RebozetTM

Eltrombopag
QUALITATIVE AND QUANTITATIVE COMPOSITION
25 mg Tablet
Eltrornbopag olamine 25 mg
Each lm-coated tablet contains eltrombopag olamine equivalent to 25 mg of
eltrombopag as eltrombopag free acid. The 25 mg tablets are round, biconvex, white
or and lm-coated, with and on one

50 mg
Eltrombopag olamine 50 mg
Each lm-coated tablet contains olamine equivalent to 50 mg of
eltrombopag as eltrombopag free acid. The 50 mg tablets are round, blue or
and lm-coated, debossed with and on one side.

PHARMACEUTICAL FORM
Film-coated tablets

CLINICAL PARTICULARS

Indications
RebozetTM is indicated the treatment of thrombocytopenia in patients with chronic
immune thrombocytopenic purpura (lTP) who have had an insufcient
response to immunoglobulins, or splenectomy.
M
should be used only in patients with [TP whose of
thrombocytopenia and clinical condition increases the for bleeding.
should not be used in an attempt to normalize platelet counts.
is in patients with hepatitis C virus (HCV) infection
whose degree of thrombocytopenia prevents the initiation of based
or limits the ability to maintain interferon based therapy.

Dosage
treatment should remain under the of a physician who is
experienced in the treatment of haematological diseases.
RebozetTM dosing requirements must be individualised based on the platelet
The objective of treatment with should not be to normalise platelet
counts but to maintain platelet counts above the level for haemorrhagio risk
In most measurable elevations in platelet counts 1-2 weeks
(see section Clinical studies).
The tablets should be administered orally. RebozetTM should be taken at least
hours before or any products such as dairy products (or other calcium
containing food or mineral supplements containing polyvalent cations (e. g.

Page I of
iron, calcium, aluminium, and zinc) (see section Interaction with
other medicinal products and other of and section Pharmacokinetic).
may be taken with food containing little (<50 mg) or no calcium
(see section and section Phannacokinctics).

Use the lowest dose of to achieve and maintain a platelet count

dose adjustments are based upon the platelet count response. Do not use to
normalise platelet counts. In clinical platelet counts generally increased within
1 to 2 weeks after and decreased within 1 to 2 weeks after
discontinuation.

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

Asian ancestry (e.g. Chinese, Taiwanese, Korean or RebozetTM
should be initiated at a reduced dose of 25 mg once daily (see section Clinical
Special Populations).

and adjustment
After initiating adjust the dose to and maintain a platelet count
as to reduce the risk for bleeding. Do not exceed a dose of 75 mg
daily.
Clinical and liver tests should be monitored throughout therapy
with and the dose regimen of modied on platelet counts
in Table 1. During therapy with RebozetrM complete blood counts
including platelet count and peripheral blood smears, should be assessed weekly until
a stable platelet count 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 in ITP

Platelet count Dose adjustment or response

< following at least 2
weeks of therapy
Increase daily dose by 25 mg to a of
75 mg/day.
Use lowest dose of eltrombopag and/or
concomitant ITP treatment to maintain platelet
counts that avoid or reduce bleeding.
Decrease the daily dose by 25 mg. Wait 2
weeks to assess the effects of this and any
subsequent close adjustments.

2 0f28
 Stop eltrombopag; increase the frequency
to twice weekly.

Once the platelet count is

reinitiate at a daily dose reduced by 25
mg.

can be administered in addition to other ITP medicinal products.

the dose regimen of ITP medicinal as medically to
avoid excessive increases in platelet counts during therapy with RebozetI .
Wait for at least 2 weeks to see the of an dose adjustment on the
platelet response prior to considering another close
The standard dose adjustment, either decrease or increase, would be 25 mg
once daily. in a patients a combination of different lm-coated tablet
strengths on different days may be required.

Treatment with should be discontinued if the platelet count does not

increase to a level sufcient to avoid clinically important bleeding after four weeks of
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 The reoccurrence
of is possible upon discontinuation treatment (see section
Warnings and Precautions).

C
When RebozetTM given in combination with antiviral therapies reference should be
made to the prescribing information of the respective coadministered medicinal
products for comprehensive details of administration.

Use the lowest dose of REBOZET to achieve and maintain a platelet count necessary
to initiate and optimise antiviral therapy. Dose adjustments are based upon the platelet
count response. Do not use rebozet to normalize platelet counts. In clinical studies,
platelet counts generally increase within 1 of REBOZET.

Dose
Initiate at a close of 25 mg once daily. No dosage adjustment is necessary
for HCV patients of East Asian ancestry (eg. Chinese Japanese, or
Thai), or patients with mild hepatic impairment.

Adjust the dose of REBOZET in 25 mg increments every 2 weeks as necessary

achieve the target platelet count required to initiate antiviral therapy (see Table 2).
Monitor platelet counts every week prior to antiviral therapy.

3 of 28
During antiviral therapy adjust the dose of to avoid dose
reduction of peginterferon. Monitor weekly during therapy
until a stable platelet count is achieved. including platelet counts and
peripheral blood smears should be obtained monthly thereafter.
Do not exceed a dose of 100 mg once daily.
For specific dosage instructions for peginterferon alfa or ribavirin, refer to their
respective information.

Table 2 Dose adjustments of REBOZET in HCV during antiviral

therapy

Platelet count Dose or response

following at Increase daily dose by 25mg to a of

least 2 weeks of therapy 100

to Decrease the daily dose by 25 mg. Wait 2 weeks to

assess the effects of this and any dose
adjustments.

Stop increase the frequency of platelet

to twice weekly.
Once the platelet count is reinitiate
therapy at a lower daily dose*.
*
For patients taking 25 mg REBOZET once daily, consideration should be given to
-

reinitiating dosing at 12.5 mg once daily or alternatively a dose of 25 mg every other

The prescribing information for pegylated interferon and ribavirin include

recommendations for antiviral treatment discontinuation for treatment futility. Refer to
pegylated interferon and ribavirin information for discontinuation
recommendations for antiviral treatment futility.

treatment should be terminated when antiviral therapy is discontinued.

platelet count responses, as outlined in Table 2 or important liver test
abnormalities may also necessitate discontinuation REBOZET (see section
Warnings and Precautions).

