REVOLADE 50mg film-coated tablets medication leaflet

Revolade 12.5 mg film-coated tablets

Revolade 25 mg film-coated tablets

Revolade 50 mg film-coated tablets

Revolade 75 mg film-coated tablets

Revolade 12.5 mg film-coated tablets

Each film-coated tablet contains eltrombopag olamine equivalent to 12.5 mg eltrombopag.

Revolade 25 mg film-coated tablets

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

Revolade 50 mg film-coated tablets

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

Revolade 75 mg film-coated tablets

Each film-coated tablet contains eltrombopag olamine equivalent to 75 mg eltrombopag.

For the full list of excipients, see section 6.1.

Film-coated tablet.

Revolade 12.5 mg film-coated tablets

White, round, biconvex film-coated tablet (approximately 7.9 mm in diameter) debossed with ‘GS

MZ1’ and ‘12.5’ on one side.

Revolade 25 mg film-coated tablets

White, round, biconvex film-coated tablet (approximately 10.3 mm in diameter) debossed with ‘GS

NX3’ and ‘25’ on one side.

Revolade 50 mg film-coated tablets

Brown, round, biconvex film-coated tablet (approximately 10.3 mm in diameter) debossed with ‘GS

UFU’ and ‘50’ on one side.

Revolade 75 mg film-coated tablets

Pink, round, biconvex film-coated tablet (approximately 10.3 mm in diameter) debossed with ‘GS

FFS’ and ‘75’ on one side.

Revolade is indicated for the treatment of adult patients with primary immune thrombocytopenia (ITP)who are refractory to other treatments (e.g. corticosteroids, immunoglobulins) (see sections 4.2 and5.1).

Revolade is indicated for the treatment of paediatric patients aged 1 year and above with primaryimmune thrombocytopenia (ITP) lasting 6 months or longer from diagnosis and who are refractory toother treatments (e.g. corticosteroids, immunoglobulins) (see sections 4.2 and 5.1).

Revolade is indicated in adult patients with chronic hepatitis C virus (HCV) infection for the treatmentof thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing theinitiation or limiting the ability to maintain optimal interferon-based therapy (see sections 4.4 and 5.1).

Revolade is indicated in adult patients with acquired severe aplastic anaemia (SAA) who were eitherrefractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable forhaematopoietic stem cell transplantation (see section 5.1).

Eltrombopag treatment should be initiated by and remain under the supervision of a physician who isexperienced in the treatment of haematological diseases or the management of chronic hepatitis C andits complications.

Eltrombopag dosing requirements must be individualised based on the patient’s platelet counts. Theobjective of treatment with eltrombopag should not be to normalise platelet counts.

The powder for oral suspension may lead to higher eltrombopag exposure than the tablet formulation(see section 5.2). When switching between the tablet and the powder for oral suspension formulations,platelet counts should be monitored weekly for 2 weeks.

Immune (primary) thrombocytopenia

The lowest dose of eltrombopag to achieve and maintain a platelet count ≥50 000/µl should be used.

Dose adjustments are based upon the platelet count response. Eltrombopag must not be used tonormalise platelet counts. In clinical studies, platelet counts generally increased within 1 to 2 weeksafter starting eltrombopag and decreased within 1 to 2 weeks after discontinuation.

Adults and paediatric population aged 6 to 17 years

The recommended starting dose of eltrombopag is 50 mg once daily. For patients of East-/Southeast-

Asian ancestry, eltrombopag should be initiated at a reduced dose of 25 mg once daily (seesection 5.2).

Paediatric population aged 1 to 5 years

The recommended starting dose of eltrombopag is 25 mg once daily.

After initiating eltrombopag, the dose must be adjusted to achieve and maintain a platelet count≥50 000/µl as necessary to reduce the risk for bleeding. A daily dose of 75 mg must not be exceeded.

Clinical haematology and liver tests should be monitored regularly throughout therapy witheltrombopag and the dose regimen of eltrombopag modified based on platelet counts as outlined in

Table 1. During therapy with eltrombopag full blood counts (FBCs), including platelet count andperipheral blood smears, should be assessed weekly until a stable platelet count (≥50 000/µl for atleast 4 weeks) has been achieved. FBCs including platelet counts and peripheral blood smears shouldbe obtained monthly thereafter.

Table 1 Dose adjustments of eltrombopag in ITP patients

Platelet count Dose adjustment or response<50 000/µl following at least Increase daily dose by 25 mg to a maximum of 75 mg/day*.

2 weeks of therapy50 000/µl to 150 000/µl Use lowest dose of eltrombopag and/or concomitant ITPtreatment to maintain platelet counts that avoid or reducebleeding.

>150 000/µl to 250 000/µl Decrease the daily dose by 25 mg. Wait 2 weeks to assess theeffects of this and any subsequent dose adjustments♦.

>250 000/µl Stop eltrombopag; increase the frequency of platelet monitoringto twice weekly.

