rebozet-tykerb.pdf
TRANSCRIPT
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