Renal
No dose adjustment is necessary in patients with renal impairment. Patients with
impaired renal function should use with caution and close for
by testing serum creatinine and/or performing urine analysis (see section
Pharmacokinetic).

4 of 28
 impairment
should not be used in ITP patients with hepatic impairment
score unless the benet the identied risk of portal venous
(see section Warning and Precautions).
If the use of is deemed necessary for ITP patients with hepatic impairment,
the starting dose must be 25 mg once daily. initiating the dose of in
patients with hepatic wait 3 before the dose.
Thrombocytopenic patients with chronic HCV with hepatic impairment should initiate

.
RebozetTM at a dose of 25 mg once daily (see section Pharmacology, Special
Populations).
The risk of thromboembolic events (TEES) has been found to be increased in patients
with chronic disease treated with 75 mg eltrombopag once daily for two weeks in
preparation for procedures (see section and Precautions and Section
Adverse Reactions).

is not recommended for use in children and adolescents below age 18 due
to insufcient data on safety and efcacy.

There are limited data on the use of in patients aged 65 years and older. [n
the clinical of no clinically signicant in
of were observed between subjects aged at least 65 years and younger

.
subjects. Other reported clinical experience has not differences in responses
between the elderly and younger patients, but greater sensitivity of some older
individuals cannot be ruled out (see section Clinical Pharmacology and section Special
populations).

For patients of East Asian ancestry (such as Chinese, Korean or

Thai), including those with hepatic impairment, eltrornbopag should be initiated at a
dose of 25 mg once (see section Pharmacckinetics).
Patient platelet count should continue be monitored and the standard criteria for
further dose modication followed.

should be taken at
_
The tablets should be administered orally.
RebozetTM
as antacids, dairy products (or other calcium containing food
any products such
or mineral
supplements containing polyvalent cations (eg. iron, calcium, magnesium,
selenium and zinc) (sec Interaction with other medicinal products and other forms of
interaction and Pharmacokinetic -).

5
Contraindications
to or to any of the excipients.

Precautions
The diagnosis of ITP in adults and patients should have been confirmed by the
exclusion of other clinical entities with thrombocytopenia. Consideration
be to performing a bone marrow aspirate and biopsy over the course of
the and in patients over 60 years age, those with
systemic symptoms or abnormal signs.
The effectiveness and safety of have not been established use in other
thrombocytopenic conditions including chemotherapy-induced thrombocytopenia and
myelodysplastic syndromes (MDS).

He .' administration can cause he atobiliary laboratory

abnormalities, . In clinical
studies in chronic lTP with Rebozet , increases in serum alanine aminotransferase
aspartate aminotransferase (AST) and bilirubin were observed (see section
Adverse Reactions).
These were mostly mild (Grade 1—2), reversible and not accompanied by
clinically signicant symptoms that would indicate an impaired liver In two
placebo controlled
in 5.7% and 4.0%
in
and placebo treated
In 2 controlled clinical studies in thrombocytopenic
-
adverse events of ALT increase were

- respectively.
with HCV, ALT or AST >
3 x ULN were reported in 34% and 38% of the RebozetTM and placebo
respectively. administration in combination with peginterferon/ribavirin
therapy is associated with hyperbilirubinaemia. Overall, total bilirubin
ULN was reported in and 50% or the RebozetTM and placebo
respectively.
Measure serum ALT, AST and bilirubin should be measured prior to initiation
every 2 weeks during the dose adjustment phase and monthly following
establishment of a stable dose. If bilirubin is perform fractionation.
serum liver tests should be evaluated with repeat testing 3 to 5 days.
If the abnormalities are serum liver tests should be monitored until the
abnormalities resolve, or return to baseiine RebozetTM should be
discontinued if ALT levels increase 3X ULN) in patients with normal liver function
or 3X baseline in with elevations in transaminascs before treatment and are:
0 or
persistent for 4 weeks, or
0 accompanied by increased direct bilirubin, or
0 accompanied by clinical symptoms of liver injury or evidence for hepatic 261
decompensation

6 of 28
Exercise caution when administering RebozetTM to with disease. In
use a lower dose of Reboze’tTM when administering to patients
with hepatic impairment (see section Dosage and

( Use
Hepatic decompensation in patients with chronic hepatitis C: Monitoring is required in
patients with low albumin levels or with MELD score at baseline.
Chronic HCV patients with cirrhosis may be at risk for hepatic decompensation, some
with fatal outcomes, when alpha interferon therapy. In 2 controlled clinical
studies in thrombocytopenic patients with HCV where was used as
necessary to achieve the target platelet count required to enable antiviral
safety ndings suggestive of hepatic decompensation were reported more frequently in
the arm (13 %) than in the placebo arm (7 %). Patients with low albumin
levels (< 3.5 or Model for End-Stage Liver Disease (MELD) score at
baseline had a greater risk of hepatic decompensation. Patients with these
should be closely monitored for signs and symptoms of hepatic
decompensation. Refer to the respective interferon information for
discontinuation criteria. RebozetTM should be terminated if antiviral therapy is
discontinued for hepatic decompensation.

Platelet counts above the normal range present a theoretical risk of

thrombotic/thromboembolic complications. In clinical in ITP
thromboembolic events were observed at low and normal counts.
Caution should be used when administering eltrombopag to patients with known risk
factors thromboembolism including but not limited to inherited (e.g. Factor V
or acquired risk factors (e.g. ATIII deciency. antiphospholipid syndrome),
advanced age, patients with prolonged periods of immobilisation,
contraceptives and hormone replacement therapy, obesity and
smoking. Platelet counts should be closely monitored and consideration given to
reducing the dose or eltrombopag treatment if the platelet count
the target levels (see section Dosage and The balance
should be considered in patients at risk of thrombocmbolic events of any aetiology.
In adult ITP studies, events (TEE) were observed in 17
out of 446 subjects (3.8 %). The TEE events included: embolism including
pulmonary embolism, deep vein thrombosis, transient ischaemic attack, myocardial
infarction, ischaemic stroke, and suspected PRIND (prolonged reversible ischemic
neurologic deciency). Subject who had a prior history of AND at least 2
additional proven risk factors for TEE were the pivotal studies and
the drug in such patients has not been established.
should not be used in patients with hepatic impairment (Child-Pugh
score 5) unless the expected benet outweighs the identied risk of portal venous
thrombosis. When treatment is considered appropriate, exercise caution when
administering to patients with hepatic impairment (see section Dosage and
Administration and Adverse Reactions).