Once the platelet count is ≤ 100 000/µl, reinitiate therapy at adaily dose reduced by 25 mg.

* For patients taking 25 mg eltrombopag once every other day, increase dose to 25 mg once daily.

♦ For patients taking 25 mg eltrombopag once daily, consideration should be given to dosing at 12.5 mgonce daily or alternatively a dose of 25 mg once every other day.

Eltrombopag can be administered in addition to other ITP medicinal products. The dose regimen ofconcomitant ITP medicinal products should be modified, as medically appropriate, to avoid excessiveincreases in platelet counts during therapy with eltrombopag.

It is necessary to wait for at least 2 weeks to see the effect of any dose adjustment on the patient’splatelet response prior to considering another dose adjustment.

The standard eltrombopag dose adjustment, either decrease or increase, would be 25 mg once daily.

Treatment with eltrombopag should be discontinued if the platelet count does not increase to a levelsufficient to avoid clinically important bleeding after 4 weeks of eltrombopag therapy at 75 mg oncedaily.

Patients should be clinically evaluated periodically and continuation of treatment should be decided onan individual basis by the treating physician. In non-splenectomised patients this should includeevaluation relative to splenectomy. The reoccurrence of thrombocytopenia is possible upondiscontinuation of treatment (see section 4.4).

Chronic hepatitis C (HCV) associated thrombocytopenia

When eltrombopag is given in combination with antivirals reference should be made to the fullsummary of product characteristics of the respective coadministered medicinal products forcomprehensive details of relevant safety information or contraindications.

In clinical studies, platelet counts generally began to increase within 1 week of starting eltrombopag.

The aim of treatment with eltrombopag should be to achieve the minimum level of platelet countsneeded to initiate antiviral therapy, in adherence to clinical practice recommendations. During antiviraltherapy, the aim of treatment should be to keep platelet counts at a level that prevents the risk ofbleeding complications, normally around 50 000-75 000/µl. Platelet counts >75 000/µl should beavoided. The lowest dose of eltrombopag needed to achieve the targets should be used. Doseadjustments are based upon the platelet count response.

Eltrombopag should be initiated at a dose of 25 mg once daily. No dosage adjustment is necessary for

HCV patients of East-/Southeast-Asian ancestry or patients with mild hepatic impairment (seesection 5.2).

The dose of eltrombopag should be adjusted in 25 mg increments every 2 weeks as necessary toachieve the target platelet count required to initiate antiviral therapy. Platelet counts should bemonitored every week prior to starting antiviral therapy. On initiation of antiviral therapy the plateletcount may fall, so immediate eltrombopag dose adjustments should be avoided (see Table 2).

During antiviral therapy, the dose of eltrombopag should be adjusted as necessary to avoid dosereductions of peginterferon due to decreasing platelet counts that may put patients at risk of bleeding(see Table 2). Platelet counts should be monitored weekly during antiviral therapy until a stableplatelet count is achieved, normally around 50 000-75 000/µl. FBCs including platelet counts andperipheral blood smears should be obtained monthly thereafter. Dose reductions on the daily dose by25 mg should be considered if platelet counts exceed the required target. It is recommended to wait for2 weeks to assess the effects of this and any subsequent dose adjustments.

A dose of 100 mg eltrombopag once daily must not be exceeded.

Table 2 Dose adjustments of eltrombopag in HCV patients during antiviral therapy

Platelet count Dose adjustment or response<50 000/µl following at least Increase daily dose by 25 mg to a maximum of 100 mg/day.

2 weeks of therapy≥50 000/µl to ≤100 000/µl Use lowest dose of eltrombopag as necessary to avoid dosereductions of peginterferon.

>100 000/µl to ≤150 000/µl Decrease the daily dose by 25 mg. Wait 2 weeks to assess theeffects of this and any subsequent dose adjustments♦.

>150 000/µl Stop eltrombopag; increase the frequency of platelet monitoring totwice weekly.

Once the platelet count is ≤100 000/µl, reinitiate therapy at a dailydose reduced by 25 mg*.

* For patients taking 25 mg eltrombopag once daily, consideration should be given to reinitiating dosingat 25 mg every other day.♦ On initiation of antiviral therapy the platelet count may fall, so immediate eltrombopag dose reductionsshould be avoided.

If after 2 weeks of eltrombopag therapy at 100 mg the required platelet level to initiate antiviraltherapy is not achieved, eltrombopag should be discontinued.

Eltrombopag treatment should be terminated when antiviral therapy is discontinued unless otherwisejustified. Excessive platelet count responses or important liver test abnormalities also necessitatediscontinuation.

Severe aplastic anaemia

Eltrombopag should be initiated at a dose of 50 mg once daily. For patients of East-/Southeast-Asianancestry, eltrombopag should be initiated at a reduced dose of 25 mg once daily (see section 5.2). Thetreatment should not be initiated when the patient has existing cytogenetic abnormalities ofchromosome 7.

