ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Revolade 25 mg film-coated tablets
2.
Each film-coated tablet contains eltrombopag olamine equivalent to 25 mg eltrombopag.
Excipients
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Round, biconvex, white film-coated tablet debossed with ‘GS NX3’ and ‘25’ on one side.
4.
Revolade is indicated for adult chronic immune (idiopathic) thrombocytopenic purpura (ITP)
splenectomised patients who are refractory to other treatments (e.g. corticosteroids, immunoglobulins).
Revolade may be considered as second line treatment for adult non-splenectomised patients where
surgery is contraindicated.
Eltrombopag treatment should remain under the supervision of a physician who is experienced in the
treatment of haematological diseases.
Eltrombopag dosing requirements must be individualised based on the patient’s platelet counts. The
objective of treatment with eltrombopag 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 section 5.1).
Adults
The recommended starting dose of eltrombopag is 50 mg once daily. For patients of East Asian
ancestry, eltrombopag should be initiated at a reduced dose of 25 mg once daily (see section 5.2).
Monitoring and dose adjustment
After initiating eltrombopag, 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.
Clinical haematology and liver tests should be monitored regularly throughout therapy with
eltrombopag and the dose regimen of eltrombopag modified based on platelet counts as outlined in
Table 1. During therapy with eltrombopag 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
2
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 eltrombopag
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.
Eltrombopag 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 eltrombopag.
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 eltrombopag 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 eltrombopag should be discontinued if the platelet count does not increase to a level
sufficient to avoid clinically important bleeding after four weeks of eltrombopag 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 section 4.4).
Renal impairment
No dose adjustment is necessary in patients with renal impairment. Patients with impaired renal
function should use eltrombopag with caution and close monitoring, for example by testing serum
creatinine and/or performing urine analysis (see section 5.2).
3
Hepatic impairment
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
section 4.4).
If the use of eltrombopag 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 sections 4.4 and 4.8).
Paediatric population
Revolade 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 eltrombopag in patients aged 65 years and older. In the clinical
studies of eltrombopag, overall no clinically significant differences in safety of eltrombopag 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 eltrombopag 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 section 5.2). 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. Eltrombopag 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 sections 4.5 and 5.2).
Hypersensitivity to eltrombopag or to any of the excipients.
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 eltrombopag have not been established for use in other
thrombocytopenic conditions including chemotherapy-induced thrombocytopenia and myelodysplastic
syndromes (MDS).
Risk of hepatotoxicity
4
Eltrombopag administration can cause abnormal liver function. In clinical studies with eltrombopag,
increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin
were observed (see section 4.8).
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 eltrombopag, 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. Eltrombopag 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
section 4.2). 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 eltrombopag once daily for two weeks in preparation for invasive
procedures. 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 sections 4.2 and 4.8).
Bleeding following discontinuation of eltrombopag
Thrombocytopenia is likely to reoccur upon discontinuation of treatment with eltrombopag. Following
discontinuation of eltrombopag, 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 eltrombopag treatment is discontinued in the presence of anticoagulants or anti-platelet
agents. It is recommended that, if treatment with eltrombopag 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 eltrombopag.
5
Bone marrow reticulin formation and risk of bone marrow fibrosis
Eltrombopag 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 eltrombopag, the peripheral blood smear should be examined closely to establish
a baseline level of cellular morphologic abnormalities. Following identification of a stable dose of
eltrombopag, 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 section 5.3). 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 eltrombopag treatment within the
recommended dosing range should prompt a search for causative factors, including an increased bone
marrow reticulin.
Effects of eltrombopag on other medicinal products
HMG CoA reductase inhibitors
In vitro
studies demonstrated that eltrombopag is not a substrate for the organic anion transporter
polypeptide, OATP1B1, but is an inhibitor of this transporter.
In vitro
studies also demonstrated that
eltrombopag is a breast cancer resistance protein (BCRP) substrate and inhibitor
.
Administration of
eltrombopag 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 C
max
103 % (90 % CI:
82 %, 126 %) and AUC
0-∞
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 eltrombopag, 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 eltrombopag and OATP1B1 (e.g. methotrexate) and BCRP (e.g.
topotecan and methotrexate) substrates should be undertaken with caution.
Cytochrome P450 substrates
6
M) 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 eltrombopag 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.
μ
Effects of other medicinal products on eltrombopag
Polyvalent cations (Chelation)
Eltrombopag chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, selenium
and zinc. Administration of a single dose of eltrombopag 75 mg with a polyvalent cation-containing
antacid (1524 mg aluminium hydroxide and 1425 mg magnesium carbonate) decreased plasma
eltrombopag AUC
0-∞
by 70 % (90 % CI: 64 %, 76 %) and C
max
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 eltrombopag absorption due to chelation (see section 4.2).
Food interaction
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-∞
by 59 % (90 % CI: 54 %, 64 %) and
C
max
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 section 4.2).
Lopinavir/ritonavir
Co-administration of eltrombopag 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 section 4.2).
Pregnancy
There are no or limited amount of data from the use of eltrombopag in pregnant women. Studies in
animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
7
In studies utilizing human liver microsomes, eltrombopag (up to 100
Revolade is not recommended during pregnancy and in women of childbearing potential not using
contraception.
Breast-feeding
It is not known whether eltrombopag / metabolites are excreted in human milk. Studies in animals
have
shown that eltrombopag is likely secreted into milk (see section 5.3); 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 Revolade therapy, taking into account the benefit of breast-feeding for the
child and the benefit of therapy for the woman.
No studies on the effects on the ability to drive and use machines have been performed.