7 uf28
In 2 studies in thrombocytopenic with HCV receiving interferon
based therapy,3l out of 955 subjects (3 %) treated with RebozetTM experienced a TEE
(3 %) and 5 out of 484 subjects (1 %) in the placebo group experienced TEEs. Portal
vein thrombosis was the most common TEE in both groups (1 % in patients
treated with RebozetTM versus < 1 % for placebo). No specic temporal relationship
between start of treatment and event of TEE were observed. The majority of TEES

a controlled study in
safety population) undergoin elective
thrombosis was increased in
-
resolved and did not lead to the discontinuation of antiviral therapy.

with
with chronic liver disease (n 288,
procedures, the risk of portal vein
mg once daily for 14

experienced -
days. Six of 143

the placebo group

(4 %) adult

-
with chronic liver disease
(all of the portal venous system) and two of 145

myocardial infarction). Five

receiving
%)
(one in the portal venous system and one
treated subjects with a TEE
in

the
event within 14 days of completing dosing and at a platelet count above

RebozetTM is not indicated for the treatment of thrombocytopenia in patients with

chronic liver disease in preparation for invasive procedures.

Thromboc openia is likely to reoccur upon discontinuation of treatment with

. Following discontinuation of 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 treatment is
discontinued in the presence of anticoagulants or agents. is
recommended that, if treatment with is [TP treatment be
restarted according to current treatment guidelines. Additional medical management
may include cessation of anticoagulant anti-platelet reversal of
anticoagulation, or platelet support. counts must be monitored weekly for 4
weeks following discontinuation of

agonists are growth factors that lead to thrombopoietic progenitor cell

expansion, and platelet production. The TPO-R is predominantly
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 were observed in studies of eltrombopag in rodents (see section

Preclinical safety data). Routine monitoring of patients for cataracts is recommended.
In controlled studies in patients with HCV receiving interferon
based therapy progression of pre-existing baseline cataract(s) or incident
cataracts was reported in 8 of the group and 5 % of the placebo group.

8
Loss of
A loss of response or failure to maintain a response
within the recommended dosing range should prompt a search for causative factors,
including an increased bone marrow reticuiin.

_
Interactions

studies demonstrated that RebozetTM is not a

organic anion transporter polypeptide, OATPIBI, but is an inhibitor of this
for the

transporter. In studies also demonstrated that is a breast cancer

resistance protein (BCRP) substrate and inhibitor. Administration of 75 mg
once daily for 5 days with a single 10 mg dose of the and BCRP substrate
rosuvastatin to 39 healthy adult subjects increased plasma rosuvastatin 103 % (90
% Cl: 82 %, 126 %) and 55 % (90 % CI: 42 69 are also
with other HMG—CoA reductase inhibitors, including pravastatin, simvastatin
and lovastatin, however, signicant interactions are not expected
eltrombopag and atorvastatin or uvastatin. When co-administered with a
reduced dose of statins should be considered and careful monitoring for statin side
effects should be undertaken.

0A BCRP Concomitant administration of and

OATPlBl and BCRP (cg. topotecan and methotrexate) substrates
should be undertaken with caution.

P450 In utilizing human liver microsomes,

(up to 100 showed no inhibition of the CYP450 enzymes IA2, 2A6,
2Cl9, 2D6, 3A4/5, and 1 and was an of and CYP2C9 as
measured using paclitaxel and diclofenac as the probe substrates. Administration of
75 mg once daily for 7 days to 24 healthy male subjects did not inhibit or
induce the metabolism of probe substrates for 1A2 2Cl9 (omeprazole), 2C9
or 3A4 (midazolam) in humans. No clinically signicant interactions
are expected when eltrombopag and CYP450 substrates co—administered.

RebozetTM
chelates with polyvalent cations such as
iron, calcium, nesium, aluminium, selenium and zinc. Administration of a single
dose of Rebozet 75 mg with a polyvalent cation—containing antacid (1524 mg
aluminium hydroxide and 1425 mg magnesium carbonate) decreased plasma

9
eltrombopag b % Cl:
62 %, 76 % .

F Administration of a 50 mg—dose of with a standard

high-calorie, that included dairy products reduced plasma
eltrornbopag by % (90 % CI; 54 %, %) and by 65 (90 % CI:
59 %, 70 Food low in calcium [< 50 mg calcium] including lean ham, beef
and unfortified (no added calcium, magnesium, iron) juice, unfortied soy milk,
and unfortied grain did not signicantly impact plasma eltrombopag exposure,
regardless of calorie and fat content (see section Dosage and Adminsitration).

Co-administration of RebozetTM with lopinavir/ritonavir

(LPVfRTV) 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
eltrombopag plasma - by
400 mg twice daily resulted in a reduction in
% (90 % C]: 6.6 %, 26.6 %). Therefore, caution
should be used when co-administration of eltrombo a with
Platelet count should be monitored in
takes place.
order to ensure
appropriate medical management of the dose of eltrombopag when
therapy is initiated or discontinued.

Medicinal products used in the treatment of in combination with eltrombopag in

studies included corticosteroids, danazol, intravenous
immunoglobulin (lVlG), and anti-D immunoglobulin. Platelet counts should be
monitored when combining eltrornbopag with other medicinal products for the
treatment of ITP in order to platelet counts outside of the recommended range
(see section Dosage and Administration).

Pregnancy and

are no or limited amount data from the use of RebozetTM in pregnant women.
Studies in animals shown (see section
). The potential risk for humans is unknown.
RebozetTM is not recommended during pregnancy and in women of childbearing
potential not using contraception.

