RebozetTM

Eltrombopag

1. QUALITATIVE AND QUANTITATIVE COMPOSITION 25 mg Tablet

Eltrombopag olamine 25 mg

Each film-coated tablet contains eltrombopag olamine equivalent to 25 mg of eltrombopag as

eltrombopag free acid. The 25 mg tablets are round, biconvex, white or orange, and film-coated,

debossed with ‘GS NX3’ and ‘25’ on one side.

50 mg Tablet

Eltrombopag olamine 50 mg

Each film-coated tablet contains eltrombopag olamine equivalent to 50 mg of eltrombopag as

eltrombopag free acid. The 50 mg tablets are round, biconvex, blue or brown, and film-coated,

debossed with ‘GS UFU’ and ‘50’ on one side.

2. PHARMACEUTICAL FORM Film-coated tablets

3. CLINICAL PARTICULARS

3.1 Indications RebozetTM is indicated for the treatment of thrombocytopenia in patients with chronic immune

(idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to

corticosteroids, immunoglobulins, or splenectomy.

RebozetTM should be used only in patients with ITP whose degree of thrombocytopenia and clinical

condition increases the risk for bleeding.

RebozetTM should not be used in an attempt to normalize platelet counts.

3.2 Dosage and Administration

RebozetTM treatment should remain under the supervision of a physician who is experienced

in the treatment of haematological diseases.

RebozetTM dosing requirements must be individualised based on the patient’s platelet counts.

The objective of treatment with RebozetTM should not be to normalise platelet counts but to

maintain platelet counts above the level for haemorrhagic risk (> 50,000/μl). In most patients,

measurable elevations in platelet counts take 1-2 weeks (see Clinical studies).

Adults

The recommended starting dose of RebozetTM is 50 mg once daily. For patients of East Asian

ancestry, RebozetTM should be initiated at a reduced dose of 25 mg once daily (see Pharmacokinetic

properties).

Monitoring and dose adjustment

After initiating RebozetTM, adjust the dose to achieve and maintain a platelet count ≥

50,000/μl as necessary to reduce the risk for bleeding. Do not exceed a dose of 75 mg daily.

ID/ONC/0003/12

Clinical haematology and liver tests should be monitored regularly throughout therapy with

RebozetTM and the dose regimen of RebozetTM modified based on platelet counts as outlined

in Table 1. During therapy with RebozetTM complete blood counts (CBCs), including platelet

count and peripheral blood smears, should be assessed weekly until a stable platelet count (≥

50,000/μl for at least 4 weeks) has been achieved. CBCs including platelet counts and

peripheral blood smears should be obtained monthly thereafter.

The lowest effective dosing regimen to maintain platelet counts should be used as clinically

indicated.

Table 1 Dose adjustments of RebozetTM

Platelet count Dose adjustment or response

< 50,000/μl following at least 2

weeks of therapy

Increase daily dose by 25 mg to a maximum of 75

mg/day.

≥ 50,000/μl to ≤ 150,000/μl Use lowest dose of eltrombopag and/or

concomitant ITP treatment to maintain platelet

counts that avoid or reduce bleeding.

> 150,000/μl to ≤ 250,000/μl Decrease the daily dose by 25 mg. Wait 2 weeks to

assess the effects of this and any subsequent dose

adjustments.

> 250,000/μl Stop eltrombopag; increase the frequency of

platelet monitoring to twice weekly.

Once the platelet count is ≤ 100,000/μl, reinitiate

therapy at a daily dose reduced by 25 mg.

RebozetTM can be administered in addition to other ITP medicinal products. Modify the dose

regimen of concomitant ITP medicinal products, as medically appropriate, to avoid excessive

increases in platelet counts during therapy with RebozetTM.

Wait for at least 2 weeks to see the effect of any dose adjustment on the patient’s platelet

response prior to considering another dose adjustment.

The standard RebozetTM dose adjustment, either decrease or increase, would be 25 mg once

daily. However, in a few patients a combination of different film-coated tablet strengths on

different days may be required.

Discontinuation

Treatment with RebozetTM should be discontinued if the platelet count does not increase to a

level sufficient to avoid clinically important bleeding after four weeks of RebozetTM therapy

at 75 mg once daily. Patients should be clinically evaluated periodically and continuation of treatment should be decided

on an individual basis by the treating physician. The reoccurrence of thrombocytopenia is possible

upon discontinuation of treatment (see Special warnings and precautions for use).

Renal impairment

No dose adjustment is necessary in patients with renal impairment. Patients with impaired

renal function should use RebozetTM with caution and close monitoring, for example by

testing serum creatinine and/or performing urine analysis (see Pharmacokinetic properties).

Hepatic impairment

RebozetTM should not be used in patients with moderate to severe hepatic impairment (Child-

Pugh score ≥ 7) unless the expected benefit outweighs the identified risk of portal venous

thrombosis (see Special warnings and precautions for use).

If the use of RebozetTM is deemed necessary, the starting dose must be 25 mg once daily.

The risk of thromboembolic events (TEEs) has been found to be increased in patients with

chronic liver disease treated with 75 mg eltrombopag once daily for two weeks in preparation

for invasive procedures (see Special warnings and precautions for use and Undesirable

effects).

Paediatric population

RebozetTM is not recommended for use in children and adolescents below age 18 due to

insufficient data on safety and efficacy.

Elderly

There are limited data on the use of RebozetTM in patients aged 65 years and older. In the

clinical studies of RebozetTM, overall no clinically significant differences in safety of

RebozetTM were observed between subjects aged at least 65 years and younger subjects. Other

reported clinical experience has not identified differences in responses between the elderly

and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

East Asian patients

Initiation of RebozetTM at a reduced dose of 25 mg once daily may be considered for patients

of East Asian ancestry (such as Chinese, Japanese, Taiwanese or Korean) (see

Pharmacokinetic properties). Patient platelet count should continue to be monitored and the

standard criteria for further dose modification followed.

Method of administration The tablets should be administered orally. RebozetTM should be taken at least four hours before or

after any products such as antacids, dairy products (or other calcium containing food products), or

mineral supplements containing polyvalent cations (e.g. iron, calcium, magnesium, aluminium,

selenium and zinc) (see Interaction with other medicinal products and other forms of interaction and

Pharmacokinetic properties).

3.3 Contraindications Hypersensitivity to RebozetTM or to any of the excipients.

3.4 Warnings and Precautions The diagnosis of ITP in adults and elderly patients should have been confirmed by the exclusion of

other clinical entities presenting with thrombocytopenia. Consideration should be given to

performing a bone marrow aspirate and biopsy over the course of the disease and treatment,

particularly in patients over 60 years of age, those with systemic symptoms or abnormal signs.

The effectiveness and safety of RebozetTM have not been established for use in other

thrombocytopenic conditions including chemotherapy-induced thrombocytopenia and

myelodysplastic syndromes (MDS).

Risk of hepatotoxicity

RebozetTM administration can cause abnormal liver function. In clinical studies with RebozetTM,

increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin

were observed (see Undesirable effects).

These findings were mostly mild (Grade 1-2), reversible and not accompanied by clinically significant

symptoms that would indicate an impaired liver function. Across the 3 placebo-controlled studies, 1

patient in the placebo group and 1 patient in the eltrombopag group experienced a Grade 4 liver test

abnormality.

Serum ALT, AST and bilirubin should be measured prior to initiation of RebozetTM, every 2 weeks

during the dose adjustment phase and monthly following establishment of a stable dose. Abnormal

serum liver tests should be evaluated with repeat testing within 3 to 5 days. If the abnormalities are

confirmed, serum liver tests should be monitored until the abnormalities resolve, stabilise, or return

to baseline levels. RebozetTM should be discontinued if ALT levels increase (≥ 3X the upper limit of

normal [ULN]) and are:

progressive, or

persistent for ≥ 4 weeks, or

accompanied by increased direct bilirubin, or

accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation

Exercise caution when administering eltrombopag to patients with hepatic disease.

Thrombotic/Thromboembolic complications

Thrombotic/Thromboembolic complications may occur in patients with ITP. Platelet counts above

the normal range present a theoretical risk of thrombotic/thromboembolic complications. In

eltrombopag clinical trials thromboembolic events were observed at low and normal platelet counts.

Caution should be used when administering eltrombopag to patients with known risk factors for

thromboembolism including but not limited to inherited (e.g. Factor V Leiden) or acquired risk

factors (e.g. ATIII deficiency, antiphospholipid syndrome), advanced age, patients with prolonged

periods of immobilisation, malignancies, contraceptives and hormone replacement therapy,

surgery/trauma, obesity and smoking. Platelet counts should be closely monitored and consideration

given to reducing the dose or discontinuing eltrombopag treatment if the platelet count exceeds the

target levels (see Dosage adn Administration). The risk-benefit balance should be considered in

patients at risk of thromboembolic events of any aetiology.