Haematological response requires dose titration, generally up to 150 mg, and may take up to 16 weeksafter starting eltrombopag (see section 5.1). The dose of eltrombopag should be adjusted in 50 mgincrements every 2 weeks as necessary to achieve the target platelet count ≥50 000/µl. For patientstaking 25 mg once daily, the dose should be increased to 50 mg daily before increasing the doseamount by 50 mg. A dose of 150 mg daily must not be exceeded. Clinical haematology and liver testsshould be monitored regularly throughout therapy with eltrombopag and the dosage regimen ofeltrombopag modified based on platelet counts as outlined in Table 3.

Table 3 Dose adjustments of eltrombopag in patients with severe aplastic anaemia

Platelet count Dose adjustment or response<50 000/µl following at least Increase daily dose by 50 mg to a maximum of 150 mg/day.

2 weeks of therapy

For patients taking 25 mg once daily, increase the dose to50 mg daily before increasing the dose amount by 50 mg.

≥50 000/µl to ≤150 000/µl Use lowest dose of eltrombopag to maintain platelet counts.

>150 000/µl to ≤250 000/µl Decrease the daily dose by 50 mg. Wait 2 weeks to assess theeffects of this and any subsequent dose adjustments.

>250 000/µl Stop eltrombopag; for at least one week.

Once the platelet count is ≤100 000/µl, reinitiate therapy at adaily dose reduced by 50 mg.

Tapering for tri-lineage (white blood cells, red blood cells, and platelets) responders

For patients who achieve tri-lineage response, including transfusion independence, lasting at least8 weeks: the dose of eltrombopag may be reduced by 50%.

If counts remain stable after 8 weeks at the reduced dose, then eltrombopag must be discontinued andblood counts monitored. If platelet counts drop to <30 000/µl, haemoglobin drops to < 9 g/dl orabsolute neutrophil count (ANC) to <0.5 x 109/l, eltrombopag may be reinitiated at the previouseffective dose.

If no haematological response has occurred after 16 weeks of therapy with eltrombopag, therapyshould be discontinued. If new cytogenetic abnormalities are detected, it must be evaluated whethercontinuation of eltrombopag is appropriate (see sections 4.4 and 4.8). Excessive platelet countresponses (as outlined in Table 3) or important liver test abnormalities also necessitate discontinuationof eltrombopag (see section 4.8).

No dose adjustment is necessary in patients with renal impairment. Patients with impaired renalfunction should use eltrombopag with caution and close monitoring, for example by testing serumcreatinine and/or performing urine analysis (see section 5.2).

Eltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥5) unlessthe expected benefit outweighs the identified risk of portal venous thrombosis (see section 4.4).

If the use of eltrombopag is deemed necessary for ITP patients with hepatic impairment the startingdose must be 25 mg once daily. After initiating the dose of eltrombopag in patients with hepaticimpairment an interval of 3 weeks should be observed before increasing the dose.

No dose adjustment is required for thrombocytopenic patients with chronic HCV and mild hepaticimpairment (Child-Pugh score ≤6). Chronic HCV patients and SAA patients with hepatic impairmentshould initiate eltrombopag at a dose of 25 mg once daily (see section 5.2). After initiating the dose ofeltrombopag in patients with hepatic impairment an interval of 2 weeks should be observed beforeincreasing the dose.

There is an increased risk for adverse events, including hepatic decompensation and thromboembolicevents (TEEs), in thrombocytopenic patients with advanced chronic liver disease treated witheltrombopag, either in preparation for invasive procedure or in HCV patients undergoing antiviraltherapy (see sections 4.4 and 4.8).

There are limited data on the use of eltrombopag in ITP patients aged 65 years and older and noclinical experience in ITP patients aged over 85 years. In the clinical studies of eltrombopag, overallno clinically significant differences in safety of eltrombopag were observed between patients aged atleast 65 years and younger patients. Other reported clinical experience has not identified differences inresponses between the elderly and younger patients, but greater sensitivity of some older individualscannot be ruled out (see section 5.2).

There are limited data on the use of eltrombopag in HCV and SAA patients aged over 75 years.

Caution should be exercised in these patients (see section 4.4).

East-/Southeast-Asian patients

For adult and paediatric patients of East-/Southeast-Asian ancestry including those with hepaticimpairment, eltrombopag should be initiated at a dose of 25 mg once daily (see section 5.2).

Patient platelet count should continue to be monitored and the standard criteria for further dosemodification followed.

Revolade is not recommended for use in children under the age of 1 year with ITP due to insufficientdata on safety and efficacy.

The safety and efficacy of eltrombopag has not been established in children and adolescents(<18 years) with chronic HCV related thrombocytopenia. No data are available.

The safety and efficacy of eltrombopag has not been established in children and adolescents(<18 years) with SAA. Currently available data are described in sections 4.8, 5.1 and 5.2 but norecommendation on a posology can be made.