It is not known whether metabolites are in human milk.

in animals have shown that eltrombopag is likely secreted into milk (see section
; therefore a risk to the suckling child cannot be A
decision must be made whether to discontinue breast—feeding or to continue abstain
-
Page
from taking into the benet of breast-feeding for the
and the benet of therapy for the woman.

Effects on to Drive and Use

No studies on the on the ability to drive and use machines have been

Adverse Reactions
Based on an of all chronic ITP patients receiving RebozetTM in 3 controlled
and 2 uncontrolled clinical studies, the overall incidence of adverse events in
treated eltrombopag was 82 % The median duration of to
was 304 days and year’s was 377 in this study population.
ENABLE 1 (TPL103922 N=716) and ENABLE 2 were
randomized, double—blind, placebo-controlled, multicentre studies to assess the
and safety of in thrombocytopenic subjects with HCV infection
who were otherwise eligible to initiate antiviral therapy (see section Clinical

[n the HCV studies the safety population consisted of all randomized subjects who
double-blind study Part 2 of ENABLE 1 (RebozetTM treatment
N=449, placebo and ENABLE treatment placebo
N=252). Subjects are analysed to the treatment received (total safety double
blind population, and placebo N=484).
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 dened as:
Very common 1/10)
Common 1/100 to <
Uncommon 1,000 to < 100)
Rare to < 1/1,000)
Very rare (<
Not known (cannot be estimated from the available data)

ITP

Pharyngitis, Urinary tract infection, inuenza, Nasopharyngitis,

herpes, Pneumonia, Sinusitis, Tonsillitis, Upper respiratory tract infection

benign, (incl and

Rectosigmoid cancer

Blood and
Uncommon Anaemia, Anisocytosis, Eosinophilia, Haemolytic anaemia,
Leukocytosis, Myelocytosis, Thrombocytopenia, Haemoglobin Band
neutrophil count increased, decreased, Myelocyte present, Platelet count
White blood cell count decreased

Page 28
 disorders
Uncommon

disorders
Hypokalacmia, appetite, Increased appetite, Gout,
Blood uric acid increased

Sleep Anxiety, Depression, Apathy, Mood altered,

disorders
Very
Paraesthesia
Dizziness, Dysgeusia, Hypoaesthesia, Somnolence, Migraine, Tremor,
Balance disorder, Dysaesthesia, Hemiparesis, Migraine with aura, Neuropathy
peripheral, Peripheral sensory neuropathy, Speech disorder, neuropathy,
Vascular

Eye
Common Cataract, Dry eye
Vision blurred, Lenticular Astigmatism,
haemorrhage, Eye pain, Lacrimation increased, Retinal haemorrhage,
epitheliopathy, Visual acuity reduced, Visual impairment, Visual
acuity tests abnormal, Blepharitis and Keratoconjunctivitis sicca

and
Uncommon Ear pain, Vertigo

Uncommon Tachycardia, Acute myocardial infarction, Cardiovascular disorder,

Cyanosis, Palpitations, Sinus Electrocardiogram QT

disorders
Uncommon Deep vein Embolism, Hot flush,
Thrombophlebitis supercial, Flushing, Haematoma

disorders
Uncommon Puimonary embolism, Pulmonary infarction, Cough, Nasal
discomfort, Oropharyngeal Oropharyngeal pain, Sinus disorder, Sleep
apnoea syndrome

disorders
Common Nausea, Diarrhoea, Constipation, Abdominal pain upper
Uncommon Abdominal discomfort, Abdominal distension, Dry mouth, Dyspepsia,
Abdominal pain, Gingival bleeding, Haemorrhoids, Mouth

of 28
haemorrhage, Abdominal tenderness, Faeces Flatulence, Food
Frequent bowel movements, Oral discomfort

Common Alanine aminotransferase aminotransferase

increased*, Blood bilirubin Hyperbilirubinaernia, Hepatic function
abnormal
Cholestasis, Hepatic lesion, Hepatiti—
of alanine aminotransferase and aspartate may occur
although at a lower frequency.

Skin
Common Rash, Pruritus, Alopecia
Uncommon Ecchymosis, Pruritus Urticaria, Dermatosis,
Petechiae, Cold sweat, Erythema, Melanosis, Night sweats, disorder,
Skin discolouration, Skin exfoliation, Swelling

and
Common Arthralgia, Myalgia, Muscle spasm, Bone pain
Muscular weakness, Pain in Sensation of heaviness

and
Uncommon Renal Lupus Nocturia, Proteinuria,
Blood urea increased, Blood creatinine increased, Urine ratio
increased

Common Fatigue, Oedema peripheral

Uncommon Chest pain, F hot, Pain, Vessel site haemorrhage,
Asthenia, jittery, Ill-defined disorder, Inammation wound, like
illness, Malaise, Mucosal inammation, Non-cardiac chest pain, Pyrexia, Sensation
body

Uncommon Blood albumin increased, Blood phosphatase increased,

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

poisoning and
Uncommon Contusion, Sunburn

HCV (REBOZET in combination with interferon

and
Common Urinary tract infection, Upper respiratory tract infection, Bronchitis,
Nasopharyngitis, Oral herpes, Gastroenteritis, Pharyngitis

Page I3
 and (incl cysts and polyps)
Common Hepatic malignant

Blood and system

Very common
Common Haemolytic anaemia

and nutrition disorders

Very common Decreased
Hyperglycaemia, loss of weight

Very common Insomnia

Common Depression, Anxiety, Sleep disorder, Confusional state, Agitation

Nervous system
Very common Headache
Common Disturbance in Dysgeusia, Hepatic
Lethargy, Memory impairment, Paraesthesia

Eye
Common Cataract, Retinal Dry Eye, Ocular icterus, Retinal haemorrhage

Ear and labyrinth disorders

Common
disorders
Common Palpitations

thoracic and disorders

Very common Cough
Common Dyspnoea, Dyspnoea Productive cough

disorders
common Nausea, Diarrhoea
Common Vomiting, Ascites, Abdominal pain, Abdominal pain upper, Dyspepsia, Dry
mouth, Constipation, Abdominal distension, Toothache, Stomatitis, Gastrooesophagal
reux disease, Haemorrhoids, Abdominal discomfort, Gastritis, Varices oesophagea],
Aphthous stomatitis, Oesophageal haemorrhage