The risk of thromboembolic events (TEEs) has been found to be increased in patients with chronic

liver disease treated with 75 mg RebozetTM once daily for two weeks in preparation for invasive

procedures. Therefore, RebozetTM should not be used in patients with moderate to severe hepatic

impairment (Child-Pugh score ≥ 7) unless the expected benefit outweighs the identified risk of portal

venous thrombosis (see Dosage and Adminsitration and Undesirable effects).

Bleeding following discontinuation of eltrombopag

Thrombocytopenia is likely to reoccur upon discontinuation of treatment with RebozetTM. Following

discontinuation of RebozetTM, platelet counts return to baseline levels within 2 weeks in the majority

of patients, which increase the bleeding risk and in some cases may lead to bleeding. This risk is

increased if RebozetTM treatment is discontinued in the presence of anticoagulants or anti-platelet

agents. It is recommended that, if treatment with RebozetTM is discontinued, ITP treatment be

restarted according to current treatment guidelines. Additional medical management may include

cessation of anticoagulant and/or anti-platelet therapy, reversal of anticoagulation, or platelet

support. Platelet counts must be monitored weekly for 4 weeks following discontinuation of

RebozetTM.

Bone marrow reticulin formation and risk of bone marrow fibrosis

RebozetTM may increase the risk for development or progression of reticulin fibers within the bone

marrow. The relevance of this finding, as with other thrombopoietin receptor (TPO-R) agonists, has

not been established yet.

Prior to initiation of RebozetTM, the peripheral blood smear should be examined closely to establish a

baseline level of cellular morphologic abnormalities. Following identification of a stable dose of

RebozetTM, complete blood count (CBC) with white blood cell count (WBC) differential should be

performed monthly. If immature or dysplastic cells are observed, peripheral blood smears should be

examined for new or worsening morphological abnormalities (e.g., teardrop and nucleated red

blood cells, immature white blood cells) or cytopenia(s). If the patient develops new or worsening

morphological abnormalities or cytopenia(s), treatment with eltrombopag should be discontinued

and a bone marrow biopsy considered, including staining for fibrosis.

Malignancies and progression of malignancies

TPO-R agonists are growth factors that lead to thrombopoietic progenitor cell expansion,

differentiation and platelet production. The TPO-R is predominantly expressed on the surface of cells

of the myeloid lineage. For TPO-R agonists there is a theoretical concern that they may stimulate the

progression of existing haematopoietic malignancies such as MDS.

Cataracts

Cataracts were observed in toxicology studies of eltrombopag in rodents (see Preclinical safety

data). The clinical relevance of this finding is unknown. Routine monitoring of patients for cataracts

is recommended.

Loss of response to eltrombopag

A loss of response or failure to maintain a platelet response with RebozetTM

treatment within

the recommended dosing range should prompt a search for causative factors, including an

increased bone marrow reticulin.

3.5 Interactions

Effects of eltrombopag on other medicinal products

HMG CoA reductase inhibitors

In vitro studies demonstrated that RebozetTM

is not a substrate for the organic anion

transporter polypeptide, OATP1B1, but is an inhibitor of this transporter. In vitro studies also

demonstrated that RebozetTM

is a breast cancer resistance protein (BCRP) substrate and

inhibitor. Administration of RebozetTM

75 mg once daily for 5 days with a single 10 mg dose

of the OATP1B1 and BCRP substrate rosuvastatin to 39 healthy adult subjects increased

plasma rosuvastatin Cmax 103 % (90 % CI: 82 %, 126 %) and AUC0-∞ 55 % (90 % CI: 42 %,

69 %). Interactions are also expected with other HMG-CoA reductase inhibitors, including

pravastatin, simvastatin and lovastatin, however, clinically significant interactions are not

expected between eltrombopag and atorvastatin or fluvastatin. When co-administered with

RebozetTM

, a reduced dose of statins should be considered and careful monitoring for statin

side effects should be undertaken.

OATP1B1 and BCRP substrates

Concomitant administration of RebozetTM

and OATP1B1 (e.g. methotrexate) and BCRP (e.g.

topotecan and methotrexate) substrates should be undertaken with caution.

Cytochrome P450 substrates

In studies utilizing human liver microsomes, RebozetTM

(up to 100 μM) showed no in vitro

inhibition of the CYP450 enzymes 1A2, 2A6, 2C19, 2D6, 2E1, 3A4/5, and 4A9/11 and was

an inhibitor of CYP2C8 and CYP2C9 as measured using paclitaxel and diclofenac as the

probe substrates. Administration of RebozetTM

75 mg once daily for 7 days to 24 healthy

male subjects did not inhibit or induce the metabolism of probe substrates for 1A2 (caffeine),

2C19 (omeprazole), 2C9 (flurbiprofen), or 3A4 (midazolam) in humans. No clinically

significant interactions are expected when eltrombopag and CYP450 substrates are co-

administered.

Effects of other medicinal products on eltrombopag

Polyvalent cations (Chelation)

RebozetTM

chelates with polyvalent cations such as iron, calcium, magnesium, aluminium,

selenium and zinc. Administration of a single dose of RebozetTM

75 mg with a polyvalent

cation-containing antacid (1524 mg aluminium hydroxide and 1425 mg magnesium

carbonate) decreased plasma eltrombopag AUC0-∞ by 70 % (90 % CI: 64 %, 76 %) and Cmax

by 70 % (90 % CI: 62 %, 76 %). Antacids, dairy products and other products containing

polyvalent cations, such as mineral supplements, must be administered at least four hours

apart from eltrombopag dosing to avoid significant reduction in RebozetTM

absorption due to

chelation (see Dosage and Adminstration).

Food interaction

Administration of a single 50 mg-dose of RebozetTM

with a standard high-calorie, high-fat

breakfast that included dairy products reduced plasma eltrombopag AUC0-∞ by 59 % (90 %

CI: 54 %, 64 %) and Cmax by 65 % (90 % CI: 59 %, 70 %). Food low in calcium [< 50 mg

calcium] including fruit, lean ham, beef and unfortified (no added calcium, magnesium, iron)

fruit juice, unfortified soy milk, and unfortified grain did not significantly impact plasma

eltrombopag exposure, regardless of calorie and fat content (see Dosage and Adminsitration).

Lopinavir/ritonavir

Co-administration of RebozetTM

with lopinavir/ritonavir (LPV/RTV) may cause a decrease in

the concentration of eltrombopag. A study in 40 healthy volunteers showed that the co-

administration of single dose eltrombopag 100 mg with repeat dose LPV/RTV 400 /100 mg

twice daily resulted in a reduction in eltrombopag plasma AUC(0-∞) by 17 % (90 % CI: 6.6 %,

26.6 %). Therefore, caution should be used when co-administration of eltrombopag with

LPV/RTV takes place. Platelet count should be closely monitored in order to ensure

appropriate medical management of the dose of eltrombopag when lopinavir/ritonavir therapy

is initiated or discontinued.

Medicinal products for treatment of ITP Medicinal products used in the treatment of ITP in combination with eltrombopag in clinical studies

included corticosteroids, danazol, and/or azathioprine, intravenous immunoglobulin (IVIG), and anti-

D immunoglobulin. Platelet counts should be monitored when combining eltrombopag with other

medicinal products for the treatment of ITP in order to avoid platelet counts outside of the

recommended range (see Dosage and Administration).

3.6 Pregnancy and Lactation

Pregnancy

There are no or limited amount of data from the use of RebozetTM

in pregnant women.

Studies in animals have shown reproductive toxicity (see Preclinical safety data). The

potential risk for humans is unknown.

RebozetTM

is not recommended during pregnancy and in women of childbearing potential not

using contraception.

Breast-feeding It is not known whether RebozetTM / metabolites are excreted in human milk. Studies in animals

have shown that eltrombopag is likely secreted into milk (see Preclinical safety data); therefore a risk

to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-

feeding or to continue / abstain from RebozetTM therapy, taking into account the benefit of breast-

feeding for the child and the benefit of therapy for the woman.

3.7 Effects on Ability to Drive and Use Machines No studies on the effects on the ability to drive and use machines have been performed.

3.8 Adverse Reactions

Based on an analysis of all chronic ITP patients receiving RebozetTM

in 3 controlled and 2

uncontrolled clinical studies, the overall incidence of adverse events in subjects treated with

eltrombopag was 82 % (367/446). The median duration of exposure to RebozetTM

was 304

days and patient year’s exposure was 377 in this study population.