Oral use

The tablets should be taken at least two hours before or four hours after any products containingpolyvalent cations (e.g. iron, calcium, magnesium, aluminium, selenium and zinc), such as antacids,dairy products (or other calcium containing food products), or mineral supplements (see sections 4.5and 5.2).

Hypersensitivity to eltrombopag or to any of the excipients listed in section 6.1.

There is an increased risk for adverse reactions, including potentially fatal hepatic decompensation andthromboembolic events, in thrombocytopenic HCV patients with advanced chronic liver disease, asdefined by low albumin levels ≤35 g/l or model for end stage liver disease (MELD) score ≥10, whentreated with eltrombopag in combination with interferon-based therapy. In addition, the benefits oftreatment in terms of the proportion achieving sustained virological response (SVR) compared withplacebo were modest in these patients (especially for those with baseline albumin ≤35 g/l) comparedwith the group overall. Treatment with eltrombopag in these patients should be initiated only byphysicians experienced in the management of advanced HCV, and only when the risks ofthrombocytopenia or withholding antiviral therapy necessitate intervention. If treatment is consideredclinically indicated, close monitoring of these patients is required.

Combination with direct-acting antiviral agents

Safety and efficacy have not been established in combination with direct-acting antiviral agentsapproved for treatment of chronic hepatitis C infection.

Risk of hepatotoxicity

Eltrombopag administration can cause abnormal liver function and severe hepatotoxicity, which mightbe life-threatening (see section 4.8).

Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin should bemeasured prior to initiation of eltrombopag, every 2 weeks during the dose adjustment phase andmonthly following establishment of a stable dose. Eltrombopag inhibits UGT1A1 and OATP1B1,which may lead to indirect hyperbilirubinaemia. If bilirubin is elevated fractionation should beperformed. Abnormal serum liver tests should be evaluated with repeat testing within 3 to 5 days. Ifthe 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(3 times the upper limit of normal [x ULN] in patients with normal liver function, or ≥3 x baseline or>5 x ULN, whichever is the lower, in patients with pre-treatment elevations in transaminases) 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.

Caution is required when administering eltrombopag to patients with hepatic disease. In ITP and SAApatients a lower starting dose of eltrombopag should be used. Close monitoring is required whenadministering to patients with hepatic impairment (see section 4.2).

Hepatic decompensation (use with interferon)

Hepatic decompensation in patients with chronic hepatitis C: Monitoring is required in patients withlow albumin levels (≤35 g/l) or with MELD score ≥10 at baseline.

Chronic HCV patients with liver cirrhosis may be at risk of hepatic decompensation when receivingalfa interferon therapy. In two controlled clinical studies in thrombocytopenic patients with HCV,hepatic decompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterialperitonitis) occurred more frequently in the eltrombopag arm (11%) than in the placebo arm (6%). Inpatients with low albumin levels (≤35 g/l) or with a MELD score ≥10 at baseline, there was a 3-foldgreater risk of hepatic decompensation and an increase in the risk of a fatal adverse event compared tothose with less advanced liver disease. In addition, the benefits of treatment in terms of the proportionachieving SVR compared with placebo were modest in these patients (especially for those withbaseline albumin ≤35 g/l) compared with the group overall. Eltrombopag should only be administeredto such patients after careful consideration of the expected benefits in comparison with the risks.

Patients with these characteristics should be closely monitored for signs and symptoms of hepaticdecompensation. The respective interferon summary of product characteristics should be referencedfor discontinuation criteria. Eltrombopag should be terminated if antiviral therapy is discontinued forhepatic decompensation.

Thrombotic/thromboembolic complications

In controlled studies in thrombocytopenic patients with HCV receiving interferon-based therapy(n=1 439), 38 out of 955 patients (4%) treated with eltrombopag and 6 out of 484 patients (1%) in theplacebo group experienced TEEs. Reported thrombotic/thromboembolic complications included bothvenous and arterial events. The majority of TEEs were non-serious and resolved by the end of thestudy. Portal vein thrombosis was the most common TEE in both treatment groups (2% in patientstreated with eltrombopag versus <1% for placebo). No specific temporal relationship between start oftreatment and event of TEE were observed. Patients with low albumin levels (≤35 g/l) or MELD ≥10had a 2-fold greater risk of TEEs than those with higher albumin levels; those aged ≥60 years had a 2-fold greater risk of TEEs compared to younger patients. Eltrombopag should only be administered tosuch patients after careful consideration of the expected benefits in comparison with the risks. Patientsshould be closely monitored for signs and symptoms of TEE.