Hepatobiliary disorders
Common Hyperbilirubinaemia, Jaundice, Portal vein thrombosis, failure

Skin and disorders

Very common Pruritus, Alopecia
Common Rash, Dry Rash pruritic, Hyperhidrosis, Pruritus
Night sweats, Skin lesion

and tissue disorder

 Myalgia
Common Arthralgia, Muscle spasms, Back pain, Pain in Musculoskeletal
pain, Bone pain

Uncommon Dysuria

common Pyrexia, Inuenza like illness, Asthenia, Chills, Oedema

Common Irritability, Pain, Malaise, Injection site Non—cardiac chest pain,

Oedcma, site rash, Chest discomfort, Injection site pruritus

Common Blood bilirubin increased, White blood cell count

decreased, Haemoglobin decreased, Neutrophil count decreased, International
normalised ratio increased, Activated partial thromboplastin time prolonged, Blood
glucose Blood albumin decreased, Electrocardiogram QT prolonged

Thromboernbolic events (TEES)

In 3 controlled and 2 uncontrolled clinical 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 section Warnings and Precautions).
In a placebo-controlled study, following 2 weeks in preparation for invasive
procedures, 6 of 261 patients with chronic liver disease 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.

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 section Warnings and
Precautions).

Increased bone reticulin

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
Ssection Warnings and Precautions).

Data
0verdos.e
Symptoms Signs
In the clinical there was one report of overdose where the subject ingested
5000 mg of Reported adverse events mild transient
ALT and AST and fatigue. Liver enzymes measured between
2 and 18 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 on
day 18 ingestion and the maximum platelet count was All events
were resolved without sequelae following treatment.

Treatment
In the event overdose, platelet counts increase and result in
complications. In case of an overdose, consider oral
administration of a metal cation-containing preparation, such as
or magnesium preparations to chelate eltrombopag and thus limit absorption. Closely
monitor platelet counts. Reinitiate treatment with in accordance with
dosing and administration recommendations (see section Dosage and Administration).
Because is not signicantly renally excreted and is highly bound to plasma
proteins, would not be expected to be an effective method to enhance
the elimination of

PHARMACOLOGICAL PROPERTIES
Pharmacodynamics
Pharmacotherapeutic group: Antihemorrhagics, code: 05.

of
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
but not identical to that of endogenous thrombopoietin inducing
proliferation and differentiation of megakaryocytes from bone marrow progenitor
cells.

16
ITP Studies
Two Phase II], placebo—controlled studies RAISE
(TRA102537) and and two open-label studies
and EXTEND (TRA105325) evaluated the safety and efcacy of eltrornbopag in adult
patients with previously chronic ITP. eltrombopag was administered
to 277 for at least 6 months and 202 patients for at least 1 year.

RAISE: 197 patients were 2:1, eltrombopag to

and randomisation was stratied 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
15 to 28 % of eltrombopag treated patients were maintained on 25 mg and
29 to 53 % received 75 mg.
In patients could taper concomitant ITP medicinal products and receive
rescue treatments as dictated by local standard of care. More half of all patients in
each treatment group had ITP therapies and 36 % had a prior splenectomy.
Median platelet counts at baseline were for both treatment groups and in the
eltrombopag group were maintained above at all visits starting
at Day 15; in contrast, median platelet counts in the placebo remained <
throughout the study.
Platelet count response between in the absence of rescue
medication was by more patients in the eltrombopag treated
group during the 6 month treatment period, p 0.001. percent of the
eltrombopag—treated patients and 13 placebo—treated patients achieved this level
response after 6 weeks 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 3: Secondary efcacy results from RAISE

Eltrombopag Placebo
N = 135 N = 62
Key secondary endpoints
Number of cumulative weeks with platelet counts 11.3 2.4 (5.95)
Mean (SD)
Patients with 75 % assessments in the target 51 (38) 4 (7)
range (50,000 to n
P-value
< 0.001
Patients with bleeding (WHO Grades 1—4) at any 106 (79) 56 (93)
6 11 (%)

7
 0.012
Patients with bleeding (WHO Grades 2—4) at any 44 (33) 32 (53)
time during 6 months, n (%)
P-value
0.002
Requiring rescue n (%) 24 (18) 25 (40)
P-value
0.001
Patients ITP at baseline (n) 63 31
Patients who attempted to reduce or 37 (59) 10 (32)
baseline
P value
0.016

63 (33 %) who

baseline, more than 70 % of patients in each treatment group reported any bleeding
(WHO Grades 1—4) and more than 20 % reported clinically signicant bleeding (WHO
Grades 2—4), respectively. The proportion of eltrombopag-treated patients with
bleeding (Grades 1-4) and clinically bleeding (Grades 2-4) was reduced
baseline by approximately 50 from Day 15 to the end of treatment throughout
the 6 month treatment period.
The primary efcacy endpoint the of responders,
dened as patients who had an increase in platelet counts to at Day
from a baseline < patients who withdrew prematurely due to a platelet
count > 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 eltrornbopag (n =
76) to placebo (n = 38).