The adverse events listed below by MedDRA system organ class and by frequency are those

that the investigator considered treatment related (N = 446). The frequency categories are

defined as:

Very common (≥ 1/10)

Common (≥ 1/100 to < 1/10)

Uncommon (≥ 1/1,000 to < 1/100)

Rare (≥ 1/10,000 to < 1/1,000)

Very rare (< 1/10,000)

Not known (cannot be estimated from the available data)

Infections and infestations

Uncommon Pharyngitis, Urinary tract infection, Influenza, Nasopharyngitis, Oral herpes,

Pneumonia, Sinusitis, Tonsillitis, Upper respiratory tract infection

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Uncommon Rectosigmoid cancer

Blood and lymphatic system disorders

Uncommon Anaemia, Anisocytosis, Eosinophilia, Haemolytic anaemia, Leukocytosis,

Myelocytosis, Thrombocytopenia, Haemoglobin increased, Band neutrophil count increased,

Haemoglobin decreased, Myelocyte present, Platelet count increased, White blood cell count

decreased

Immune system disorders

Uncommon Hypersensitivity

Metabolism and nutrition disorders

Uncommon Anorexia, Hypokalaemia, Decreased appetite, Increased appetite, Gout,

Hypocalcaemia, Blood uric acid increased

Psychiatric disorders

Common Insomnia

Uncommon Sleep disorder, Anxiety, Depression, Apathy, Mood altered, Tearfulness

Nervous systems disorders

Very Common Headache

Common Paraesthesia

Uncommon Dizziness, Dysgeusia, Hypoaesthesia, Somnolence, Migraine, Tremor,

Balance disorder, Dysaesthesia, Hemiparesis, Migraine with aura, Neuropathy peripheral,

Peripheral sensory neuropathy, Speech disorder, Toxic neuropathy, Vascular headache

Eye disorders

Common Cataract, Dry eye

Uncommon Vision blurred, Lenticular opacities, Astigmatism, Cataract cortical,

Conjunctival haemorrhage, Eye pain, Lacrimation increased, Retinal haemorrhage, Retinal

pigment epitheliopathy, Visual acuity reduced, Visual impairment, Visual acuity tests

abnormal, Blepharitis and Keratoconjunctivitis sicca

Ear and labyrinth disorders

Uncommon Ear pain, Vertigo

Cardiac disorders

Uncommon Tachycardia, Acute myocardial infarction, Cardiovascular disorder, Cyanosis,

Palpitations, Sinus tachycardia, Electrocardiogram QT prolonged

Vascular disorders

Uncommon Deep vein thrombosis, Hypertension, Embolism, Hot flush, Thrombophlebitis

superficial, Flushing, Haematoma

Respiratory, thoracic and mediastinal disorders

Uncommon Epistaxis, Pulmonary embolism, Pulmonary infarction, Cough, Nasal

discomfort, Oropharyngeal blistering, Oropharyngeal pain, Sinus disorder, Sleep apnoea

syndrome

Gastrointestinal disorders

Common Nausea, Diarrhoea, Constipation, Abdominal pain upper

Uncommon Abdominal discomfort, Abdominal distension, Dry mouth, Dyspepsia,

Vomiting, Abdominal pain, Gingival bleeding, Glossodynia, Haemorrhoids, Mouth

haemorrhage, Abdominal tenderness, Faeces discoloured, Flatulence, Food poisoning,

Frequent bowel movements, Haematemesis, Oral discomfort

Hepatobiliary disorders

Common Alanine aminotransferase increased*, Aspartate aminotransferase increased*,

Blood bilirubin increased, Hyperbilirubinaemia, Hepatic function abnormal

Uncommon Cholestasis, Hepatic lesion, Hepatitis

*Increase of alanine aminotransferase and aspartate aminotransferase may occur

simultaneously, although at a lower frequency.

Skin and subcutaneous tissue disorders

Common Rash, Pruritus, Alopecia

Uncommon Ecchymosis, Hyperhidrosis, Pruritus generalised, Urticaria, Dermatosis,

Petechiae, Cold sweat, Erythema, Melanosis, Night sweats, Pigmentation disorder, Skin

discolouration, Skin exfoliation, Swelling face

Musculoskeletal and connective tissue disorder

Common Arthralgia, Myalgia, Muscle spasm, Bone pain

Uncommon Muscular weakness, Pain in extremity, Sensation of heaviness

Renal and urinary disorders

Uncommon Renal failure, Leukocyturia, Lupus nephritis, Nocturia, Proteinuria, Blood

urea increased, Blood creatinine increased, Urine protein/creatinine ratio increased

General disorders and administrative site conditions

Common Fatigue, Oedema peripheral

Uncommon Chest pain, Feeling hot, Pain, Vessel puncture site haemorrhage, Asthenia,

Feeling jittery, Ill-defined disorder, Inflammation of wound, Influenza like illness, Malaise,

Mucosal inflammation, Non-cardiac chest pain, Pyrexia, Sensation of foreign body

Investigations

Uncommon Blood albumin increased, Blood alkaline phosphatase increased, Protein total

increased, Weight increased, Blood albumin decreased, pH urine increased

Injury, poisoning and procedural complications

Uncommon Contusion, Sunburn

Thromboembolic events (TEEs)

In 3 controlled and 2 uncontrolled clinical studies, among adult chronic ITP patients

receiving eltrombopag (n = 446), 17 subjects experienced a total of 19 TEEs, which included

(in descending order of occurrence) deep vein thrombosis (n = 6), pulmonary embolism (n =

6), acute myocardial infarction (n = 2), cerebral infarction (n = 2), embolism (n = 1) (see

Special warnings and precautions for use).

In a placebo-controlled study, following 2 weeks treatment in preparation for invasive

procedures, 6 of 261 patients with chronic liver disease experienced 7 thromboembolic events

of the portal venous system. One additional patient developed a myocardial infarction 20

days after the last dose of study medication, which remains blinded.

Thrombocytopenia following discontinuation of treatment

In the 3 controlled clinical studies, transient decreases in platelet counts to levels lower than

baseline were observed following discontinuation of treatment in 8 % and 8 % of the

eltrombopag and placebo groups, respectively (see Special warnings and precautions for use).

Increased bone marrow reticulin Across the programme, no subjects had evidence of clinically relevant bone marrow abnormalities or

clinical findings that would indicate bone marrow dysfunction. In one patient, eltrombopag

treatment was discontinued due to bone marrow reticulin (see Special warnings and precautions for

use).

3.9 Postmarketing Data No post marketing data are currently available.

3.10 Overdose

In the event of overdose, platelet counts may increase excessively and result in

thrombotic/thromboembolic complications. In case of an overdose, consider oral

administration of a metal cation-containing preparation, such as calcium, aluminium, or

magnesium preparations to chelate eltrombopag and thus limit absorption. Closely monitor

platelet counts. Reinitiate treatment with RebozetTM

in accordance with dosing and

administration recommendations (see Dosage and Administration).

In the clinical studies there was one report of overdose where the subject ingested 5000 mg of

RebozetTM

. Reported adverse events included mild rash, transient bradycardia, ALT and AST

elevation, and fatigue. Liver enzymes measured between Days 2 and 18 after ingestion

peaked at a 1.6-fold ULN in AST, a 3.9-fold ULN in ALT, and a 2.4-fold ULN in total

bilirubin, The platelet counts were 672,000/μl on day 18 after ingestion and the maximum

platelet count was 929,000/μl. All events were resolved without sequelae following

treatment.

Because RebozetTM

is not significantly renally excreted and is highly bound to plasma

proteins, haemodialysis would not be expected to be an effective method to enhance the

elimination of RebozetTM

.

4. PHARMACOLOGICAL PROPERTIES

4.1 Pharmacodynamics

Pharmacotherapeutic group: Antihemorrhagics, ATC code: B02BX 05.

Mechanism of action

TPO is the main cytokine involved in regulation of megakaryopoiesis and platelet production, and is

the endogenous ligand for the TPO-R. Eltrombopag interacts with the transmembrane domain of the

human TPO-R and initiates signaling cascades similar but not identical to that of endogenous

thrombopoietin (TPO), inducing proliferation and differentiation of megakaryocytes from bone

marrow progenitor cells.

Clinical studies

Two Phase III, randomised, double-blind, placebo-controlled studies RAISE (TRA102537) and

TRA100773B and two open-label studies REPEAT (TRA108057) and EXTEND (TRA105325) evaluated

the safety and efficacy of eltrombopag in adult patients with previously treated chronic ITP. Overall,

eltrombopag was administered to 277 patients for at least 6 months and 202 patients for at least 1

year.

Double-blind placebo-controlled studies

RAISE: 197 patients were randomised 2:1, eltrombopag (n=135) to placebo (n=62), and

randomisation was stratified based upon splenectomy status, use of ITP medication at baseline and

baseline platelet count. The dose of eltrombopag was adjusted during the 6 month treatment period

based on individual platelet counts. All subjects initiated treatment with eltrombopag 50 mg. From

Day 29 to the end of treatment, 15 to 28 % of eltrombopag treated patients were maintained on ≤

25 mg and 29 to 53 % received 75 mg.

In addition, patients could taper off concomitant ITP medicinal products and receive rescue

treatments as dictated by local standard of care. More than half of all patients in each treatment

group had ≥ 3 prior ITP therapies and 36 % had a prior splenectomy.

Median platelet counts at baseline were 16,000/μl for both treatment groups and in the

eltrombopag group were maintained above 50,000/μl at all on-therapy visits starting at Day 15; in

contrast, median platelet counts in the placebo group remained < 30,000/μl throughout the study.