Based on an analysis of all chronic ITP patients receiving eltrombopag 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 eltrombopag 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)
are
(
≥
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
8
Psychiatric disorders
Common
Inso nia
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
9
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 section 4.4).
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
10
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 section 4.4).
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 section 4.4).
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 eltrombopag in accordance with dosing and administration recommendations (see section 4.2).
In the clinical studies there was one report of overdose where the subject ingested 5000 mg of
eltrombopag. 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 eltrombopag 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
eltrombopag.
5.
5.1 Pharmacodynamic properties
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.
11
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.
l 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.
μ
l 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
μ
Eltrombopag
N = 135
Placebo
N = 62
Key secondary endpoints
Number of cumulative weeks with platelet counts
≥
50,000-
11.3 (9.46)
2.4 (5.95)
400,000/µl, Mean (SD)
Patients with ≥ 75 % of assessments in the target range (50,000 to
400,000/
51 (38)
4 (7)
< 0.001
Patients with bleeding (WHO Grades 1-4) at any time during 6
months, n (%)
106 (79)
56 (93)
P-
value
a
0.012
Patients with bleeding (WHO Grades 2-4) at any time during 6
months, n (%)
44 (33)
32 (53)
P-
value
a
0.002
Requiring rescue therapy, n (%)
24 (18)
25 (40)
P-
value
a
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.
12
Median platelet counts at baseline were 16,000/
Platelet count response between 50,000-400,000/
l), n (%)
P-
value
a
μ
TRA100773B: The primary efficacy endpoint was the proportion of responders, defined as patients
who had an increase in platelet counts to
≥
50,000/
μ
l at Day 43 from a baseline of < 30,000/
μ
l;
l 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).
>
200,000/
μ
Table 3: Efficacy results from TRA100773B
Eltrombopag
N = 74
Placebo
N = 38
Key primary endpoints
Eligible for efficacy analysis, n
73
37
l after up to 42 days of
dosing (compared to a baseline count of < 30,000/
≥
50,000/
μ
μ
l), n (%)
43 (59)
6 (16)
P
value
a
< 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
a
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.
l), 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.
μ
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/
μ
l, 75,000/
μ
l and 119,000/
μ
l, respectively.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with
Revolade in one or more subsets of the paediatric population in chronic idiopathic thrombocytopenic
purpura (ITP) (see section 4.2 for information on paediatric use).
13
patients who withdrew prematurely due to a platelet count
Patients with platelet count
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/
l prior to eltrombopag administration. Median platelet counts at 12, 18 and 24
months on study were 68,000/
μ
5.2 Pharmacokinetic properties
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 C
max
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
,
μ
g.h/ml
C
max
a
,
μ
g/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 C
max
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 AUC
0-∞
. 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.
14
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 section 4.5).
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 section 4.5). 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 sections 4.2 and 4.5).
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 C
max
. Whereas, low-calcium
food [< 50 mg calcium] did not significantly impact plasma eltrombopag exposure, regardless of
calorie and fat content (see sections 4.2 and 4.5).
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 AUC
0-∞
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
section 4.2).
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 AUC
0-∞
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 sections 4.2 and 4.4).
15
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 section 4.2).
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.
5.3 Preclinical 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.
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.
16
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
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 C
max
).
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 F
0
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 (F
1
). Eltrombopag was detected in the plasma of all F
1
rat pups
for the entire 22 hour sampling period following administration of medicinal product to the F
0
dams,
suggesting that rat pup exposure to eltrombopag was likely via lactation.
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.
≥
6.
6.1
List of excipients
Tablet core
Magnesium stearate
Mannitol (E421)
Microcrystalline cellulose
Povidone (K30)
Sodium starch glycolate Type A
Tablet coating
Hypromellose
Macrogol 400
Polysorbate 80
Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable.
17
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 (
6.3 Shelf life
4 years.
6.4
Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
Aluminum blisters (PA/Alu/PVC/Alu) in a carton containing 14 or 28 film-coated tablets and
multipacks containg 84 (3 packs of 28) film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
GlaxoSmithKline Trading Services Limited
6900 Cork Airport Business Park
Kinsale Road
Cork
Ireland
8.
9.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.ema.europa.eu
/.
18
1.
Revolade 50 mg film-coated tablets
2.
Each film-coated tablet contains eltrombopag olamine equivalent to 50 mg eltrombopag.
Excipients
For a full list of excipients, see section 6.1
3.
Film-coated tablet.
Round, biconvex, brown film-coated tablet debossed with ‘GS UFU’ and ‘50’ on one side.
4.
Revolade is indicated for adult chronic immune (idiopathic) thrombocytopenic purpura (ITP)
splenectomised patients who are refractory to other treatments (e.g. corticosteroids, immunoglobulins).
Revolade may be considered as second line treatment for adult non-splenectomised patients where
surgery is contraindicated.
Eltrombopag treatment should remain under the supervision of a physician who is experienced in the
treatment of haematological diseases.
Eltrombopag dosing requirements must be individualised based on the patient’s platelet counts. The
objective of treatment with eltrombopag 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 section 5.1).
Adults
The recommended starting dose of eltrombopag is 50 mg once daily. For patients of East Asian
ancestry, eltrombopag should be initiated at a reduced dose of 25 mg once daily (see section 5.2).
Monitoring and dose adjustment
After initiating eltrombopag, 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.
Clinical haematology and liver tests should be monitored regularly throughout therapy with
eltrombopag and the dose regimen of eltrombopag modified based on platelet counts as outlined in
Table 1. During therapy with eltrombopag 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
19
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 eltrombopag
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.
Eltrombopag 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 eltrombopag.