Table 4: results from TRA100773B

N N 38
Key primary endpoints
for efcacy analysis, 73 37
Patients with platelet count up to (59) 6 (16)
42 days of dosing to a baseline count of
< n
P
< 0.001
Key secondary endpoints
Patients with a Day 43 bleeding assessment, n 51 30
Bleeding (WHO Grades 1-4) n (%) 20 (39) 18 (60)
P value
| | 0.029 |
for
In both RAISE and the response to eltrombopag relative to placebo was
of [TP splenectomy status and platelet
count at
In RAISE and in the subgroup of patients with baseline platelet
count the median platelet counts did not reach the target level
although in both studies 43 % of these patients treated with eltrombopag
responded 6 weeks of treatment. In addition, in the study, 42 % of
patients with baseline count treated with eltrombopag responded
at the end of the 6 month treatment Forty-two to 60 % of the
treated patients in the RAISE study were receiving 75 mg from Day 29 to the end of
treatment.
An open repeat dose study (3 cycles of 6 weeks treatment, followed by 4
weeks off treatment) showed that episodic use with multiple courses of eltrombopag
has demonstrated no loss response.
Eltrombopag was administered to 299 patients in an open—label extension study, 126
patients completed 1 48 completed 18 months and 17 completed 2 years. The
median baseline platelet count was to eltrombopag administration.
Median platelet counts at 18 and 24 months on study were
and respectively.

was an study which evaluated the

and consistency of response following repeated. short-
term dosing eltrombopag cycles therapy in adults with previously treated
chronic A cycle was dened as an up to on-therapy period by an
up to 4-week The endpoint in was the proportion
of subjects who achieved a platelet count and at least baseline in
2 or given this response in I.
the 52 who responded in (63%) achieved a platelet count
and at least baseline on Day 8 in Cycle 1; on Day 37 47
evaluable subjects achieved this level response.
A reduction in any bleeding (WHO Grade 1-4) and clinically signicant bleeding
(WHO Grade during the treatment phases was demonstrated in each cycle. At the
baseline visit 50% and ]9% any bleeding and
clinically signicant respectively. At the Day Visit 1. the
proportion subjects reduced: 12% subjects reported any
bleeding and clinically signicant respectively. Similar results were
during the subsequent treatment cycles.
Eight subjects 10 haemostatic challenges without need
additional therapy to elevate platelet counts and without unexpected bleeding.
is an open label study which has evaluated the
and of cltrombopag in with chronic who were previously

Page 9 of 28
enrolled in an trial. In this subjects were permitted to their
study as well as decrease or eliminate concomitant
medications.
was to 302 completed I year of
I80 2 years. 3 years. 75
5 years and 18 completed 6 year years therapy. The
count was prior to Median platelet
counts at l_. and 7 years on study were
. _. and The median
daily dose 6 months was 50 mg (n-=-74)[l I.
At subjects had any (Wllt) and 18%
had clinically The with any and
clinically decreased baseline by approximately 50% the
884 assessments up to 1 year.
Seventy percent who reduced a medication permanently
discontinued or had a sustained reduction their baseline lTP medication and did not
require any subsequent rescue treatment. Sixty-live percent these subjects
maintained this or reduction at 24 weeks. percent
subjects discontinued at least one lTP medication. and
subjects permanently discontinued all baseline lTP medications. without subsequent
rescue treatment.
Twenty-four at least one haemostatic the study.
No subject unexpected complications related to the procedure
while on study.

The Medicines Agency has deferred the obligation to submit the of

studies with in one or more subsets the paediatric population in
chronic idiopathic thrombocytopenic purpura (lTP) (see section Dosage and
Administration for information on paediatric use).

Chronic C associated studies

The and safety of REBOZET the treatment of thrombocytopenia in

subjects with HCV infection were evaluated in two randomized, double—blind,
placebo-controlled studies. ENABLE I utilized peginterferon plus ribavirin for
antiviral treatment and utilized peginterferon alfa-2b plus ribavirin. In
both subjects with a platelet count of < were enrolled and stratied
by platelet count (< and to < HCV RNA
(< 800,000 and and HCV (genotype and
genotype 1/4/6).
The studies consisted of two phases a pre-antiviral treatment phase and an antiviral
—

treatment phase. In the pre-antiviral treatment phase, subjects received open-label

REBOZET to increase the platelet count to for ENABLE 1 and
for ENABLE 2. REBOZET was administered at an initial dose of 25
once daily for 2 weeks and increased in 25 mg increments over 2 to 3 week periods to

20 of28
achieve the platelet count for phase 2 of the study. The maximal time subjects
could receive open—label REBOZET was 9 weeks. If sufcient platelet counts were
achieved, subjects were randomized (2:1) to the same dose of REBOZET at the end of
the pre-treatment phase or to placebo. REBOZET was in combination
with antiviral treatment per their respective information for up to
48 weeks.
primary efcacy endpoint for both studies was sustained virological response
dened as the percentage of subjects with no detectable HCV-RNA at
24 after completion of the planned treatment period. of
were genotype and 30 % were 2/3. Approximately 30 % of
subjects had been treated with prior HCV therapies, primarily pegylated interferon
plus ribavirin. The median baseline platelet counts (approximately were
among all treatment groups. The median time to the target platelet
count (ENABLE l) or (ENABLE was 2 weeks.
In both HCV a greater proportion of subjects treated with
REBOZET achieved SVR compared to those treated with placebo (see Table 7).
Signicantly fewer subjects treated with REBOZET had any antiviral close reductions
compared to placebo. The ot'subjects with no antiviral dose reductions was
45 % REBOZET compared to 27 % for placebo. Signicantly subjects
treated with REBOZET prematurely discontinued antiviral therapy compared to
placebo % vs. 60 %, p= The majority subjects treated with
REBOZET (76 %) had minimum platelet counts that were compared to
19 % for placebo. A greater proportion of subjects in the placebo group (20 %) had
minimum platelet counts fall below during treatment compared the
REBOZET group (3 In the REBOZET group, rates in subjects with high
viral loads were 18 % as compared to 8% in the placebo group.
Signicantly more subjects reached the later antiviral milestones of early virologic
response (EVR), complete early virologic response (cEVR), end of treatment response
(ETR) and sustained virologic response at 12—week follow-up when treated
with REBOZE'I‘.

Table 5: ENABLE 1 and ENABLE 2 Virologic Res onse

ENABLE 1 .
Pre—antiviral N N 805 |
Treatment Phase

% Achieving target 95 % 94
platelet counts and
initiating antiviral
therapy

REBOZET Placebo REBOZET Placebo

Page
 n=232 n=253
Antiviral
Phase % % % %

Overall SVR 23 14 19 13

Overall EVR 66 50 62 41

b P < 0.05

Pharmacokinetics
_
a. Target platelet count was
REBOZET
for ENABLE 1 and
placebo

The plasma eltrombopag concentration-time

ENABLE 2.

collected in 88 with ITP in

TRA100773A and TRA100773B were combined with data from 111 healthy
adult subjects in a population PK analysis. Plasma eltrornbopag and
estimates for ITP subjects are presented (Table 6).