Platelet count response between 50,000-400,000/μl in the absence of rescue medication was

achieved by significantly more patients in the eltrombopag treated group during the 6 month

treatment period, p < 0.001. Fifty-four percent of the eltrombopag-treated patients and 13 % of

placebo-treated patients achieved this level of response after 6 weeks of treatment. A similar

platelet response was maintained throughout the study, with 52 % and 16 % of patients responding

at the end of the 6-month treatment period.

Table 2: Secondary efficacy results from RAISE

Eltrombopag

N = 135

Placebo

N = 62

Key secondary endpoints

Number of cumulative weeks with platelet counts ≥

50,000-400,000/μl, Mean (SD)

11.3 (9.46) 2.4 (5.95)

Patients with ≥ 75 % of assessments in the target

range (50,000 to 400,000/μl), n (%)

P-value a

51 (38) 4 (7)

< 0.001

Patients with bleeding (WHO Grades 1-4) at any time

during 6 months, n (%)

P-value a

106 (79) 56 (93)

0.012

Patients with bleeding (WHO Grades 2-4) at any time

during 6 months, n (%)

P-value a

44 (33) 32 (53)

0.002

Requiring rescue therapy, n (%)

P-value a

24 (18) 25 (40)

0.001

Patients receiving ITP therapy at baseline (n) 63 31

Patients who attempted to reduce or discontinue

baseline therapy, n (%)b

P value a

37 (59) 10 (32)

0.016

a. Logistic regression model adjusted for randomisation stratification variables

b. 21 out of 63 (33 %) patients treated with eltrombopag who were taking an ITP medication at baseline

permanently discontinued all baseline ITP medications.

At baseline, more than 70 % of patients in each treatment group reported any bleeding (WHO

Grades 1-4) and more than 20 % reported clinically significant bleeding (WHO Grades 2-4),

respectively. The proportion of eltrombopag-treated patients with any bleeding (Grades 1-4)

and clinically significant bleeding (Grades 2-4) was reduced from baseline by approximately

50 % from Day 15 to the end of treatment throughout the 6 month treatment period.

TRA100773B: The primary efficacy endpoint was the proportion of responders, defined as

patients who had an increase in platelet counts to ≥ 50,000/μl at Day 43 from a baseline of <

30,000/μl; patients who withdrew prematurely due to a platelet count > 200,000/μl were

considered responders, those that discontinued for any other reason were considered non-

responders irrespective of platelet count. A total of 114 patients with previously treated

chronic ITP were randomised 2:1 eltrombopag (n = 76) to placebo (n = 38).

Table 3: Efficacy results from TRA100773B

Eltrombopag

N = 74

Placebo

N = 38

Key primary endpoints

Eligible for efficacy analysis, n 73 37

Patients with platelet count ≥ 50,000/μl after up to 42

days of dosing (compared to a baseline count of <

30,000/μl), n (%)

P valuea

43 (59) 6 (16)

< 0.001

Key secondary endpoints

Patients with a Day 43 bleeding assessment, n 51 30

Bleeding (WHO Grades 1-4) n (%)

P value a

20 (39) 18 (60)

0.029

a. Logistic regression model adjusted for randomisation stratification variables

In both RAISE and TRA100773B the response to eltrombopag relative to placebo was

similar irrespective of ITP medication use, splenectomy status and baseline platelet count (≤

15,000/μl, > 15,000/μl) at randomisation.

In RAISE and TRA100773B studies, in the subgroup of patients with baseline platelet count

≤ 15,000/μl the median platelet counts did not reach the target level (> 50,000/μl), although

in both studies 43 % of these patients treated with eltrombopag responded after 6 weeks of

treatment. In addition, in the RAISE study, 42 % of patients with baseline platelet count ≤

15,000/μl treated with eltrombopag responded at the end of the 6 month treatment period.

Forty-two to 60 % of the eltrombopag-treated patients in the RAISE study were receiving 75

mg from Day 29 to the end of treatment.

An open label, repeat dose study (3 cycles of 6 weeks of treatment, followed by 4 weeks off

treatment) showed that episodic use with multiple courses of eltrombopag has demonstrated

no loss of response.

Eltrombopag was administered to 299 patients in an open-label extension study, 126 patients

completed 1 year, 48 completed 18 months and 17 completed 2 years. The median baseline

platelet count was 19,500/μl prior to eltrombopag administration. Median platelet counts at

12, 18 and 24 months on study were 68,000/μl, 75,000/μl and 119,000/μl, respectively.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies

with eltrombopag in one or more subsets of the paediatric population in chronic idiopathic

thrombocytopenic purpura (ITP) (see Dosage and Administration for information on

paediatric use).

4.2 Pharmacokinetics The plasma eltrombopag concentration-time data collected in 88 subjects with ITP in Studies

TRA100773A and TRA100773B were combined with data from 111 healthy adult subjects in a

population PK analysis. Plasma eltrombopag AUC(0-τ) and Cmax estimates for ITP subjects are

presented (Table 4).

Table 4: Geometric mean (95 % confidence intervals) of steady-state plasma eltrombopag

pharmacokinetic parameters in adults with ITP

Eltrombopag dose, once daily N AUC(0-τ)a, μg.h/ml Cmax

a , μg/ml

30 mg 28 47 (39, 58) 3.78 (3.18, 4.49)

50 mg 34 108 (88, 134) 8.01 (6.73, 9.53)

75 mg 26 168 (143, 198) 12.7 (11.0, 14.5)

a - AUC(0-τ) and Cmax based on population PK post-hoc estimates.

Absorption and bioavailability

Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral

administration. Administration of eltrombopag concomitantly with antacids and other

products containing polyvalent cations such as dairy products and mineral supplements

significantly reduces eltrombopag exposure (see section 4.2). The absolute oral

bioavailability of eltrombopag after administration to humans has not been established. Based

on urinary excretion and metabolites eliminated in faeces, the oral absorption of drug-related

material following administration of a single 75 mg eltrombopag solution dose was estimated

to be at least 52 %.

Distribution

Eltrombopag is highly bound to human plasma proteins (> 99.9 %), predominantly to

albumin. Eltrombopag is a substrate for BCRP, but is not a substrate for P-glycoprotein or

OATP1B1.

Metabolism

Eltrombopag is primarily metabolized through cleavage, oxidation and conjugation with

glucuronic acid, glutathione, or cysteine. In a human radiolabel study, eltrombopag accounted

for approximately 64 % of plasma radiocarbon AUC0-∞. Minor metabolites due to

glucuronidation and oxidation were also detected. In vitro studies suggest that CYP1A2 and

CYP2C8 are responsible for oxidative metabolism of eltrombopag. Uridine

diphosphoglucuronyl transferase UGT1A1 and UGT1A3 are responsible for glucuronidation,

and bacteria in the lower gastrointestinal tract may be responsible for the cleavage pathway.

Elimination

Absorbed eltrombopag is extensively metabolised. The predominant route of eltrombopag

excretion is via faeces (59 %) with 31 % of the dose found in the urine as metabolites.

Unchanged parent compound (eltrombopag) is not detected in urine. Unchanged eltrombopag

excreted in faeces accounts for approximately 20 % of the dose. The plasma elimination half-

life of eltrombopag is approximately 21-32 hours.

Pharmacokinetic interactions

Based on a human study with radiolabelled eltrombopag, glucuronidation plays a minor role

in the metabolism of eltrombopag. Human liver microsome studies identified UGT1A1 and

UGT1A3 as the enzymes responsible for eltrombopag glucuronidation. Eltrombopag was an

inhibitor of a number of UGT enzymes in vitro. Clinically significant drug interactions

involving glucuronidation are not anticipated due to limited contribution of individual UGT

enzymes in the glucuronidation of eltrombopag.

Approximately 21 % of an eltrombopag dose could undergo oxidative metabolism. Human

liver microsome studies identified CYP1A2 and CYP2C8 as the enzymes responsible for

eltrombopag oxidation. Eltrombopag does not inhibit or induce CYP enzymes based on in

vitro and in vivo data (see Interactions).

In vitro studies demonstrate that eltrombopag is an inhibitor of the OATP1B1 transporter and

an inhibitor of the BCRP transporter and eltrombopag increased exposure of the OATP1B1

and BCRP substrate rosuvastatin in a clinical drug interaction study (see Interactions). In

clinical studies with eltrombopag, a dose reduction of statins by 50 % was recommended.

Eltrombopag chelates with polyvalent cations such as iron, calcium, magnesium, aluminium,

selenium and zinc (see Dosage and Administrations and Interactions).

Administration of a single 50 mg dose of eltrombopag with a standard high-calorie, high-fat

breakfast that included dairy products reduced plasma eltrombopag AUC(0-∞) and Cmax.

Whereas, low-calcium food [< 50 mg calcium] did not significantly impact plasma

eltrombopag exposure, regardless of calorie and fat content (see Dosage and Administrations

and Interactions).

