.novartis.com.au.

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

All medicines have risks and benefits. Your doctor has weighed the expected benefits of you taking Tykerb against the risks this medicine could have for you.

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

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

What is Tykerb used for

Tykerb contains the active ingredient lapatinib, which belongs to a group of medicines called protein kinase inhibitors.

Tykerb is used in combination with other medicines to treat certain types of advanced or metastatic breast cancers. Breast cancer is caused by cells that divide abnormally in the breast. These cells may reach other tissues of the body at a later stage in a process called metastasis. Tykerb may slow or stop cancer cells from growing, or may kill them.

Advanced or metastatic breast cancers have spread beyond an original tumour. These types of breast cancers are more likely to grow in the presence of hormones, like oestrogen and progesterone.

Tykerb may be used with any of the following medicines:

  • An aromatase inhibitor tablet to treat tumours that are hormone sensitive
  • Capecitabine tablet to treat advanced or metastatic breast cancer whose tumours produce large amounts of a protein called human epidermal growth factor receptor-2 (HER2, also known as ErbB2) on the surface of the tumour cells.
  • Paclitaxel infusion to treat metastatic breast cancer whose tumours produce large amounts of HER2 (ErbB2). These patients are unable to take another medicine containing trastuzumab.

Information about these other medicines is available in separate Consumer Medicine Information leaflets.

If you are taking any of these other medicines together with Tykerb, please read about the other medicine in the Consumer Medicine Information as well as this one carefully. If not included in the pack, the other medicine leaflets are available from your doctor or pharmacist.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed Tykerb for another reason.

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

It is not recommended for use in children and adolescents, under the age of 18 years.

Tykerb is not addictive.

Before you take Tykerb

When you must not take it

Do not take Tykerb if you have an allergy to:

  • Lapatinib (active ingredient) or
  • Any of the ingredients listed at the end of this leaflet.
    (See "Ingredients".)

Some of the symptoms of an allergic reaction may include:

  • Shortness of breath
  • Wheezing or difficulty breathing
  • Swelling of the face, lips, tongue or other parts of the body
  • Rash, itching or hives on the skin

Do not take this medicine after the expiry date (EXP) printed on the pack has passed, or if the pack is torn or shows signs of tampering.

The expiry date refers to the last day of that month. If it is expired or damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor or nurse if you have allergies to any other medicines, foods, preservatives or dyes. Your doctor will want to know if you are prone to allergies.

Also tell your doctor if you have any of the following problems:

  • Heart disorders, such as an irregular heartbeat.
  • Lung disorders or problems breathing, including pain while breathing.
  • Liver disorders.

Check with your doctor if you think any of these may apply to you. You may need extra tests to check that your heart and liver are working properly. Your doctor may decide to adjust your dose or stop treatment based on the results of these tests.

Taking other medicines

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. This includes herbal medicines and other medicines or complementary therapies that you may have bought without a prescription from your pharmacy, supermarket, or health food shop.

Keep a list of the medicines you take, so you can show it to your doctor, nurse or pharmacist when you get a new medicine. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

Some medicines may affect the way Tykerb works or Tykerb may affect how other medicines work. These include:

  • 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 (a herb extract used to treat depression)
  • Cyclosporin (used to prevent the rejection of transplanted organs)
  • Topotecan, paclitaxel, irinotecan, docetaxel (used to treat cancer).

Tell your doctor if you are taking any of these.

Taking Tykerb with food and drink

Tykerb is affected by food intake and 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

If you are pregnant, think you could be pregnant, or are planning to have a baby, ask your doctor or healthcare provider for advice before taking Tykerb.

Tykerb may harm your unborn baby.

You should avoid becoming pregnant while taking Tykerb.

Use a reliable method of birth control (contraception) during treatment and for at least 5 days after stopping Tykerb.

Ask your doctor about effective contraception options. Your doctor may recommend that you don't take Tykerb while you are pregnant.

If you become pregnant or think you are pregnant, tell your doctor or healthcare provider right away.

Breast feeding

Do not breast-feed while taking Tykerb and for 5 days after the last dose as it may harm your baby. Ask your doctor for advice.

Tell your doctor if you are breast-feeding. Your doctor will discuss with you the risks of taking Tykerb during breast-feeding.

Driving and using machines

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

Do not drive or operate machinery unless you're feeling well and are sure that you are not affected by tiredness.

How to take Tykerb

Follow all directions given to you by your doctor or pharmacist. The directions may differ from the information contained in this leaflet.