The risk of TEEs has been found to be increased in patients with chronic liver disease (CLD) treatedwith 75 mg eltrombopag once daily for 2 weeks in preparation for invasive procedures. Six of 143(4%) adult patients with CLD receiving eltrombopag experienced TEEs (all of the portal venoussystem) and two of 145 (1%) patients in the placebo group experienced TEEs (one in the portal venoussystem and one myocardial infarction). Five of the 6 patients treated with eltrombopag experienced thethrombotic complication at a platelet count >200 000/µl and within 30 days of the last dose ofeltrombopag. Eltrombopag is not indicated for the treatment of thrombocytopenia in patients withchronic liver disease in preparation for invasive procedures.

In eltrombopag clinical studies in ITP thromboembolic events were observed at low and normalplatelet counts. Caution should be used when administering eltrombopag to patients with known riskfactors for thromboembolism including but not limited to inherited (e.g. Factor V Leiden) or acquiredrisk factors (e.g. ATIII deficiency, antiphospholipid syndrome), advanced age, patients with prolongedperiods of immobilisation, malignancies, contraceptives and hormone replacement therapy,surgery/trauma, obesity and smoking. Platelet counts should be closely monitored and considerationgiven to reducing the dose or discontinuing eltrombopag treatment if the platelet count exceeds thetarget levels (see section 4.2). The risk-benefit balance should be considered in patients at risk of TEEsof any aetiology.

No case of TEE was identified from a clinical study in refractory SAA, however the risk of theseevents cannot be excluded in this patient population due to the limited number of exposed patients. Asthe highest authorised dose is indicated for patients with SAA (150 mg/day) and due to the nature ofthe reaction, TEEs might be expected in this patient population.

Eltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥5) unlessthe expected benefit outweighs the identified risk of portal venous thrombosis. When treatment isconsidered appropriate, caution is required when administering eltrombopag to patients with hepaticimpairment (see sections 4.2 and 4.8).

Bleeding following discontinuation of eltrombopag

Thrombocytopenia is likely to reoccur in ITP patients upon discontinuation of treatment witheltrombopag. Following discontinuation of eltrombopag, platelet counts return to baseline levelswithin 2 weeks in the majority of patients, which increases the bleeding risk and in some cases maylead to bleeding. This risk is increased if eltrombopag treatment is discontinued in the presence ofanticoagulants or anti-platelet agents. It is recommended that, if treatment with eltrombopag isdiscontinued, ITP treatment be restarted according to current treatment guidelines. Additional medicalmanagement may include cessation of anticoagulant and/or anti-platelet therapy, reversal ofanticoagulation, or platelet support. Platelet counts must be monitored weekly for 4 weeks followingdiscontinuation of eltrombopag.

In HCV clinical studies, a higher incidence of gastrointestinal bleeding, including serious and fatalcases, was reported following discontinuation of peginterferon, ribavirin, and eltrombopag. Followingdiscontinuation of therapy, patients should be monitored for any signs or symptoms of gastrointestinalbleeding.

Bone marrow reticulin formation and risk of bone marrow fibrosis

Eltrombopag may increase the risk for development or progression of reticulin fibres within the bonemarrow. The relevance of this finding, as with other thrombopoietin-receptor (TPO-R) agonists, hasnot been established yet.

Prior to initiation of eltrombopag, the peripheral blood smear should be examined closely to establisha baseline level of cellular morphologic abnormalities. Following identification of a stable dose ofeltrombopag, full blood count (FBC) with white blood cell count (WBC) differential should beperformed monthly. If immature or dysplastic cells are observed, peripheral blood smears should beexamined for new or worsening morphological abnormalities (e.g. teardrop and nucleated red bloodcells, immature white blood cells) or cytopenia(s). If the patient develops new or worseningmorphological abnormalities or cytopenia(s), treatment with eltrombopag should be discontinued anda bone marrow biopsy considered, including staining for fibrosis.

There is a theoretical concern that TPO-R agonists may stimulate the progression of existinghaematological malignancies such as MDS. TPO-R agonists are growth factors that lead tothrombopoietic progenitor cell expansion, differentiation and platelet production. The TPO-R ispredominantly expressed on the surface of cells of the myeloid lineage.

In clinical studies with a TPO-R agonist in patients with MDS, cases of transient increases in blast cellcounts were observed and cases of MDS disease progression to acute myeloid leukaemia (AML) werereported.

The diagnosis of ITP or SAA in adults and elderly patients should be confirmed by the exclusion ofother clinical entities presenting with thrombocytopenia, in particular the diagnosis of MDS must beexcluded. Consideration should be given to performing a bone marrow aspirate and biopsy over thecourse of the disease and treatment, particularly in patients over 60 years of age, those with systemicsymptoms, or abnormal signs such as increased peripheral blast cells.

The effectiveness and safety of Revolade have not been established for the treatment ofthrombocytopenia due to MDS. Revolade should not be used outside of clinical studies for thetreatment of thrombocytopenia due to MDS.