Special patient populations

Renal impairment

The pharmacokinetics of eltrombopag has been studied after administration of eltrombopag

to adult subjects with renal impairment. Following administration of a single 50 mg-dose, the

AUC0-∞ of eltrombopag was 32 % to 36 % lower in subjects with mild to moderate renal

impairment, and 60 % lower in subjects with severe renal impairment compared with healthy

volunteers. There was substantial variability and significant overlap in exposures between

patients with renal impairment and healthy volunteers. Unbound eltrombopag (active)

concentrations for this highly protein bound medicinal product were not measured. Patients

with impaired renal function should use eltrombopag with caution and close monitoring, for

example by testing serum creatinine and/or urine analysis (see Dosage and Administrations).

Hepatic impairment

The pharmacokinetics of eltrombopag has been studied after administration of eltrombopag

to adult subjects with hepatic impairment. Following the administration of a single 50 mg

dose, the AUC0-∞ of eltrombopag was 41 % higher in subjects with mild hepatic impairment

and 80 % to 93 % higher in subjects with moderate to severe hepatic impairment compared

with healthy volunteers. There was substantial variability and significant overlap in exposures

between patients with hepatic impairment and healthy volunteers. Unbound eltrombopag

(active) concentrations for this highly protein bound medicinal product were not measured.

Therefore, eltrombopag should not be used in patients with moderate to severe hepatic

impairment (Child-Pugh score ≥ 7) unless the expected benefit outweighs the identified risk

of portal venous thrombosis (see Dosage and Administrations and Warnings and

precautions).

Race

The influence of East Asian ethnicity on the pharmacokinetics of eltrombopag was evaluated

using a population pharmacokinetic analysis in 111 healthy adults (31 East Asians) and 88

patients with ITP (18 East Asians). Based on estimates from the population pharmacokinetic

analysis, East Asian (i.e. Japanese, Chinese, Taiwanese and Korean) ITP patients had

approximately 87 % higher plasma eltrombopag AUC(0-τ) values as compared to non-East

Asian patients who were predominantly Caucasian, without adjustment for body weight

differences (see Dosage and Administrations).

Gender

The influence of gender on the pharmacokinetics of eltrombopag was evaluated using a

population pharmacokinetic analysis in 111 healthy adults (14 females) and 88 patients with

ITP (57 females). Based on estimates from the population pharmacokinetic analysis, female

ITP patients had approximately 50 % higher plasma eltrombopag AUC(0-τ) as compared to

male patients, without adjustment for body weight differences.

4.3 Pre-clinical Safety Data

Eltrombopag does not stimulate platelet production in mice, rats or dogs because of unique

TPO receptor specificity. Therefore, data from these animals do not fully model potential

adverse effects related to the pharmacology of eltrombopag in humans, including the

reproduction and carcinogenicity studies.

Treatment-related cataracts were detected in rodents and were dose and time-dependent. At ≥

6 times the human clinical exposure based on AUC, cataracts were observed in mice after 6

weeks and rats after 28 weeks of dosing. At ≥ 4 times the human clinical exposure based on

AUC, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing.

Cataracts have not been observed in dogs after 52 weeks of dosing (2 times the human

clinical exposure based on AUC). The clinical relevance of these findings is unknown (see

section 4.4).

Renal tubular toxicity was observed in studies of up to 14 days duration in mice and rats at

exposures that were generally associated with morbidity and mortality. Tubular toxicity was

also observed in a 2 year oral carcinogenicity study in mice at doses of 25, 75 and 150

mg/kg/day. Effects were less severe at lower doses and were characterized by a spectrum of

regenerative changes. The exposure at the lowest dose was 1.2 times the human clinical

exposure based on AUC. Renal effects were not observed in rats after 28 weeks or in dogs

after 52 weeks at exposures 4 and 2 times respectively, the human clinical exposure based on

AUC. The clinical relevance of these findings is unknown.

Hepatocyte degeneration and/or necrosis, often accompanied by increased serum liver

enzymes, was observed in mice, rats and dogs at doses that were associated with morbidity

and mortality or were poorly tolerated. No hepatic effects were observed after chronic dosing

in rats (28 weeks) or dogs (52 weeks) at exposures up to 4 or 2 times, respectively, the human

clinical exposure based on AUC.

At poorly tolerated doses in rats and dogs (> 10 times maximum human clinical exposure

based on AUC), decreased reticulocyte counts and regenerative bone marrow erythroid

hyperplasia (rats only) were observed in short term studies. There were no effects of note on

red cell mass or reticulocyte counts after dosing for up to 28 weeks in rats, 52 weeks in dogs

and 2 years in mice or rats at maximally tolerated doses which were 2 to 4 times maximum

human clinical exposure based on AUC.

Endosteal hyperostosis was observed in a 28 week toxicity study in rats at a non-tolerated

dose of 60 mg/kg/day (6 times maximum human clinical exposure based on AUC). There

were no bone changes observed in mice or rats after lifetime exposure (2 years) at 4 times

maximum human clinical exposure based on AUC.

Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up

to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC).

Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo

assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical

exposure based on Cmax). In the in vitro mouse lymphoma assay, eltrombopag was

marginally positive (< 3-fold increase in mutation frequency). These in vitro and in vivo

findings suggest that eltrombopag does not pose a genotoxic risk to humans.

Eltrombopag did not affect female fertility, early embryonic development or embryofoetal

development in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based

on AUC). Also there was no effect on embryofoetal development in rabbits at doses up to

150 mg/kg/day, the highest dose tested (0.5 times the human clinical exposure based on

AUC). However, at a maternally toxic dose of 60 mg/kg/day (6 times the human clinical

exposure based on AUC) in rats, eltrombopag treatment was associated with embryo lethality

(increased pre- and post-implantation loss), reduced foetal body weight and gravid uterine

weight in the female fertility study and a low incidence of cervical ribs and reduced foetal

body weight in the embryofoetal development study. Eltrombopag did not affect male

fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human

clinical exposure based on AUC). In the pre- and post-natal development study in rats, there

were no undesirable effects on pregnancy, parturition or lactation of F0 female rats at

maternally non-toxic doses (10 and 20 mg/kg/day) and no effects on the growth,

development, neurobehavioral or reproductive function of the offspring (F1). Eltrombopag

was detected in the plasma of all F1 rat pups for the entire 22 hour sampling period following

administration of medicinal product to the F0 dams, suggesting that rat pup exposure to

eltrombopag was likely via lactation.

In vitro studies with eltrombopag suggest a potential phototoxicity risk; however, in rodents there

was no evidence of cutaneous phototoxicity (10 times the human clinical exposure based on AUC) or

ocular phototoxicity (≥ 5 times the human clinical exposure based on AUC). Furthermore, a clinical

pharmacology study in 36 subjects showed no evidence that photosensitivity was increased

following administration of eltrombopag 75 mg. This was measured by delayed phototoxic index.

Nevertheless, a potential risk of photoallergy cannot be ruled out since no specific preclinical study

could be performed.

5. PHARMACEUTICAL PARTICULARS

5.1 List of Excipients

Tablet Core:

Magnesium stearate, Mannitol, Microcrystalline cellulose, Povidone, Sodium starch

glycolate

Tablet Coating:

Hypromellose, Macrogol 400, Polysorbate 80, Titanium dioxide (E171)

5.2 Incompatibilities No known incompatibilities

5.3 Shelf Life The expiry date is indicated on the packaging.

5.4 Special Precautions for Storage Do not store above 30°C.

5.5 Nature and Contents of Container

Blister packs containing either 25 mg or 50 mg tablets

Each pack of RebozetTM contains 14, 28 film-coated-tablets in aluminium foil – aluminium foil

blisters.

Not all presentations are available in every country.

5.6 Instructions for Use/Handling No special requirements

RebozetTM is trademark of the GlaxoSmithKline group of companies

HARUS DENGAN RESEP DOKTER

Rebozet 25 mg, Dus, 2 blister @ 7 tablet salut selaput DKI1291600817A1

Rebozet 25 mg, Dus, 4 blister @ 7 tablet salut selaput DKI1291600817A1

Rebozet 50 mg, Dus, 2 blister @ 7 tablet salut selaput DKI1291600817B1

Rebozet 50 mg, Dus, 4 blister @ 7 tablet salut selaput DKI1291600817B1

Manufactured by

Glaxo Operations UK Limited (trading as GlaxoWellcome Operations)

Ware, UK

Imported by

PT. Glaxo Wellcome Indonesia

Jakarta, Indonesia

PI based on ver number: GDS03/IPI02 (+EMA rev)

Date of issue: 10 March 2010

TYKERB TM

Lapatinib Ditosylate

QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains lapatinib ditosylate monohydrate, equivalent to 250 mg lapatinib.

PHARMACEUTICAL FORM Film-coated tablets

Oval, biconvex, yellow film-coated tablets, with one side plain and the opposite side debossed with

GS XJG.