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

Your doctor will tell you exactly how many Tykerb tablets that you should take. Depending on your response to Tykerb or if you have heart, lung or liver problems, or experience serious episodes of diarrhoea or skin reactions during treatment with Tykerb, your doctor may prescribe a lower dose or temporarily stop treatment.

When to take Tykerb

It is important that you take Tykerb tablets either at least one hour before or at least one hour after food.

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

How much to take

Your doctor will tell you the dose of capecitabine, paclitaxel or aromatase inhibitor that you should take and when you should take it.

If you are aged 65 years or over you can use Tykerb at the same dose as for other adults.

In combination with capecitabine:
The usual dose is 5 (five) Tykerb tablets (a total dose of 1250 mg) taken once a day.

In combination with paclitaxel:
The usual dose is 6 (six) Tykerb tablets (a total dose of 1500 mg) taken once a day.

In combination with an aromatase inhibitor:
The usual dose is 6 (six) Tykerb tablets (a total dose of 1500 mg) taken once a day.

How to take it

Tykerb tablets should be swallowed with a whole with water. Tykerb film-coated tablets should not be chewed, crushed or split prior to swallowing.

If you have to take another medicine to treat your breast cancer in addition to Tykerb, follow your doctor's instructions on how to take that medicine

If you forget to take Tykerb

Take the next dose at the scheduled time. Then go back to taking your medicine as you would normally.

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

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

If you have trouble remembering to take your medicine, ask your doctor, nurse or pharmacist for some hints.

How long to take it for

Keep taking Tykerb for as long as your doctor recommends. Don't stop unless your doctor advises you to. Stopping your treatment with Tykerb is likely to cause your condition to become worse.

This is a long-term treatment that may continue for months or years. Your doctor will regularly monitor your condition to check that the treatment is having the desired effect.

If you have questions about how long to take Tykerb, talk to your doctor or healthcare provider.

If you take more Tykerb than you should (Overdose)

If you have taken too much Tykerb, or if somebody else accidentally takes your medicine, immediately telephone your doctor or Poisons Information Centre (In Australia call 131126) for advice, or go to Accident and Emergency at the nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You/they may need urgent medical attention.

Take the Tykerb pack with you. You may need to show medical staff your pack.

While you are taking Tykerb

Things you must do

Take Tykerb for as long as your doctor recommends.

Don't stop taking this medicine unless your doctor advises you to.

Tell your doctor if, for any reason, you have not taken your medicine exactly as directed. Otherwise, your doctor may think that it was not working as it should and change your treatment unnecessarily.

Keep all of your doctor's appointments so that your progress can be checked. Your heart, lung and liver function will be regularly checked before and during treatment with Tykerb.

If you are a woman that could become pregnant, you must use an effective contraceptive to prevent pregnancy during treatment with Tykerb and for 5 days after the last dose of Tykerb.

If you become pregnant while taking this medicine, tell your doctor immediately.

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

Tell any doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Things you must not do

Do not drink grapefruit juice while you are being treated with Tykerb. (See "Taking Tykerb with food and drink.")

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Do not use Tykerb to treat any other complaints unless your doctor says to.

Do not stop taking Tykerb unless your doctor advises you to.

Do not dispose of medicines in wastewater or household rubbish. This will help to protect the environment.

Possible side effects

As with all medicines, patients treated with Tykerb alone or in combination with capecitabine, paclitaxel, or an aromatase inhibitor may experience side effects, although not everybody gets them.

Do not be alarmed by these possible side effects. You may not experience any of them. If they occur, they are most likely to be minor and temporary. However, some may be serious and need medical attention.

Check with your doctor as soon as possible if you think you are experiencing any side effects or allergic reactions due to taking Tykerb, even if the problem is not listed below.

These side effects have occurred with Tykerb alone, or in combination with capecitabine, paclitaxel or letrozole (an aromatase inhibitor).

Serious side effects

STOP taking Tykerb and seek medical help immediately if you experience any of the following side effects.

Very common serious side effects

These may affect more than 1 in 10 people:

  • Fever, sore throat, frequent infections as signs of low level of white blood cells (leukopenia)
  • Pale skin, weakness, frequent infections with fever, chills and sore throat as signs of low level of red blood cells (anaemia)

Common serious side effects

These may affect up to 1 in 10 people:

  • Irregular heartbeat and shortness of breath (decreased left ventricular ejection fraction)

Uncommon serious side effects

These may affect up to 1 in 100 people:

  • Itching, yellow eyes or skin (jaundice), dark urine or pain or discomfort in the right upper area of the stomach (hepatotoxicity or hyperbilirubinemia)
  • Cough or shortness of breath (interstitial lung disease and/or pneumonitis).