Cytogenetic abnormalities and progression to MDS/AML in patients with SAA

Cytogenetic abnormalities are known to occur in SAA patients. It is not known whether eltrombopagincreases the risk of cytogenetic abnormalities in patients with SAA. In the phase II refractory SAAclinical study with eltrombopag with a starting dose of 50 mg/day (escalated every 2 weeks to amaximum of 150 mg/day) (ELT112523), the incidence of new cytogenetic abnormalities wasobserved in 17.1% of adult patients [7/41 (where 4 of them had changes in chromosome 7)]. Themedian time on study to a cytogenetic abnormality was 2.9 months.

In the phase II refractory SAA clinical study with eltrombopag at a dose of 150 mg/day (with ethnic orage related modifications as indicated) (ELT116826), the incidence of new cytogenetic abnormalitieswas observed in 22.6% of adult patients [7/31 (where 3 of them had changes in chromosome 7)]. All7 patients had normal cytogenetics at baseline. Six patients had cytogenetic abnormality at Month 3 ofeltrombopag therapy and one patient had cytogenetic abnormality at Month 6.

In clinical studies with eltrombopag in SAA, 4% of patients (5/133) were diagnosed with MDS. Themedian time to diagnosis was 3 months from the start of eltrombopag treatment.

For SAA patients refractory to or heavily pretreated with prior immunosuppressive therapy, bonemarrow examination with aspirations for cytogenetics is recommended prior to initiation ofeltrombopag, at 3 months of treatment and 6 months thereafter. If new cytogenetic abnormalities aredetected, it must be evaluated whether continuation of eltrombopag is appropriate.

Ocular changes

Cataracts were observed in toxicology studies of eltrombopag in rodents (see section 5.3). Incontrolled studies in thrombocytopenic patients with HCV receiving interferon therapy (n=1 439),progression of pre-existing baseline cataract(s) or incident cataracts was reported in 8% of theeltrombopag group and 5% of the placebo group. Retinal haemorrhages, mostly Grade 1 or 2, havebeen reported in HCV patients receiving interferon, ribavirin and eltrombopag (2% of the eltrombopaggroup and 2% of the placebo group. Haemorrhages occurred on the surface of the retina (preretinal),under the retina (subretinal), or within the retinal tissue. Routine ophthalmologic monitoring ofpatients is recommended.

QT/QTc prolongation

A QTc study in healthy volunteers dosed 150 mg eltrombopag per day did not show a clinicallysignificant effect on cardiac repolarisation. QTc interval prolongation has been reported in clinicalstudies of patients with ITP and thrombocytopenic patients with HCV. The clinical significance ofthese QTc prolongation events is unknown.

Loss of response to eltrombopag

A loss of response or failure to maintain a platelet response with eltrombopag treatment within therecommended dosing range should prompt a search for causative factors, including an increased bonemarrow reticulin.

The above warnings and precautions for ITP also apply to the paediatric population.

Eltrombopag is highly coloured and so has the potential to interfere with some laboratory tests. Serumdiscolouration and interference with total bilirubin and creatinine testing have been reported inpatients taking Revolade. If the laboratory results and clinical observations are inconsistent, re-testingusing another method may help in determining the validity of the result.

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to sayessentially ‘sodium-free’.

Effects of eltrombopag on other medicinal products

HMG CoA reductase inhibitors

Administration of eltrombopag 75 mg once daily for 5 days with a single 10 mg dose of the OATP1B1and BCRP substrate rosuvastatin to 39 healthy adult subjects increased plasma rosuvastatin Cmax 103%(90% confidence interval [CI]: 82%, 126%) and AUC0- 55% (90% CI: 42%, 69%). Interactions arealso expected with other HMG-CoA reductase inhibitors, including atorvastatin, fluvastatin, lovastatin,pravastatin and simvastatin. When co-administered with eltrombopag, a reduced dose of statins shouldbe considered and careful monitoring for statin adverse reactions should be undertaken (seesection 5.2).

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 (see section 5.2).

Cytochrome P450 substrates

In studies utilising human liver microsomes, eltrombopag (up to 100 M) showed no in vitroinhibition of the CYP450 enzymes 1A2, 2A6, 2C19, 2D6, 2E1, 3A4/5, and 4A9/11 and was aninhibitor of CYP2C8 and CYP2C9 as measured using paclitaxel and diclofenac as the probesubstrates. Administration of eltrombopag 75 mg once daily for 7 days to 24 healthy male subjects didnot 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 expectedwhen eltrombopag and CYP450 substrates are co-administered (see section 5.2).

HCV protease inhibitors

Dose adjustment is not required when eltrombopag is co-administered with either telaprevir orboceprevir. Co-administration of a single dose of eltrombopag 200 mg with telaprevir 750 mg every8 hours did not alter plasma telaprevir exposure.

Co-administration of a single dose of eltrombopag 200 mg with boceprevir 800 mg every 8 hours didnot alter plasma boceprevir AUC(0-), but increased Cmax by 20%, and decreased Cmin by 32%. Theclinical relevance of the decrease in Cmin has not been established, increased clinical and laboratorymonitoring for HCV suppression is recommended.