CLINICAL PARTICULARS

Indications TYKERB, in combination with capecitabine, is indicated for the treatment of patients with advanced

or metastatic breast cancer, whose tumours overexpress HER2+/neu (Erb2+) and who have received

prior therapy including trastuzumab (see Clinical Studies).

TYKERB, in combination with letrozole for the treatment of postmenopausal women with hormone

receptor-positive metastatic breast cancer, that overexpress the HER2 receptor

(immunohistochemistry / IHC2+) for whom hormonal therapy is indicated (see Clinical Studies).

Dosage and Administration TYKERB treatment should only be initiated by a physician experienced in the administration of anti-

cancer agents.

Prior to the initiation of treatment, left ventricular ejection fraction (LVEF) must be evaluated to

ensure that baseline LVEF is within the institutional limits of normal (see Warnings and Precautions).

LVEF must continue to be monitored during treatment with TYKERB to ensure that LVEF does not

decline below the institutional lower limit of normal (see dose delay and dose reduction — cardiac

events).

TYKERB should be taken at least one hour before, or at least one hour after food (see Interactions

and Pharmacokinetics — Absorption).

Missed doses should not be replaced and the dosing should resume with the next scheduled daily

dose (see Overdosage).

Consult the full prescribing information of the co-administered medicinal product for relevant details

of their posology, contraindications and safety information.

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 Clinical Studies). Capecitabine should be taken with food or within 30

minutes after food.

TYKERB in combination letrozole

The recommended dose of TYKERB is 1500 mg (i.e. six tablets) once daily continuously when taken in

combination with letrozole.

When TYKERB is co-administered with letrozole, the recommended dose of letrozole is 2.5 mg once

daily. The dose of TYKERB should be once daily (6 tablets administered all at once), dividing the daily

dose is not recommended.

Dose delay and dose reduction

Cardiac events (see Warnings and Precautions)

TYKERB should be discontinued 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 institutions lower limit of normal. TYKERB may be restarted

at a reduced dose (1000 mg/day when administered with capecitabine or 1250 mg/day when

administered with letrozole) 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

9 weeks of treatment, however, there is limited data on long term exposure.

Interstitial lung disease/pneumonitis (see Warnings and Precautions and Adverse Reactions)

TYKERB should be discontinued in patients who experience pulmonary symptoms indicative of

interstitial lung disease/pneumonitis which are NCI CTCAE grade 3 or greater.

Other toxicities

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 either 1250

mg/day when administered with capecitabine or 1500 mg/day when administered with letrozole,

when the toxicity improves to grade 1 or less. If the toxicity recurs, then TYKERB should be restarted

at a lower dose (1000 mg/day when administered with capecitabine or 1250 mg/day when

administered with letrozole).

Populations

Renal Impairment There is no experience of TYKERB in patients with severe renal impairment, however patients with

renal impairment are unlikely to require dose modification of TYKERB given that less than 2% of an

administered dose (lapatinib and metabolites) is eliminated by the kidneys (see Pharmacokinetics —

Special Patient Populations).

Hepatic Impairment Lapatinib is metabolised in the liver. Moderate and severe hepatic impairment have been

associated, respectively, with 56% and 85% increases in systemic exposure, respectively.

Administration of TYKERB to patients with hepatic impairment should be undertaken with caution

due to increased exposure to the drug (see Warnings and Precautions and Pharmacokinetics —

Special Patient Populations).

Patients with severe hepatic impairment (Child-Pugh Class C) should have their dose of TYKERB

reduced. A dose reduction to from 1250 mg 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 is no clinical data with this dose adjustment in patients with severe

hepatic impairment (see Warnings and Precautions and Pharmacokinetics – Special Patient

Populations).

Children

The safety and efficacy of TYKERB in paediatric patients has not been established.

Elderly

There are limited data of the use of TYKERB in patients aged 65 years and older. Of the total number

of metastatic breast cancer patients in clinical studies of TYKERB in combination with capecitabine

(N=164) 15% were 65 and over and 1% were 75 and over. For single agent TYKERB (N=307) 15%

were 65 and over and 2% were 75 and over. No overall differences in safety of the combination of

TYKERB and capecitabine or single agent TYKERB were observed between these subjects and

younger subjects. Of the total number of hormone receptor positive, HER2 positive metastatic

breast cancer patients in the clinical studies of TYKERB in combination with letrozole (N=642) 44%

were 65 and over. No overall differences in safety of the combination of TYKERB and letrozole were

observed between these subjects and younger subjects. Other reported clinical experience has not

identified differences in responses between the elderly and younger patients, but greater sensitivity

of some older individuals cannot be ruled out. Similarly no differences in effectiveness for the

combination of either TYKERB and capecitabine or TYKERB and letrozole on the basis of age were

observed.

Contraindications TYKERB is contraindicated in patients with hypersensitivity to any of the ingredients (see Adverse

Reactions).

Warnings and Precautions TYKERB has been associated with reports of decreases in left ventricular ejection fraction [LVEF] (see

Adverse Reactions). 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 the patient has a baseline LVEF that is within

the institutions normal limits. LVEF should continue to be evaluated during treatment with TYKERB

to ensure that LVEF does not decline to an unacceptable level (see Dosage and Administration —

dose delay and dose reduction — cardiac events and Clinical Studies).

TYKERB has been associated with reports of interstitial lung disease and pneumonitis (see Adverse

Reactions). Patients should be monitored for pulmonary symptoms indicative of interstitial lung

disease/pneumonitis (see Dosage and Administration).

Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin

>1.5 times the upper limit of normal) 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 and patients should not be retreated

with TYKERB (see Adverse Reactions).

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 Dosage and

Administration and Pharmacokinetics – Special patient Populations).

Diarrhoea, including severe diarrhoea, has been reported with TYKERB treatment (see Adverse

Reactions). Proactive management of diarrhoea with anti-diarrhoeal agents is important. Severe

cases of diarrhoea may require administration of oral or intravenous electrolytes and fluids, and

interruption or discontinuation of TYKERB therapy (see Dosage and Administration – dose delay and

dose reduction – other toxicities).

Concomitant treatment with inhibitors or inducers of CYP3A4 should proceed with caution due to

risk of increased or decreased exposure to lapatinib, respectively (see Interactions).

Coadministration of TYKERB with medications with narrow therapeutic windows that are substrates

of CYP3A4 or CYP2C8 should be avoided (see Interactions).

Interactions Lapatinib is predominantly metabolised by CYP3A (see Pharmacokinetics). Therefore, inhibitors or

inducers of these enzymes may alter the pharmacokinetics of lapatinib.

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 Warnings and Precautions). 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 lapatinib 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.

Coadministration of TYKERB with known inducers of CYP3A4 (e.g., rifampin, carbamazepine, or

phenytoin) should proceed with caution and clinical response and adverse events should be carefully

monitored (see Warnings and Precautions). If patients must be coadministered a strong CYP3A4

inducer, based on pharmacokinetic studies, the dose of TYKERB should be titrated gradually from

1250 mg/day up to 4500 mg/day or from 1500 mg/day to 5500 mg/day based on tolerability. This

dose of TYKERB is predicted to adjust the lapatinib AUC to the range observed without inducers and

should be considered. 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.

Lapatinib inhibits CYP3A4 and CYP2C8 in vitro at clinically relevant concentrations. Caution should be

exercised when dosing TYKERB concurrently with medications with narrow therapeutic windows

that are substrates of CYP3A4 or CYP2C8 (see Warnings and Precautions and Pharmacokinetics).

Lapatinib is a substrate for the transport proteins Pgp and BCRP. Inhibitors and inducers of

these proteins may alter the exposure and/or distribution of lapatinib (see Pharmacokinetics).

Lapatinib inhibits the transport proteins Pgp, 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 Pgp (e.g. digoxin), BCRP (e.g. topotecan) and OATP1B1 (e.g.

rosuvastatin) (see Pharmacokinetics).

Concomitant administration of TYKERB with capecitabine, letrozole or trastuzumab did not

meaningfully alter the pharmacokinetics of these agents (or the metabolites of capecitabine) or

lapatinib.

The bioavailability of lapatinib is affected by food (see Dosage and Administration and

Pharmacokinetics).

Pregnancy and Lactation

Fertility No relevant information

Pregnancy There are no adequate and well-controlled studies of TYKERB in pregnant women. The effect of

TYKERB on human pregnancy is unknown. TYKERB should be used during pregnancy only if the

expected benefit justifies the potential risk to the foetus. Women of childbearing potential should be

advised to use adequate contraception and avoid becoming pregnant while receiving treatment with

TYKERB.

TYKERB was not teratogenic when studied in pregnant rats and rabbits but caused minor

abnormalities at doses which were maternally toxic (see Non-clinical Information).

Lactation It is not known whether lapatinib is excreted in human milk. Because many drugs are excreted in

human milk and because of the potential for adverse reactions in breast-feeding infants from

lapatinib, it is recommended that breast-feeding be discontinued in women who are receiving

therapy with TYKERB.