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 eltrombopag 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 eltrombopag should be discontinued if the platelet count does not increase to a level
sufficient to avoid clinically important bleeding after four weeks of eltrombopag 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 section 4.4).
Renal impairment
No dose adjustment is necessary in patients with renal impairment. Patients with impaired renal
function should use eltrombopag with caution and close monitoring, for example by testing serum
creatinine and/or performing urine analysis (see section 5.2).
20
Hepatic impairment
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
section 4.4).
If the use of eltrombopag 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 sections 4.4 and 4.8).
Paediatric population
Revolade 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 eltrombopag in patients aged 65 years and older. In the clinical
studies of eltrombopag, overall no clinically significant differences in safety of eltrombopag 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 eltrombopag 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 section 5.2). 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. Eltrombopag 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 sections 4.5 and 5.2).
Hypersensitivity to eltrombopag or to any of the excipients.
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 eltrombopag have not been established for use in other
thrombocytopenic conditions including chemotherapy-induced thrombocytopenia and myelodysplastic
syndromes (MDS).
21
Risk of hepatotoxicity
Eltrombopag administration can cause abnormal liver function. In clinical studies with eltrombopag,
increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin
were observed (see section 4.8).
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 eltrombopag, 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. Eltrombopag 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
section 4.2). 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 eltrombopag once daily for two weeks in preparation for invasive
procedures. 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 sections 4.2 and 4.8).
Bleeding following discontinuation of eltrombopag
Thrombocytopenia is likely to reoccur upon discontinuation of treatment with eltrombopag. Following
discontinuation of eltrombopag, 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 eltrombopag treatment is discontinued in the presence of anticoagulants or anti-platelet
agents. It is recommended that, if treatment with eltrombopag 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 eltrombopag.
22
Bone marrow reticulin formation and risk of bone marrow fibrosis
Eltrombopag 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 eltrombopag, the peripheral blood smear should be examined closely to establish
a baseline level of cellular morphologic abnormalities. Following identification of a stable dose of
eltrombopag, 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 section 5.3). 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 eltrombopag treatment within the
recommended dosing range should prompt a search for causative factors, including an increased bone
marrow reticulin.
Effects of eltrombopag on other medicinal products
HMG CoA reductase inhibitors
In vitro
studies demonstrated that eltrombopag is not a substrate for the organic anion transporter
polypeptide, OATP1B1, but is an inhibitor of this transporter.
In vitro
studies also demonstrated that
eltrombopag is a breast cancer resistance protein (BCRP) substrate and inhibitor
.
Administration of
eltrombopag 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 C
max
103 % (90 % CI:
82 %, 126 %) and AUC
0-∞
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 eltrombopag, 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 eltrombopag and OATP1B1 (e.g. methotrexate) and BCRP (e.g.
topotecan and methotrexate) substrates should be undertaken with caution.
23
Cytochrome P450 substrates
M) 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 eltrombopag 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.
μ
Effects of other medicinal products on eltrombopag
Polyvalent cations (Chelation)
Eltrombopag chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, selenium
and zinc. Administration of a single dose of eltrombopag 75 mg with a polyvalent cation-containing
antacid (1524 mg aluminium hydroxide and 1425 mg magnesium carbonate) decreased plasma
eltrombopag AUC
0-∞
by 70 % (90 % CI: 64 %, 76 %) and C
max
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 eltrombopag absorption due to chelation (see section 4.2).
Food interaction
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-∞
by 59 % (90 % CI: 54 %, 64 %) and
C
max
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 section 4.2).
Lopinavir/ritonavir
Co-administration of eltrombopag 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 section 4.2).
Pregnancy
There are no or limited amount of data from the use of eltrombopag in pregnant women. Studies in
animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
24
In studies utilizing human liver microsomes, eltrombopag (up to 100
Revolade is not recommended during pregnancy and in women of childbearing potential not using
contraception.
Breast-feeding
It is not known whether eltrombopag / metabolites are excreted in human milk. Studies in animals
have
shown that eltrombopag is likely secreted into milk (see section 5.3); 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 Revolade therapy, taking into account the benefit of breast-feeding for the
child and the benefit of therapy for the woman.
No studies on the effects on the ability to drive and use machines have been performed.
Based on an analysis of all chronic ITP patients receiving eltrombopag 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 eltrombopag 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)
are
(
≥
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
25
Metabolism and nutrition disorders
Uncommon
Anorexia, Hypokalaemia, Decreased appetite, Increased appetite, Gout,
Hypocalcaemia, Blood uric acid increased
Psychiatric disorders
Common
Inso nia
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,
26
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 section 4.4).
27
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 section 4.4).
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 section 4.4).
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 eltrombopag in accordance with dosing and administration recommendations (see section 4.2).
In the clinical studies there was one report of overdose where the subject ingested 5000 mg of
eltrombopag. 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 eltrombopag 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
eltrombopag.
5.
5.1 Pharmacodynamic properties
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)
28
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.
l 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.
μ
l 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
μ
Eltrombopag
N = 135
Placebo
N = 62
Key secondary endpoints
Number of cumulative weeks with platelet counts
≥
50,000-
11.3 (9.46)
2.4 (5.95)
400,000/µl, Mean (SD)
Patients with ≥ 75% of assessments in the target range (50,000 to
400,000/
51 (38)
4 (7)
< 0.001
Patients with bleeding (WHO Grades 1-4) at any time during 6
months, n (%)
106 (79)
56 (93)
P-
value
a
0.012
Patients with bleeding (WHO Grades 2-4) at any time during 6
months, n (%)
44 (33)
32 (53)
P-
value
a
0.002
Requiring rescue therapy, n (%)
24 (18)
25 (40)
P-
value
a
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.