Effects of other medicinal products on eltrombopag

A decrease in eltrombopag exposure was observed with co-administration of 200 mg and 600 mgciclosporin (a BCRP inhibitor). The co-administration of 200 mg ciclosporin decreased the Cmax andthe AUC0- of eltrombopag by 25% and 18%, respectively. The co-administration of 600 mgciclosporin decreased the Cmax and the AUC0- of eltrombopag by 39% and 24%, respectively.

Eltrombopag dose adjustment is permitted during the course of the treatment based on the patient’splatelet count (see section 4.2). Platelet count should be monitored at least weekly for 2 to 3 weekswhen eltrombopag is co-administered with ciclosporin. Eltrombopag dose may need to be increasedbased on these platelet counts.

Polyvalent cations (chelation)

Eltrombopag chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, seleniumand zinc. Administration of a single dose of eltrombopag 75 mg with a polyvalent cation-containingantacid (1 524 mg aluminium hydroxide and 1 425 mg magnesium carbonate) decreased plasmaeltrombopag AUC0- by 70% (90% CI: 64%, 76%) and Cmax by 70% (90% CI: 62%, 76%).

Eltrombopag should be taken at least two hours before or four hours after any products such asantacids, dairy products or mineral supplements containing polyvalent cations to avoid significantreduction in eltrombopag absorption due to chelation (see sections 4.2 and 5.2).

Lopinavir/ritonavir

Co-administration of eltrombopag with lopinavir/ritonavir may cause a decrease in the concentrationof eltrombopag. A study in 40 healthy volunteers showed that the co-administration of a single 100 mgdose of eltrombopag with repeat dose lopinavir/ritonavir 400/100 mg twice daily resulted in areduction in eltrombopag plasma AUC0- by 17% (90% CI: 6.6%, 26.6%). Therefore, caution shouldbe used when co-administration of eltrombopag with lopinavir/ritonavir takes place. Platelet countshould be closely monitored in order to ensure appropriate medical management of the dose ofeltrombopag when lopinavir/ritonavir therapy is initiated or discontinued.

CYP1A2 and CYP2C8 inhibitors and inducers

Eltrombopag is metabolised through multiple pathways including CYP1A2, CYP2C8, UGT1A1, and

UGT1A3 (see section 5.2). Medicinal products that inhibit or induce a single enzyme are unlikely tosignificantly affect plasma eltrombopag concentrations, whereas medicinal products that inhibit orinduce multiple enzymes have the potential to increase (e.g. fluvoxamine) or decrease (e.g. rifampicin)eltrombopag concentrations.

HCV protease inhibitors

Results of a drug-drug pharmacokinetic (PK) interaction study show that co-administration of repeatdoses of boceprevir 800 mg every 8 hours or telaprevir 750 mg every 8 hours with a single dose ofeltrombopag 200 mg did not alter plasma eltrombopag exposure to a clinically significant extent.

Medicinal products used in the treatment of ITP in combination with eltrombopag in clinical studiesincluded corticosteroids, danazol, and/or azathioprine, intravenous immunoglobulin (IVIG), and anti-

D immunoglobulin. Platelet counts should be monitored when combining eltrombopag with othermedicinal products for the treatment of ITP in order to avoid platelet counts outside of therecommended range (see section 4.2).

The administration of eltrombopag tablet or powder for oral suspension formulations with a high-calcium meal (e.g. a meal that included dairy products) significantly reduced plasma eltrombopag

AUC0-∞ and Cmax. In contrast, the administration of eltrombopag 2 hours before or 4 hours after a high-calcium meal or with low-calcium food [<50 mg calcium] did not alter plasma eltrombopag exposureto a clinically significant extent (see section 4.2).

Administration of a single 50 mg dose of eltrombopag in tablet form with a standard high-calorie,high-fat breakfast that included dairy products reduced plasma eltrombopag mean AUC0-∞ by 59% andmean Cmax by 65%.

Administration of a single 25 mg dose of eltrombopag as powder for oral suspension with a high-calcium, moderate-fat and moderate-calorie meal reduced plasma eltrombopag mean AUC0-∞ by 75%and mean Cmax by 79%. This decrease of exposure was attenuated when a single 25 mg dose ofeltrombopag powder for oral suspension was administered 2 hours before a high-calcium meal (mean

AUC0-∞ was decreased by 20% and mean Cmax by 14%).

Food low in calcium (<50 mg calcium), including fruit, lean ham, beef and unfortified (no addedcalcium, magnesium or iron) fruit juice, unfortified soya milk and unfortified grain, did notsignificantly impact plasma eltrombopag exposure, regardless of calorie and fat content (seesections 4.2 and 4.5).

There are no or limited amount of data from the use of eltrombopag in pregnant women. Studies inanimals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Revolade is not recommended during pregnancy.