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 the TYKERB. The clinical status of the patient and the adverse event profile of

TYKERB should be borne in mind when considering the patient's ability to perform tasks that require

judgement, motor or cognitive skills.

Adverse Reactions

Clinical Trial Data The safety of TYKERB has been evaluated as monotherapy and in combination with other

chemotherapeutic agents for various cancers in more than 11,000 patients including 164 patients

who received TYKERB in combination with capecitabine and 654 patients who received TYKERB in

combination with letrozole (see Clinical Studies).

The following convention has been utilised for the classification of frequency: Very common

(greater than or equal to 1/10), common (greater than or equal to 1/100 and less than 1/10),

uncommon (greater than or equal to 1/1000 and less than 1/100), rare (greater than or equal to

1/10,000 and less than 1/1000) and very rare (less than 1/10,000).

The following adverse reactions have been reported to be associated with TYKERB:

Metabolism and nutrition disorders

Very common Anorexia.

Cardiac disorders

Common Decreased left ventricular ejection fraction1 (see Dosage and Administration – dose

delay and dose reduction – cardiac events and Warnings and Precautions). 1Left ventricular ejection fraction (LVEF) decreases have been reported in approximately 1% of patients

and were asymptomatic in more than 90% of cases. LVEF decreases resolved or improved in more than

60% of cases on discontinuation of treatment with TYKERB. Symptomatic LVEF decreases were

observed in approximately 0.1% of patients who received TYKERB monotherapy. Observed symptoms

included dyspnoea, cardiac failure and palpitations. All events resolved promptly on discontinuation of

TYKERB.

Respiratory, thoracic and mediastinal disorders:

Uncommon Interstitial lung disease / pneumonitis

Gastrointestinal disorders

Very common Diarrhoea2, which may lead to dehydration3 (see Dosage and Administration – dose

delay and dose reduction – other toxicities and Warnings and Precautions).

Nausea.

Vomiting. 3Most events of diarrhoea were grade 1 or 2.

Hepatobiliary disorders

Uncommon Hyperbilirubinaemia4, hepatotoxicity. 4Elevated bilirubin may be due to lapatinib inhibition of hepatic uptake by OATP1B1 or inhibition of

excretion into bile by Pgp or BCRP.

Skin and subcutaneous tissue disorders

Very common Rash2 (including dermatitis acneform) (see Dosage and Administration – dose delay

and dose reduction – other toxicities).

Common Nail disorders including paronychia.

Immune System Disorders

Rare Hypersensitivity reactions including anaphylaxis (see Contraindications).

General disorders and administration site conditions

Very common Fatigue. 2Diarrhoea and rash were generally low grade and did not result in discontinuation of

treatment with TYKERB. Diarrhoea responds well to proactive management (see Warnings

and Precautions). Rash was transient in the majority of cases.

The following additional 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. These data are based on exposure to this combination in 164

patients. Gastrointestinal disorders

Very common Dyspepsia.

Skin and subcutaneous tissue disorders

Very common Dry skin.

In addition, the following adverse reactions were reported to be associated with TYKERB in

combination with capecitabine but were seen at a similar frequency in the capecitabine alone arm.

Gastrointestinal disorders

Very common Stomatitis, constipation, abdominal pain.

Skin and subcutaneous tissue disorders

Very common Palmar-plantar erythrodysaesthesia.

General disorders and administrative site conditions

Very common Mucosal inflammation.

Musculoskeletal and connective tissue disorders

Very common Pain in extremity, back pain.

Nervous system disorders

Common Headache.

Psychiatric disorders

Very common Insomnia.

The following additional 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.

Respiratory, thoracic and mediastinal disorders

Very Common Epistaxis

Skin and subcutaneous tissue disorders

Very Common Alopecia

Dry skin

Overdose There is no specific antidote for the inhibition of ErbB1 (EGFR) and/or ErbB2 tyrosine

phosphorylation. 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 Dosage and Administration).

Symptoms and Signs There has been a report of one patient who took an overdose of 3000 mg of TYKERB for 10 days and

suffered grade 3 diarrhoea and vomiting on day 10. The symptoms resolved following IV hydration

and interruption of treatment with TYKERB and letrozole.

Treatment 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

TYKERB.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics

Mechanism of Action Lapatinib is a novel 4-anilinoquinazoline kinase inhibitor with a unique mechanism of action, since it

is a potent, reversible, and selective inhibitor of the intracellular tyrosine kinase domains of both

ErbB1 and of ErbB2 receptors (estimated Kiapp values of 3nM and 13nM, respectively) with a slow

off-rate from these receptors (half-life greater than or equal to 300 minutes). This dissociation rate

was found to be slower than other 4-anilinoquinazoline kinase inhibitors studied. Lapatinib inhibits

ErbB-driven tumour cell growth in vitro and in various animal models. In addition to its activity as a

single agent, an additive effect was demonstrated in an in vitro study when lapatinib and 5-FU (the

active metabolite of capecitabine) were used in combination in the four tumour cell lines tested. The

clinical significance of these in vitro data is unknown.

The growth inhibitory effects of lapatinib were evaluated in trastuzumab-conditioned cell lines.

Lapatinib retained significant activity against breast cancer cell lines selected for long-term growth in

trastuzumab-containing medium in vitro. These findings suggest non-cross-resistance between

these two ErbB2-directed agents.

Hormone receptor-positive breast cancer cells (oestrogen receptor [ER] positive and/or

progesterone receptor [PgR] positive) that co-express ErbB2 tend to become resistant to established

endocrine therapies. Hormone receptor-positive breast cancer cells initially lack overexpression of

EGFR or HER2 will up regulate these receptors as the tumour becomes resistant to endocrine

therapy. Randomised trials in hormone receptor-positive metastatic breast cancer indicate that an

HER2 or EGFR tyrosine kinase inhibitor may potentially improve PFS when added to endocrine

therapy.

Pharmacokinetics

Absorption Absorption following oral administration of lapatinib is incomplete and variable (approximately 50 to

100% coefficient of variation in AUC). 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) µg/mL and AUC values

of 36.2 (23.4 to 56) µg*hr/mL.

Systemic exposure to lapatinib is increased when administered with food (see Dosage and

Administration and 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 in vitro to inhibit these efflux transporters, as well as the

hepatic uptake transporter OATP 1B1, at clinically relevant concentrations (IC50 values were less than

or equal to 2.3µg/ml). The clinical significance of these effects on the pharmacokinetics of other

drugs or the pharmacological activity of other anti-cancer agents is not known.

Metabolism Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor

contributions from CYP2C19 and CYP2C8 to variety of oxidated metabolites, none of which account

for more than 14% of the dose recovered in the faeces or 10% of lapatinib concentration in plasma.

Lapatinib inhibits CYP3A (Ki 0.6 to 2.3 µg/mL) and CYP2C8 (0.3 µg/mL) in vitro at clinically relevant

concentrations. Lapatinib did not significantly inhibit the following enzymes in human liver

microsomes: CYP1A2, CYP2C9, CYP2C19, and CYP2D6 or UGT enzymes (in vitro IC50 values were

greater than or equal to 6.9 µg/mL).

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%.

Elimination The half-life of lapatinib measured after single doses increases with increasing dose. However, daily

dosing of lapatinib results in achievement of steady state within 6 to 7 days, indicating an effective

half-life of 24 hours. Lapatinib is predominantly eliminated through metabolism by CYP3A4/5. 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 lapatinib in faeces accounts for a

median 27% (range 3 to 67%) of an oral dose.

Special Patient 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 TYKERB 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, TYKERB should be discontinued and patients should not be

retreated with TYKERB (see Dosage and Administration and Warnings and Precautions).

Clinical Studies Combination treatment with TYKERB and capecitabine

The efficacy and safety of TYKERB in combination with capecitabine in breast cancer was evaluated

in a randomised, phase III trial. Patients eligible for enrolment had ErbB2 over-expressing, locally

advanced or metastatic breast cancer, progressing after prior treatment that included taxanes,

anthracyclines and trastuzumab. LVEF was evaluated in all patients (using echocardiogram or MUGA)

prior to initiation of treatment with TYKERB to ensure baseline LVEF was within the institutions

normal limits. In clinical trials LVEF was monitored at approximately eight week intervals during

treatment with lapatinib to ensure it did not decline to below the institutions 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 endpoint was time to progression (TTP) and

results are based on review by an independent review panel. The study was halted based on the

results of a pre-specified interim analysis that showed an improvement in TTP (51% reduction in the

hazard of achieving progression) for patients receiving TYKERB plus capecitabine.