29
Median platelet counts at baseline were 16,000/
Platelet count response between 50,000-400,000/
l), n (%)
P-
value
a
μ
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/
μ
l at Day 43 from a baseline of < 30,000/
μ
l;
l 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).
>
200,000/
μ
Table 3: Efficacy results from TRA100773B
Eltrombopag
N = 74
Placebo
N = 38
Key primary endpoints
Eligible for efficacy analysis, n
73
37
l after up to 42 days of
dosing (compared to a baseline count of < 30,000/
≥
50,000/
μ
μ
l), n (%)
43 (59)
6 (16)
P
value
a
< 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
a
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.
l) 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.
μ
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/
μ
l, 75,000/
μ
l and 119,000/
μ
l, respectively.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with
Revolade in one or more subsets of the paediatric population in chronic idiopathic thrombocytopenic
purpura (ITP) (see section 4.2 for information on paediatric use).
30
patients who withdrew prematurely due to a platelet count
Patients with platelet count
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/
l prior to eltrombopag administration. Median platelet counts at 12, 18 and 24
months on study were 68,000/
μ
5.2 Pharmacokinetic properties
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 C
max
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
,
μ
g.h/ml
C
max
a
,
μ
g/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 C
max
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 AUC
0-∞
. 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.
31
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 section 4.5).
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 section 4.5). 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 sections 4.2 and 4.5).
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 C
max
. Whereas, low-calcium
food [< 50 mg calcium] did not significantly impact plasma eltrombopag exposure, regardless of
calorie and fat content (see sections 4.2 and 4.5).
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 AUC
0-∞
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
section 4.2).
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 AUC
0-∞
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 sections 4.2 and 4.4).
32
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 section 4.2).
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.
5.3 Preclinical 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.
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.
33
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
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 C
max
).
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 F
0
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 (F
1
). Eltrombopag was detected in the plasma of all F
1
rat pups
for the entire 22 hour sampling period following administration of medicinal product to the F
0
dams,
suggesting that rat pup exposure to eltrombopag was likely via lactation.
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.
≥
6.
6.1
List of excipients
Tablet core
Magnesium stearate
Mannitol (E421)
Microcrystalline cellulose
Povidone (K30)
Sodium starch glycolate Type A
Tablet coating
Hypromellose
Iron oxide red (E172)
Iron oxide yellow (E172)
Macrogol 400
Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable.
34
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 (
6.3 Shelf life
4 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
Aluminum blisters (PA/Alu/PVC/Alu) in a carton containing 14 or 28 film-coated tablets and
multipacks containg 84 (3 packs of 28) film-coated tablets).
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
GlaxoSmithKline Trading Services Limited
6900 Cork Airport Business Park
Kinsale Road
Cork
Ireland
8.
9.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.ema.europa.eu
/.
35
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
36
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Glaxo Operations UK Ltd (trading as Glaxo Wellcome Operations)
Priory Street
Ware, Herts SG12 0DJ
United Kingdom
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription. (See Annex I: Summary of Product
Characteristics, 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
The MAH shall agree the details of an educational programme with the National Competent
Authorities and must implement such programme nationally to ensure that, prior to prescribing,
all physicians are provided with a healthcare professional information pack containing the
following:
•
Educational material
•
Summary of Product Characteristics (SPC) and Package Leaflet and Labelling
Key elements to be included in the educational material
Hepatotoxicity
• Educate patients about the potential for hepatic enzyme elevations, importance of monthly laboratory
monitoring of ALT and AST, as well as the signs and symptoms associated with liver injury (e.g.
jaundice).
• Measure serum ALT, AST and bilirubin prior to initiation of Revolade, every 2 weeks during the
dose adjustment phase and monthly following establishment of a stable dose.
• Discontinue Revolade 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.
• Administration to patients with moderate to severe hepatic impairment should be undertaken with
caution and close monitoring due to increased exposure to the medicinal product.
Thromboembolic events
• Eltrombopag should not be used in patients with moderate to severe hepatic impairment unless the
expected benefit outweighs the identified risk of portal venous thrombosis. If use of eltrombopag is
deemed necessary, the starting dose must be 25mg once daily.
• Educate patients about the potential for thromboembolic events in patients with chronic ITP and
those known risk factors for thromboembolic events (e.g., Factor V Leiden, ATIII deficiency,
antiphospholipid syndrome).
37
• Educate patients about chronic liver disease and the risk of thromboembolic events.
• A dose reduction is recommended for patients with platelet counts between 150,000-250,000/μl.
• Revolade should be interrupted if platelet counts increase to > 250,000/μl. Once the platelet count is
< 100,000/μl, reinitiate therapy at a reduced daily dose.
Posology
• Educate patients on the appropriate administration of Revolade (e.g. titration of Revolade, food-drug
interaction, dose recommendations for special populations [e.g. east Asians]).
• Awareness to prescribers of the labelled indication and warnings associated with non-indicated
populations (e.g. not recommended for use in children, pregnant or lactating females, other off label
uses).
Food Interactions
• Educate patients about the potential food-drug interaction (i.e. chelation with polyvalent cations such
as iron, calcium, magnesium, aluminium, selenium and zinc). Antacids, dairy products and other
products containing polyvalent cations, such as mineral supplements, must be administered at least
four hours apart from Revolade dosing to avoid significant reduction in Revolade absorption due to
chelation.
• Assist patient in developing a plan to administer Revolade at a time each day that fits into the
patient’s own daily schedule.
Reoccurrence of Thrombocytopenia
• Educate patients about the potential risk of bleeding after treatment has stopped (include incidence in
clinical trials and likelihood of reoccurrence of thrombocytopenia after cessation of treatment).