Table6 Geometric mean (95 % condence intervals) of steady-state plasma

eltrombopag pharmacoklnetic parameters in adults with ITP
Eltrombopag once N ,
daily
30 mg 28 47 3.78 (3.18, 4.49)
50 mg 34 108 (88, 8.01 9.53)
75 mg 26 168 12.7 (1
a - and based on population PK

22 of 28
Plasma eltrombopag concentration—time data in 590 subjects with HCV
in III studies and TPL108390/ENABLE2
were combined with data from subjects with HCV in the Phase II study
TPL1023S7 and adult in a population PK Plasma
eltrombopag and estimates for patients with HCV enrolled in the
Phase III studies are presented for each dose studied in Table 7. A higher eltrombopag
was observed in patients with HCV at a given REBOZET dose.

Table 7 Geometric Mean (95 % CI) Steady-State Plasma

Parameters in Patients with Chronic HCV
REBOZET Dose N
(once daily)
25 mg 330 6.40 118
(5.97, 6.86) (109, 128)
50 mg 119 9.08 166
(7.96, 10.35) (143,
75 45 16.71 301
(14.26, 19.58) (250, 363)
100 mg 96 19.19
(16.81,21.91) (304,411)
presented as geometric mean AUC and Cmax based on population PK
estimates at the highest dose in the data for each subject.

is absorbed with a peak concentration occurring 2 6 hours oral

administration. Administration of eltrombopag concomitantly with antacids and other
products containing cations such as dairy products and mineral
signicantly reduces eltrombopag (see Dosage and
The absolute oral bioavailability of eltrombopag administration
to humans has not been established. Based on urinary and metabolites
eliminated in faeces, the oral absorption drug-related material following
administration a single 75 mg eltrombopag dose was estimated to be at
least 52 %.

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

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

Eltrombopag is primarily metabolized through cleavage, oxidation and conjugation

with glucuronic acid, glutathione, or cysteine. In a human radiolabel stud ,
accounted for approximately 64 % of plasma radiocarbon
Minor metabolites due to giucuronidation and oxidation were also detected.

23 qf28
studies suggest that and are for oxidative metabolism
of eltrombopag. Uridine transferase UGTlAl and UGT1A3 are
responsible for glucuronidation, and bacteria in the lower gastrointestinal tract may be
responsible for the cleavage

Absorbed eltrombopag is extensively metabolised. The predominant route of

eltrornbopag excretion is via faeces (59 %) with % dose in urine as
metabolites. Unchanged parent compound (eltrornbopag) 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.

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

minor role in the metabolism of eltrombopag. Human liver microsome studies
UGTlAl and UGT1A3 as the enzymes responsible for eltrombopag
glucuronidation. was an inhibitor of a of enzymes
Clinically signicant interactions involving glucutonidation are not anticipated
due to limited contribution of individual UGT enzymes in the glucuronidation of
eltrombopag.
Approximately 21% an eltrombopag dose could undergo oxidative metabolism.
Human liver microsome studies identied CYP1A2 and as the enzymes
responsible for eltrombopag oxidation. Eltrombopag does not inhibit or induce CYP
enzymes based on and data (see section Interactions).
studies demonstrate that eltrombopag is an inhibitor of the OATPlBl
transporter and an inhibitor of the BCRP transporter and eltrombopag increased
of the OATPIB] and BCRP substrate rosuvastatin in a clinical drug
interaction study (see section Interactions). In clinical studies with a dose
reduction of statins by 50 % was recommended.

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

aluminium, selenium and zinc (see section Dosage and Administrations and section
Interactions).
Administration of a single 50 mg dose of eltrombopag with a standard
breakfast that included dairy products reduced plasma eltrombopag
and Cmax. Whereas, low-calcium food [< 50 mg calcium] not impact
plasma eltrombopag exposure, regardless of calorie and fat content (see section
Dosage and Administrations and section Interactions).

The pharmacokinetics of has been studied administration of

eltrombopag to adult sub'ects with renal impairment. Following administration a
single 50 mg—dose, the of eltrombopag was 32 % to 36 % lower in subjects
with mild to moderate renal impairment, and 60 % lower in subjects with severe renal
 with healthy volunteers. There was variability and
overlap in between patients with renal impairment and healthy
volunteers. Unbound eltrombopag (active) concentrations for this bound
medicinal were not measured. Patients with impaired renal function should
use eltrombopag with caution and close for example by testing serum
creatinine urine analysis (see section Dosage and Administrations).

Hepatic
The pharmacokinetics of eltrornbopag has been studied administration of
eltrombopag to adult subjects with hepatic impairment. administration
ofa single 50 mg close, the-of eltrombopag was 41 % higher in subjects with
mild hepatic impairment and 80 % to 93 % higher in subjects with moderate to severe
hepatic compared with healthy volunteers. There was substantial
and signicant overlap in exposures between patients with hepatic
impairment and healthy volunteers.
The inuence of hepatic impairment on the pharmacokinetics of eltrombopag

-
with HCV and 4]
-
chronic liver disease of other
(673

642 were with mild hepatic impairment, 67 with moderate hepatic

-
following repeat administration was evaluated using a population pharmacokinetic
in 28 health adults and with hepatic
the

im airment, and 2 with sever hepatic impairment. Compared to healthly volunteers,

with mild hepatic impairment had 111% (85% CI: 45% to
283%) higher plasma eltrombopag values and with moderate hepatic
impairment had approximately 183% (95% CI: 90% to higher plasma
eltrombopag values.
Therefore, eltrombopag should not be used in ITP patients with hepatic impairment
(Child—Pugh score unless the expected benet outweighs the identied risk of
portal venous thrombosis (see section Dosage and Administration and section Warning

.
and Precautions). For patients with 1le initiate eltrombopag at a dose of 25 mg once
daily (see section Dosage and Administration).