Table 1 Key efficacy data from Study EGF100151 (TYKERB / capecitabine)

Efficacy Outcome TYKERB plus

capecitabine

(N=163)

Capecitabine alone

(N=161)

Time to progression

Progressed or died due to breast cancer 30% 45%

Median time to progression (weeks) 36.7 19.1

- Hazard ratio, 95% CI

- (p value) 0.49 (0.34, 0.71)

0.00008

Overall Response Rate, 95% CI 22.1% (16.0, 29.2) 14.3% (9.3, 20.7)

Median Duration of Response (weeks) 35.1 30.7

TYKERB when given in combination with capecitabine significantly prolonged the progression free

survival compared to capecitabine alone. At the time of interim analysis, the survival data were not

sufficiently mature to detect a difference in overall survival (OS) between the treatment groups, 36

subjects (22%) in the TYKERB+capecitabine group and 35 subjects (22%) in the capecitabine group

had died. On the combination arm, there were 4 progressions in the central nervous system as

compared with the 11 progressions on the capecitabine alone arm. This difference was not

statistically significant.

Combination treatment with TYKERB and letrozole TYKERB has been studied in combination with 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.

EGF30008 was a randomised, double-blind, controlled trial in patients with hormone-receptor

positive (HR+) 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 with placebo. Randomisation was stratified

by sites of disease and prior adjuvant anti-oestrogen therapy. HER2 receptor status was

retrospectively determined by central laboratory testing. Of all patients randomised to treatment,

219 (17%) patients had tumours over-expressing the HER2 receptor defined as fluorescence in situ

hybridization (FISH) ≥ 2 or 3+ immunohistochemistry (IHC). There were 952 (74%) HER2 -negative

patients and a total of 115 (9%) patients whose HER2 status was unconfirmed.

The primary objective was to evaluate and compare progression-free survival (PFS) in the HER2

positive population. Progression-free survival was defined as the interval of time between date of

randomisation and the earlier date of first documented sign of disease progression or death due to

any cause. The baseline demographic and disease characteristic were balanced between the two

treatment arms. The median age was 63 years and 45% were 65 years of age or older. Eighty four

percent (84%) of the patients were White. Approximately 50% of the HER2 positive population had

prior adjuvant/neo-adjuvant chemotherapy and 56% had prior hormonal therapy. Only 2 patients

had prior trastuzumab.

In the HER2-positive population, investigator-determined progression-free survival (PFS)

was significantly greater with letrozole plus TYKERB compared with letrozole plus placebo

(see Table 2).

Table 2 Progression Free Survival data from Study EGF30008 (TYKERB / letrozole)

Primary population Secondary population HER2-Positive Population Intent-to-Treat Population HER2-Negative Population

N = 111 N = 108 N = 642 N = 644 N = 478 N = 474

TYKERB

1500 mg /

day

+ Letrozole

2.5 mg /day

Letrozole

2.5 mg /day

+ placebo

TYKERB

1500 mg /

day

+ Letrozole

2.5 mg /day

Letrozole

2.5 mg /day

+ placebo

TYKERB

1500 mg /

day

+ Letrozole

2.5 mg /day

Letrozole

2.5 mg /day

+ placebo

Median PFS,

weeks (95% CI)

35.4

(24.1, 39.4)

13.0

(12.0, 23.7)

51.7

(47.6, 59.6)

47.0

(36.9, 50.9)

59.7

(48.6, 69.7)

58.3

(47.9, 62.0)

Hazard Ratio 0.71 (0.53, 0.96) 0.86 (0.76, 0.98) 0.90 (0.77, 1.05)

P-value 0.019 0.026 0.188

CI= confidence interval

The benefit of TYKERB and 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-positive population, combination therapy of

TYKERB and letrozole was associated with a significant improvement in objective respose

rate (27.9% and 14.8% respectively) (p=0.021) and in Clinical Benefit Rate (CBR; complete

plus partial response plus stable disease for > 6 moths) (47.7% and 28.7% respectively)

(p=0.003) compared with treatment with letrozole plus placebo. Although not yet mature, a

trend toward a survival benefit was noted for the TYKERB and letrozole combination, HR=

0.77 (95% CI 0.52-1.14) p=0.185.

In the Intent-to-Treat (ITT) population, investigator-determined PFS was greater between the

two treatment arms (see Table 2). 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 2). However, the pre-planned Cox

regression model taking into account a number of baseline covariates for PFS did show an

improvement with the TYKERB and letrozole combination in HER2-negative population. (HR=0.77

(95% CI 0.64-0.94) p=0.010) In addition, age (younger), performance status (0), baseline serum HER2

ECD (< 15 ng/ml), number of metastatic sites (< 3) and prior adjuvant anti-oestrogen stratification (<

6 months since discontinuation) were identified as being significant prognostic factors.

Growth factor receptor upregulation occurs with anti-oestrogen or endrocrine therapy resistance.

Therefore, the treatment effect in the pre-defined trial strata of prior endocrine therapy was further

analysed (< 6 months since discontinuation of endocrine therapy and > 6 months since

discontinuation of endocrine therapy or never having received endocrine therapy). Table 3 below

describes the PFS in these two subgroups of HER2-negative population. In addition to the PFS benefit

of TYKERB and letrozole therapy in the < 6 months stratum, a benefit in CBR was also noted when

compared with letrozole treatment alone (43.8% and 31.7% respectively).

Table 3 Efficacy data for two subgroups of HER2-negative population

HER2-Negative Population:

< 6months 1

HER2-Negative Population:

6 months2

N=200 N = 752

TYKERB 1500

mg / day

+ Letrozole 2.5

mg /day

Letrozole alone

2.5 mg /day

TYKERB 1500

mg / day

+ Letrozole 2.5

mg /day

Letrozole alone

2.5 mg /day

N = 96 N =104 N = 382 N = 370

Median PFS Kaplan Meier,

weeks (95% CI)

36.3

(21.9, 55.3)

13.3

(12.1, 23.7)

64.0

(58.3, 73.1)

65.3

(59.1, 74.3)

Hazard Ratio 0.78 (0.57, 1.07) 0.94 (0.79, 1.13)

P-value 0.117 0.522

CI= confidence interval 1 months since discontinuation of endocrine therapy 2 months since discontinuation of endocrine therapy/never received

Pre-clinical Safety Data Lapatinib was studied in pregnant rats and rabbits given oral doses of 30, 60, and 120 mg/kg/day.

There were no teratogenic effects; however, minor anomalies (left-sided umbilical artery, cervical rib

and precocious ossification) occurred in rats at the maternally toxic dose of 120 mg/kg/day (6.4

times the expected clinical exposure in humans given 1250 mg lapatinib and 2000 mg/m2

capecitabine). In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day

(6.5% and 19% of the expected clinical exposure in humans given 1250 mg lapatinib and 2000 mg/m2

capecitabine, respectively) and abortions at 120 mg/kg/day. Maternal toxicity was associated with

decreased foetal body weights, and minor skeletal variations. In the rat pre- and postnatal

development study, a decrease in pup survival occurred between birth and postnatal day 21 at doses

of 60 mg/kg/day or higher (3.3 times the expected clinical exposure in humans given 1250 mg

lapatinib and 2000 mg/m2 capecitabine). The highest no-effect dose for this study was 20

mg/kg/day.

In oral carcinogenicity studies with lapatinib, severe skin lesions were seen at the highest doses

tested which produced exposures based on AUC up to 1.7-fold in mice and male rats, and up to 12-

fold in female rats, compared to humans given 1250 mg of lapatinib and 2000 mg/m2 capecitabine).

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 6 and 8-fold compared to humans given 1250 mg of lapatinib and 2000 mg/m2

capecitabine). The relevance of these findings for humans is uncertain.

Lapatinib was not clastogenic or mutagenic in a battery of assays including the Chinese hamster

chromosome aberration assay, the Ames assay, human lymphocyte chromosome aberration assay

and an in vivo rat bone marrow chromosome aberration assay. There were no effects on male or

female rat gonadal function, mating, or fertility at doses up to 120 mg/kg/day (females) and up to

180 mg/kg/day (males) (8 and 3 times the expected human clinical exposure, respectively). The

effect on human fertility is unknown.

PHARMACEUTICAL PARTICULARS

List of Excipients All tablets

- Microcrystalline Cellulose

- Povidone

- Sodium Starch Glycolate

- Magnesium Stearate

Yellow tablet film-coat

- Hypromellose

- Titanium Dioxide

- Macrogol/PEG 400

- Polysorbate 80

- Iron Oxide Yellow

- Iron Oxide Red

Incompatibilities No known incompatibilities.

Shelf Life The expiry date is indicated on the packaging.

Special Precautions for Storage

Do not store above 30 C.

Nature and Contents of Container TYKERB film-coated tablets are supplied in 7 blisters of 10 tablets.

Instructions for Use/Handling No relevant information.

Not all presentations are available in every country.

TYKERB is a trademark of the GlaxoSmithKline group of companies

HARUS DENGAN RESEP DOKTER

Manufactured by

Glaxo Operations UK Limited

(trading as Glaxo Wellcome Operations)

Ware, United Kingdom

Imported by

PT. SmithKline Beecham Pharmaceuticals

Bogor, Indonesia

PI based on GDS06 - 19 February 2009 / IPI07 - 19 February 2009