• Following discontinuation of Revolade, 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.
• Monitor platelet count weekly for 4 weeks following discontinuation of Revolade.
Increased Bone Marrow Reticulin Fibres
• Educate patients about the potential for bone marrow reticulin fibre formation.
• Background information on reticulin in the bone marrow (i.e. background rates of reticulin in bone
marrow in ITP patients and the observed incidence and potential mechanism of action of reticulin
deposition in response to Revolade).
• Prior to initiation of Revolade, examine the peripheral blood smear closely to establish a baseline
level of cellular morphologic abnormalities.
• Following identification of a stable dose of Revolade, perform complete blood count (CBC) with
white blood cell count (WBC) differential monthly.
• If immature or dysplastic cells are observed, examine peripheral blood smears 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), discontinue
treatment with Revolade and consider a bone marrow biopsy, including staining for fibrosis.
Haematological malignancies
• The diagnosis of ITP in adults and elderly patients should have been confirmed by excluding other
clinical entities 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.
• Educate patients about the theoretical risk of haematological malignancies with thrombopoietin
receptor agonists.
38
• Importance of not using Revolade outside the context of its license unless in a clinical trial setting.
Potential for Off-label Use
• The risk-benefit for the treatment of thrombocytopenia in non ITP patient populations has not been
established.
• The risk-benefit of Revolade in paediatric ITP has not been established.
39
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version v.07.1 presented
in Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 10 of the Risk Management Plan (RMP) presented in
Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMEA
40
ANNEX III
LABELLING AND PACKAGE LEAFLET
41
A. LABELLING
42
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON OF 25 mg – 14, 28, 84 (3 PACKS of 28) TABLETS
1.
Revolade 25 mg film-coated tablets
eltrombopag
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains eltrombopag olamine equivalent to 25 mg eltrombopag.
3.
LIST OF EXCIPIENTS
4.
14 film-coated tablets
28 film-coated tablets
Multipack containing 84 (3 packs of 28) film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
GlaxoSmithKline Trading Services Limited
6900 Cork Airport Business Park
43
Kinsale Road
Cork
Ireland
EU/0/00/000/000 (14 film-coated tablets)
EU/0/00/000/000 (28 film-coated tablets)
EU/0/00/000/000 Multipack containing 84 (3 packs of 28) film-coated tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
revolade 25 mg
44
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON OF 50 mg – 14, 28, 84 (3 PACKS of 28) TABLETS
1.
Revolade 50 mg film-coated tablets
eltrombopag
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains eltrombopag olamine equivalent to 50 mg eltrombopag.
3.
LIST OF EXCIPIENTS
4.
14 film-coated tablets
28 film-coated tablets
Multipack containing 84 (3 packs of 28) film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
GlaxoSmithKline Trading Services Limited
45
6900 Cork Airport Business Park
Kinsale Road
Cork
Ireland
EU/0/00/000/000 (14 film-coated tablets)
EU/0/00/000/000 (28 film-coated tablets)
EU/0/00/000/000 Multipack containing 84 (3 packs of 28) film-coated tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
revolade 50 mg
46
PARTICULARS TO APPEAR ON INTERMEDIATE CARTON
Multipacks of 84 (3 packs of 28 film-coated tablets) – without blue box – 25 mg film-coated
tablets
1.
Revolade 25 mg film-coated tablets
eltrombopag
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains eltrombopag olamine equivalent to 25 mg eltrombopag.
3.
LIST OF EXCIPIENTS
4.
Component of a multipack comprising 3 packs, each containing 28 film-coated tablets.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
GlaxoSmithKline Trading Services Limited
6900 Cork Airport Business Park
47
Kinsale Road
Cork
Ireland
EU/0/00/000/000
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
revolade 25 mg
48
PARTICULARS TO APPEAR ON INTERMEDIATE CARTON
Multipacks of 84 (3 packs of 28 film-coated tablets) – without blue box – 50 mg film-coated
tablets
1.
Revolade 50 mg film-coated tablets
eltrombopag
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains eltrombopag olamine equivalent to 50 mg eltrombopag.
3.
LIST OF EXCIPIENTS
4.
Component of a multipack comprising 3 packs, each containing 28 film-coated tablets.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
GlaxoSmithKline Trading Services Limited
6900 Cork Airport Business Park
Kinsale Road
49
Cork
Ireland
EU/0/00/000/000
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
revolade 50 mg
50
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister
1.
Revolade 25 mg film-coated tablets
eltrombopag
2.
GlaxoSmithKline Trading Services Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
51
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister
1.
Revolade 50 mg film-coated tablets
eltrombopag
2.
GlaxoSmithKline Trading Services Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
52
B. PACKAGE LEAFLET
53
PACKAGE LEAFLET: INFORMATION FOR THE USER
Revolade 25 mg film-coated tablets
Revolade 50 mg film-coated tablets
eltrombopag
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1. What Revolade is and what it is used for
2. Before you take Revolade
3. How to take Revolade
4. Possible side effects
5.
How to store Revolade
6.
Further information
1.
WHAT REVOLADE IS AND WHAT IT IS USED FOR
Revolade belongs to a group of medicines called
thrombopoietin receptor agonists.
It is used to help
increase the number of platelets in your blood. Platelets are blood cells that help to reduce or prevent
bleeding.
Revolade is used to treat a bleeding disorder called
immune
(
idiopathic) thrombocytopenic purpura
(ITP) in adult patients (aged 18 years and over) who have had their spleen removed and have received
prior treatment with corticosteroids or immunoglobulins, and these medicines did not work. ITP is
caused by a low blood platelet count (
thrombocytopenia
). People with ITP have an increased risk of
bleeding, and may notice symptoms such as
petechiae
(pinpoint sized flat round red spots under the
skin), bruising, nosebleeds, bleeding gums and not being able to control bleeding if they are cut or
injured.