Rare serious side effects

These may affect up to 1 in 1000 people:

  • Skin rash (including itchy, bumpy rash), skin reddening, hives, unusual wheezing or coughing or difficulty breathing, swollen eyelids, lips, face or tongue, blue discoloration of the lips, tongue, or skin, pain in muscles or joints, light-headedness, dizziness, loss of consciousness (passing out), hypotension (signs of severe allergic reactions).

Frequency unknown serious side effects

The frequency of these side effects is not known (events from spontaneous reports):

  • Irregular heart-beat (ventricular arrhythmia/Torsade de Pointes)
  • Change in the electrical activity of the heart (QT interval in the electrocardiogram prolonged)
  • Rash, red skin, blistering of the lips, eyes or mouth, skin peeling, fever or any combination of these (Stevens-Johnson syndrome, toxic epidermal necrolysis).

Other possible side effects

Other side effects include those listed below. If these side effects are severe, please tell your doctor, pharmacist or healthcare provider immediately.

Very common

These may affect more than 1 in 10 people:

  • Diarrhoea (can be life-threatening if severe); report any serious change in bowel patterns, such as loose stool immediately.
  • A skin reaction or pain on the palms of the hands or soles of the feet, including tingling, numbness, pain, swelling or reddening (palmar-plantar erythrodysesthesia or hand-foot syndrome)
  • Muscle pain
  • Numbness, tingling or weakness of the arms and legs
  • Loss of appetite (anorexia)
  • Indigestion or stomach pain (dyspepsia)
  • Feeling or being sick (nausea or vomiting)
  • Constipation
  • Tiredness (fatigue)
  • Unusual hair loss or thinning (alopecia)
  • Nose bleed (epistaxis)
  • Sore mouth or mouth ulcers (mucosal inflammation)
  • Trouble sleeping (insomnia)
  • Back pain
  • Pain in extremity
  • Dry skin
  • Rash.

Common

These may affect up to 1 in 10 people:

  • Headache
  • Nail disorders - such as a tender infection and swelling of the bottom part of the nail (cuticles).

If you notice any side effects not listed, please inform your doctor or healthcare provider.

After taking Tykerb

Storage

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

Store the tablets in a cool place below 30°C.

Do not leave this medicine in a car, on a window sill or in a bathroom. Heat and dampness can destroy some medicines.

Keep Tykerb in its original container until it is time to take it.

Disposal

If your doctor tells you to stop taking this medicine or if you have any unwanted medicines, ask your pharmacist what to do with them.

Product description

What Tykerb looks like

Tykerb is supplied in plastic bottle packs containing 70 tablets.

250 mg tablets
Tykerb tablets are oval, rounded on both sides, yellow film-coated, and with GS XJG imprinted on one side.

Ingredients

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

Tykerb tablets also contain the following 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).

Tykerb tablets do not contain lactose, sucrose, tartrazine or any other azo dyes.

Sponsor

Tykerb is supplied in Australia by:

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

® = Registered Trademark

This leaflet was prepared in
March 2020

Australian Registration Number:

AUST R 185997: Tykerb 250 mg bottle pack

Internal document code:

tyk200320c based on PI tyk200320i

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Tykerb

Active ingredient

Lapatinib

Schedule

S4

 

1 Name of Medicine

Lapatinib (as ditosilate monohydrate).

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.

2 Qualitative and Quantitative Composition

Active substance.

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

Excipients.

See Section 6.1 List of Excipients for the other ingredients in each Tykerb tablet.

3 Pharmaceutical Form

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

5 Pharmacological Properties

Pharmacotherapeutic group: Antineoplastic agent, other antineoplastic agents, protein kinase inhibitor.
ATC code: L01XE07.

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 (oestrogen 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)) 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 randomized 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% versus 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 (03 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 03 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 versus 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 01 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 randomized 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 randomized 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 (oestrogen 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 antioestrogen 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.

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).

4.3 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.

Paediatric use.

See Section 4.2 Dose and Method of Administration.

Use in elderly.

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).

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 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).

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 or phenytoin) 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 prenatal 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.

4.8 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 (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 categorized 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.

4.2 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, Dosage, 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, 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, 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.

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).

Renal impairment.

See Section 5.2 Pharmacokinetic Properties, Special populations.

Children.

The safety and efficacy of Tykerb in patients below 18 years of age has not been established.

Elderly.

There are limited data on the use of lapatinib in patients aged 65 years and older. See Table 1.
No aged 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.

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. 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.

4.7 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)).

4.9 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 telephone number 13 11 26.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription only medicine.

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.

Summary Table of Changes