Race
The inuence of Asian ethnicity on the of eltrombopag was

88 -
evaluated using a population
-
analysis in 111 healthy adults (31 East Asians) and
with ITP (18 East Asians). Based on estimates from the po ulation

.
analysis, East Asian (i.e. Chinese, Taiwanese and Korean) ITP had
87 % higher plasma eltrombopag values as compared to non-
East Asian who were predominantly without adjustment for body
weight (see section Dosage and Administrations).

evaluated using a population

Asian and Southeast Asian

analysis in 635 -
The inuence of East Asian ethnicity on the pharmacokinetics of eltrombopag was
with HCV 145 East Asians
and 69 Southeast Asians). Based on estimates from the population analysis, East
pharmacokinetics of eltrombopag. On
average, Asian had 55 % higher plasma
eltrombopag values as compared to of other races who were
predominantly Caucasian (see section Dosage and Administration).

Page 25 of28
The
a

.
in 111 healthy adults (14
(57 females). Based on estimates from the population
had a roximately 50 % plasma eltrombopag
, without adjustment for body
. and 88 -_
of gender on the pharmacokinetics of eltrornbopag was evaluated using

ITP
with ITP

as compared to male

The inuence of gender on eltrombo ag pharmacokinetics was evaluated using a

population in 635 with HCV (260 females). Based on model
female HCV 41 % higher plasma eltrombopag
as to male .

The age
in 28 healthy subjects and 635
from 19 to 74 years old. Based on model estimates,
approximately 36 % higher plasma eltrombopag
- -
of eltrombopag pharmacokinetics was evaluated using population
with HCV
60 years)
as compared to
had

(see section Dosage and Administration).

Eltrornbopag does not stimulate production in mice, rats or dogs because of

unique TPO receptor specicity. Therefore, data from these do not fully
model potential adverse effects related to the of eltrombopag in
humans, including the reproduction and carcinogenicity studies.
Treatment-related cataracts were detected in rodents and were dose and time—
dependent. 6 times the human clinical exposure based on AUC_in [TP patients at
75 mg/day and 3 times the human clinical exposure based on AUC in HCV patients at
100 mg/day, 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_in ITP patients at 75
mg/day and 2 times the human clinical based on AUC in HCV patients at
100 cataracts were in mice 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 based on AUC).
Renal tubular toxicity was observed in studies of up to 14 days duration in mice and
rats at that were generally associated with morbidity and mortality. Tubular
was also observed in a 2 year oral carcinogenicity study in mice at doses of
75 and 150 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 htunan clinical exposure based on AUC in ITP patients at 75
and 0.6 times the human clinical exposure based on AUC in HCV patients at 100
mg/day. Renal effects were not in rats after 28 or in dogs 52
weeks at exposures 4 and 2 respectively, the clinical exposure based on
AUC in ITP patients at 75 and 2 times and equivalent, respectively, to the
human in HCV patients at 100 mg/day.
Hepatocyte degeneration necrosis, accompanied by increased serum liver
enzymes, was observed in mice, rats and dogs at doses that were
morbidity and mortality or were poorly tolerated. No hepatic effects were observed

26
after chronic closing 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 doses in rats and dogs (> 10 times maximum human clinical
exposure based on AUC), decreased reticulocyte counts and regenerative bone
erythroid hyperplasia (rats only) were in short term studies. There were no
effects of note on red cell mass or reticulocyte dosing for up to 28 weeks
in rats, 52 weeks in dogs and 2 years in mice or rats at tolerated doses
which were 2 to 4 times maximum human clinical exposure based on AUC.
Endosteal hyperostosis was observed in a 28 week study in rats at a non—
tolerated dose of 60 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.
was not carcinogenic in mice at doses up to 75 or in rats at
doses up to 40 (exposures up to 4 times the human clinical exposure based
on AUC in lTP patients at 75 and 2 times the human clinical exposure based
on AUC in HCV patients at 100 mg/day). Eltrombopag was not mutagenic or
clastogenic in a bacterial mutation assay or in two in assays in rats (micronucleus
and unscheduled DNA synthesis, 10 times the human clinical exposure based on Cmax
in ITP patients at 75 and 7 times the human clinical exposure in HCV patients
at 100 In the mouse lymphoma assay, eltrombopag was marginally
positive (< 3-fold increase in mutation frequency). These and
suggest that eltrombopag does not pose a genotoxic risk to humans.
Eltrombopag did not affect female early embryonic development or
embryofoetal development in rats at doses up to 20 (2 times the human
clinical exposure based on AUC). Also there was no effect on embryofoctal
development in rabbits at doses up to 150 the highest dose tested (0.5
times the human clinical exposure based on AUC). However, at a maternally toxic
dose of 60 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 in
the embryofoetal Eltrombopag did not affect male fertility in rats
at doses up to 40 the highest dose tested (3 times the human clinical
exposure based on AUC). In the pre- and post-natal development study in 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 (Fl).
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,
that rat pup exposure to was likely via lactation.

PHARMACEUTICAL PARTICULARS
List of

C .'
 Mannitol, Povidone, Sodium

Hypromellose, Macrogol 400, 80, Titanium (El71)

Incom patibilities
No incompatibilities

Shelf Life
The date is on the

Special for Storage

Do not store above 30°C.

Nature and of Container

25 mg 50
Each pack of 28 in aluminium foil —

aluminium foil
Not all presentations are available in

Instructions
No special requirements

HARUS DENGAN RESEP DOKTER

Tablet 25 Box, 2 blisters @ 7 Reg. No. DKll6916012l7Al

Tablet 25 mg, Box, 4 @7 Reg. No. DKI16916012I7A1
Tablet 50 mg, 2 blisters @ 7 Reg. No. DKII6916012 I
Tablet 50 Box, 4 blisters @ 7 Reg. No. DK11691601217B]

Manufactured by:
Glaxo Operations UK Limited (trading as Wellcome UK
Novartis Pharma Basel, Switzerland
of the group of companies

Packed and released by:

Wellcome S.A.*, Aranda de Duero, Spain Novartis Pharma AG,
Basel, Switzerland
Member of the GlaxoSmithKline group of companies

Imported by
PT Indonesia
Jakarta. lndonesia
CDS

Page 28