Revolade may also be used in previously treated adult patients (aged 18 years and over) with chronic
ITP where surgery to remove the spleen is not an option.
2.
BEFORE YOU TAKE REVOLADE
Don’t take Revolade
-
if you are allergic
(
hypersensitive
) to eltrombopag or any of the other ingredients of Revolade
(listed in section 6 under ‘What Revolade contains’).
Check with your doctor
if you think this applies to you.
Take special care with Revolade
Your doctor needs to know before you take Revolade:
-
if you have
liver problems.
You should not be given Revolade unless your doctor considers that
the expected benefits outweigh the risk of blood clots
-
if you are
at risk of blood clots in your veins or arteries
, or you know that blood clots are
common in your family. The risk of blood clots may be increased in the following
54
circumstances: if you are elderly, if you have been bedridden for a long time, if you have cancer
(
malignancy
), if you are taking the contraceptive birth control pill or hormone replacement
therapy, if you have undergone recent surgery or received a physical injury (
trauma
), if you are
overweight (
obese
), if you are a smoker.
o
If any of these circumstances apply to you please tell your doctor before starting
treatment.
-
if you have
cataracts
(the lens of the eye getting cloudy)
Tell your doctor
if any of these apply to you.
Checking for cataracts
Your doctor may recommend that you are checked for cataracts as part of routine eye tests.
You will need regular blood tests
Before you start taking Revolade your doctor will carry out blood tests to check your blood cells
including platelets. These tests will be repeated at intervals while you are taking it.
Revolade can increase some blood markers indicating liver damage. You will have blood tests to
check your liver function before you start taking Revolade and at intervals while you are taking it.
You may need to stop taking Revolade if the amount of these substances increases too much, or if you
get physical signs of liver damage.
Tell your doctor
i
mmediately
if you have any of these signs and symptoms of liver
problems:
- yellowing of the skin or the whites of the eyes
(jaundice)
- unusually dark-coloured urine.
If you stop taking Revolade a low blood platelet count (
thrombocytopenia
) is likely to reoccur within
several days. If you stop taking Revolade your platelet count will have to be monitored, and your
doctor will discuss appropriate precautions with you.
If you have very high blood platelet counts, this may increase the risk of blood clotting, however
blood clots can occur with normal or even low platelet counts. Your doctor will adjust your dose of
Revolade to ensure that your platelet count does not become too high.
Tell your doctor
i
mmediately
if you have any of these signs and symptoms of a blood
clot:
swelling, pain or tenderness in one leg (
Deep vein thrombosis
)
sudden shortness of breath especially when accompanied with sharp pain in the chest and/or
rapid breathing (
Pulmonary embolism
)
abdominal pain, enlargered abdomen, blood in stool (
Portal vein thrombosis
)
Taking other medicines
Tell your doctor or pharmacist if you are taking any other medicines, have taken any recently, or if
you start new ones. This includes herbal medicines and other medicines you can obtain without a
prescription.
Some everyday medicines interact with Revolade
– including prescription and non-prescription
medicines and minerals. These include:
-
antacid medicines to treat
indigestion
,
heartburn
or
stomach ulcers
-
medicines called statins, used to
lower cholesterol
-
minerals such as iron, calcium, magnesium, aluminium, selenium and zinc which may be found in
vitamin and mineral supplements
-
medicines such as methotrexate and topotecan, used to treat
cancer
55
See Section 3, ‘How to take Revolade’, for more information about taking antacids, vitamins and
mineral supplements
Talk to your doctor
if you take any of these. Some of them are not to be taken with Revolade,,
or your dose may need adjusting, or you may need to alter the timing of when you take them. Your
doctor will review the medicines you are taking, and suggest suitable replacements if necessary.
If you are also taking medicines which are given to prevent blood clots (
anticoagulants
or
antiplatelet
therapy
) there is a greater risk of bleeding. Your doctor will discuss this with you.
If you are taking corticosteroids, danazol, and/or azathioprine these may be reduced or
stopped when given together with Revolade.
Revolade with food and drink
Revolade is not to be taken with dairy foods or drinks as the absorption of the medicine is affected by
the calcium in dairy products. For details, see Section 3,
How to take Revolade
.
Pregnancy and breast-feeding
Don’t use Revolade if you are pregnant
unless your doctor specifically recommends it. The effect of
Revolade during pregnancy is not known.
-
Tell your doctor if you are pregnant
or planning to become pregnant.
-
Use a reliable method of contraception
while you’re taking Revolade, to prevent pregnancy
-
If you do become pregnant during treatment
with Revolade, tell your doctor.
Don’t breast-feed while you are taking Revolade
. It is not known whether Revolade passes into
breast-milk.
-
If you are breast-feeding
or planning to breast-feed, tell your doctor.
Driving and using machines
No studies on the effects of Revolade on the ability to drive or use machines have been performed.
3.
HOW TO TAKE REVOLADE
Always take Revolade exactly as your doctor has told you. Check with your doctor or pharmacist if
you are not sure.
How much to take
The usual starting dose
is one 50 mg tablet of Revolade a day. People of East Asian origin (Chinese,
Japanese, Taiwanese or Korean) may need to start at a
lower dose of 25 mg.
Swallow the tablet whole, with some water
.
Revolade may take 1 to 2 weeks to work. Based on your response to Revolade your doctor may
recommend that your daily dose is changed.
Revolade is not recommended for people aged under 18
, as the safety and effectiveness have not
yet been shown.
When to take it
Don’t take Revolade
in the
4 hours
before or after:
-
dairy foods
such as cheese, butter, yoghurt or ice cream
-
milk or milk shakes,
drinks made with milk, yoghurt or cream
56
-
antacids,
which are medicines for indigestion
-
some
mineral and vitamin supplements
including iron, calcium, magnesium, aluminium,
selenium and zinc
If you do, the medicine will not be properly absorbed into your body.
For more advice about suitable foods, talk to your doctor.
If you take more Revolade than you should
Contact a doctor or pharmacist immediately
. If possible show them the pack, or this leaflet.
It is recommended that you are monitored for any signs or symptoms of side effects and that you are
given appropriate treatment immediately.
If you forget to take Revolade
Take the next dose at the usual time. Don’t take a double dose to make up for a forgotten dose.
If you stop taking Revolade
Don’t stop taking Revolade without talking to your doctor. If your doctor advises you to stop
treatment, your platelet count will then be checked each week for four weeks.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Revolade can cause side effects, although not everybody gets them.
Bleeding after you stop treatment
Within two weeks of stopping Revolade, your blood platelet count will usually drop back down to
what it was before you started taking Revolade. The lower platelet count may increase your risk of
bleeding. Your doctor will check your platelet counts for at least 4 weeks after you stop taking
Revolade.
Î
Tell your doctor
if you have any bruising or bleeding after you stop taking Revolade.
Problems with your bone marrow
People with ITP may have problems with their bone marrow. Medicines like Revolade could make
this problem worse. Signs of bone marrow changes may show up as abnormal results in your blood
tests. Your doctor may also carry out tests to directly check your bone marrow during treatment with
Revolade.
High platelet counts
Your doctor will check your blood platelet count during treatment. If your platelet count gets too high,
your dose of Revolade may need to be changed, or you may need to stop taking it.
Higher risk of blood clots
People with ITP may have a higher risk of blood clots, and medicines like Revolade could make this
problem worse.
If you develop signs and symptoms of a blood clot, such as:
swelling, pain or tenderness in one leg (
Deep vein thrombosis
)
sudden shortness of breath, especially when accompanied with sharp pain in the chest
and/or rapid breathing (
Pulmonary embolism
)
abdominal pain, enlargered abdomen, blood in stool (
Portal vein thrombosis
)
57
Contact a doctor immediately
..
Very common side effects
These may affect
more than 1 in 10
people
-
headache
Common side effects
These may affect
up to 1 in 10
people
-
difficulty in sleeping (
insomnia)
-
constipation, pain in stomach
-
feeling sick (
nausea)
-
diarrhoea
-
cloudy lens in the eye (
cataract
)
-
dry eye
-
increase in bilirubin (a substance produced by the liver) (
hyperbilirubinaemia
)
-
liver not working well (
hepatic function abnormal)
-
unusual hair loss or thinning (
alopecia
)
-
skin rash
-
itching (
pruritus
)
-
joint pain (
arthralgia
)
-
muscle pain (
myalgia
), muscle spasm
-
bone pain
-
lack of energy (fatigue)
-
tingling or numbness of the hands or feet (
paraesthesia)
-
swelling of the hands, ankles or feet (
oedema peripheral
)
Common side effects that may show up in blood tests:
-
increase of liver enzymes (
aspartate
and
alanine transaminases
)
-
increase in
bilirubin
(a substance produced by the liver)
-
increase in the amounts of proteins
Uncommon side effects
These may affect
up to 1 in 100
people
-
interruption of blood supply to part of the heart (
acute myocardial infarction
)
-
sudden blocking of a blood vessel by blood clot (
embolism
)
-
sudden shortness of breathe, especially when accompanied with sharp pain in the chest and /or
rapid breathing (
pulmonary embolism
)
-
the loss of function of part of the lung caused by a blockage in the lung artery (
pulmonary
infarction
)
-
heart beating faster (
tachycardia
), palpitations, fast or irregular heart beat, bluish discolouration of
the skin (
cyanosis
) high blood pressure (
hypertension
)
-
inflammation of a vein (
thrombophlebitis superficial
)
-
localised swelling filled with blood from a break in a blood vessel (
haematoma
)
-
sore throat and discomfort when swallowing, inflammation of the lungs, sinuses, tonsils, nose and
throat
-
loss of appetite (
anorexia
)
-
painful swollen joints caused by uric acid (food break down product) (
Gout
)
-
problems sleeping, anxiety, depression, lack of interest, mood changes
-
dizziness, feeling drowsy, problems with balance, taste, speech and nerve function, migraine,
shaking (
tremor
)
-
problems with the liver including: level of substances (enzymes) produced by the liver increased,
bile produced by liver to aid digestion of food cannot flow properly (
cholestasis
)
-
problems with the eyes, including blurred and less clear vision
-
ear pain, spinning sensation (
vertigo
)
-
cough, problems with nose, throat and sinuses, breathing problems when sleeping
58
-
problems with digestive system including: being sick (
vomiting
), painful swollen stomach, wind,
bowel movements frequent and discoloured, haemorrhoids, dry or sore mouth, indigestion,
sensitive tongue, bleeding gums, nose bleed
-
changes to skin including, excessive sweating, itching bumpy rash, red spots, changes in
appearance
-
muscular weakness, pain in arms and legs, sensation of heaviness
-
kidney problems including: inflammation of the kidney, excessive urination at night
-
generally feeling unwell, high temperature, feeling hot, chest pain, bruising
Uncommon side effects that may show up in blood tests:
-
decrease in number of red blood cells (
anaemia
), white blood cells and platelets
-
changes in the make-up of the blood
-
changes in levels of uric acid, calcium and potassium
If you get side effects
Î
Tell your doctor or pharmacist
if any of the side effects becomes severe or troublesome, or
if you notice any side effects not listed in this leaflet.
5.
HOW TO STORE REVOLADE
Keep out of the sight and reach of children.
Do not use Revolade after the expiry date which is stated on the carton and the blister.
This medicine does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Revolade contains
25 mg film-coated tablets
The active substance in Revolade is eltrombopag olamine. Each film-coated tablet contains
eltrombopag olamine equivalent to 25 mg eltrombopag.
The other ingredients are: hypromellose, macrogol 400, magnesium stearate, mannitol (E421),
microcrystalline cellulose, polysorbate 80, povidone (K30), sodium starch glycolate Type A titanium
dioxide (E171).
50 mg film-coated tablets
The active substance in Revolade is eltrombopag olamine. Each film-coated tablet contains
eltrombopag olamine equivalent to 50 mg eltrombopag.
The other ingredients are: hypromellose, iron oxide red (E172), iron oxide yellow (E172), macrogol
400, magnesium stearate, mannitol (E421), microcrystalline cellulose, povidone (K30), sodium starch
glycolate Type A, titanium dioxide (E171).
What Revolade looks like and contents of the pack
59
Revolade 25 mg film-coated tablets are round, biconvex, white, debossed with ‘GS NX3’ and ‘25’ on
one side.
Revolade 50 mg film-coated tablets are round, biconvex, brown, debossed with ‘GS UFU’ and ‘50’ on
one side.
They are supplied in aluminum blisters in a carton containing 14 or 28 film-coated tablets and
multipacks containg 84 (3 packs of 28) film-coated tablets).
Not all pack sizes may be available in your country.
Marketing authorisation holder
GlaxoSmithKline Trading Services Ltd
6900 Cork Airport Business Park
Kinsale Road
Cork
Ireland
Manufacturer
Glaxo Operations UK Ltd (trading as Glaxo Wellcome Operations)
Priory Street, Ware
Hertfordshire, SG12 0DJ
United Kingdom
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
GlaxoSmithKline s.a./n.v.
Tél/Tel: + 32 (0)2 656 21 11
Luxembourg/Luxemburg
GlaxoSmithKline s.a./n.v.
Belgique/Belgien
Tél/Tel: + 32 (0)2 656 21 11
България
ГлаксоСмитКлайн ЕООД
Teл.: + 359 2 953 10 34
Magyarország
GlaxoSmithKline Kft.
Tel.: + 36 1 225 5300
Česká republika
GlaxoSmithKline s.r.o.
Tel: + 420 222 001 111
gsk.czmail@gsk.com
Malta
GlaxoSmithKline Malta
Tel: + 356 21 238131
Danmark
GlaxoSmithKline Pharma A/S
Tlf: + 45 36 35 91 00
dk-info@gsk.com
Nederland
GlaxoSmithKline BV
Tel: + 31 (0)30 6938100
nlinfo@gsk.com
Deutschland
GlaxoSmithKline GmbH & Co. KG
Tel.: + 49 (0)89 36044 8701
produkt.info@gsk.com
Norge
GlaxoSmithKline AS
Tlf: + 47 22 70 20 00
firmapost@gsk.no
Eesti
GlaxoSmithKline Eesti OÜ
Österreich
GlaxoSmithKline Pharma GmbH
60
Tel: + 372 6676 900
estonia@gsk.com
Tel: + 43 (0)1 97075 0
at.info@gsk.com
Ελλάδα
GlaxoSmithKline A.E.B.E.
Τηλ: + 30 210 68 82 100
Polska
GSK Commercial Sp. z o.o.
Tel.: + 48 (0)22 576 9000
España
GlaxoSmithKline, S.A.
Tel: + 34 902 202 700
es-ci@gsk.com
Portugal
GlaxoSmithKline – Produtos Farmacêuticos, Lda.
Tel: + 351 21 412 95 00
FI.PT@gsk.com
France
Laboratoire GlaxoSmithKline
Tél.: + 33 (0)1 39 17 84 44
diam@gsk.com
România
GlaxoSmithKline (GSK) S.R.L.
Tel: + 4021 3028 208
Ireland
GlaxoSmithKline (Ireland) Limited
Tel: + 353 (0)1 4955000
Slovenija
GlaxoSmithKline d.o.o.
Tel: + 386 (0)1 280 25 00
medical.x.si@gsk.com
Ísland
GlaxoSmithKline ehf.
Sími: + 354 530 3700
Slovenská republika
GlaxoSmithKline Slovakia s. r. o.
Tel: + 421 (0)2 48 26 11 11
recepcia.sk@gsk.com
Italia
GlaxoSmithKline S.p.A.
Tel: + 39 (0)45 9218 111
Suomi/Finland
GlaxoSmithKline Oy
Puh/Tel: + 358 (0)10 30 30 30
Finland.tuoteinfo@gsk.com
Κύπρος
GlaxoSmithKline Cyprus Ltd
Τηλ: + 357 22 39 70 00
Sverige
GlaxoSmithKline AB
Tel: + 46 (0)8 638 93 00
info.produkt@gsk.com
Latvija
GlaxoSmithKline Latvia SIA
Tel: + 371 67312687
lv-epasts@gsk.com
United Kingdom
GlaxoSmithKline UK
Tel: + 44 (0)800 221441
customercontactuk@gsk.com
Lietuva
GlaxoSmithKline Lietuva UAB
Tel: + 370 5 264 90 00
info.lt@gsk.com
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
61
Source: European Medicines Agency
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