Revolade is not recommended in women of childbearing potential not using contraception.

It is not known whether eltrombopag/metabolites are excreted in human milk. Studies in animals haveshown that eltrombopag is likely secreted into milk (see section 5.3); therefore a risk to the sucklingchild cannot be excluded. A decision must be made whether to discontinue breast-feeding or tocontinue/abstain from Revolade therapy, taking into account the benefit of breast-feeding for the childand the benefit of therapy for the woman.

Fertility was not affected in male or female rats at exposures that were comparable to those in humans.

However, a risk for humans cannot be ruled out (see section 5.3).

Eltrombopag has negligible influence on the ability to drive and use machines. The clinical status ofthe patient and the adverse reaction profile of eltrombopag, including dizziness and lack of alertness,should be borne in mind when considering the patient’s ability to perform tasks that requirejudgement, motor and cognitive skills.

Immune thrombocytopenia in adult and paediatric patients

The safety of Revolade was assessed in adult patients (N=763) using the pooled double-blind,placebo-controlled studies TRA100773A and B, TRA102537 (RAISE) and TRA113765, in which403 patients were exposed to Revolade and 179 to placebo, in addition to data from the completedopen-label studies (N=360) TRA108057 (REPEAT), TRA105325 (EXTEND) and TRA112940 (seesection 5.1). Patients received study medication for up to 8 years (in EXTEND). The most importantserious adverse reactions were hepatotoxicity and thrombotic/thromboembolic events. The mostcommon adverse reactions occurring in at least 10% of patients included nausea, diarrhoea, increasedalanine aminotransferase and back pain.

The safety of Revolade in paediatric patients (aged 1 to 17 years) with previously treated ITP has beendemonstrated in two studies (N=171) (see section 5.1). PETIT2 (TRA115450) was a two-part, double-blind and open-label, randomised, placebo-controlled study. Patients were randomised 2:1 andreceived Revolade (n=63) or placebo (n=29) for up to 13 weeks in the randomised period of the study.

PETIT (TRA108062) was a three-part, staggered-cohort, open-label and double-blind, randomised,placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=44) or placebo(n=21), for up to 7 weeks. The profile of adverse reactions was comparable to that seen in adults withsome additional adverse reactions, marked ♦ in the table below. The most common adverse reactionsin paediatric ITP patients 1 year and older (≥3% and greater than placebo) were upper respiratory tractinfection, nasopharyngitis, cough, pyrexia, abdominal pain, oropharyngeal pain, toothache andrhinorrhoea.

Thrombocytopenia with HCV infection in adult patients

ENABLE 1 (TPL103922 n=716, 715 treated with eltrombopag) and ENABLE 2 (TPL108390 n=805)were randomised, double-blind, placebo-controlled, multicentre studies to assess the efficacy andsafety of Revolade in thrombocytopenic patients with HCV infection who were otherwise eligible toinitiate antiviral therapy. In the HCV studies the safety population consisted of all randomised patientswho received double-blind study medicinal product during Part 2 of ENABLE 1 (Revolade treatmentn=450, placebo treatment n=232) and ENABLE 2 (Revolade treatment n=506, placebo treatmentn=252). Patients are analysed according to the treatment received (total safety double-blindpopulation, Revolade n=955 and placebo n=484). The most important serious adverse reactionsidentified were hepatotoxicity and thrombotic/thromboembolic events. The most common adversereactions occurring in at least 10% of patients included headache, anaemia, decreased appetite, cough,nausea, diarrhoea, hyperbilirubinaemia, alopecia, pruritus, myalgia, pyrexia, fatigue, influenza-likeillness, asthenia, chills and oedema.

Severe aplastic anaemia in adult patients

The safety of Revolade in adult patients with SAA was assessed in a single-arm, open-label study(N=43) in which 11 patients (26%) were treated for >6 months and 7 patients (16%) were treated for>1 year (see section 5.1). The most common adverse reactions occurring in at least 10% of patientsincluded headache, dizziness, cough, oropharyngeal pain, rhinorrhoea, nausea, diarrhoea, abdominalpain, transaminases increased, arthralgia, pain in extremity, muscle spasms, fatigue and pyrexia.

Severe aplastic anaemia in paediatric population

The safety of Revolade in paediatric patients with refractory/relapsed (cohort A; n=14) or treatment-naive (cohort B; n=37) SAA was assessed in an open-label, uncontrolled, intra-patient dose escalationstudy (total N=51) (see also section 5.1 for study details). Adverse events of special interest, includingacute kidney injury, hepatotoxicity, thromboembolic events, and clonal evolution or cytogeneticabnormality, were reported in 29 (56.9%), 39 (76.5%), 2 (3.9%), and 1 (2.0%) patients, respectively.

Overall, the frequency, type and severity of adverse reactions observed for eltrombopag in paediatricpatients with SAA were consistent with those observed in adult patients with SAA.

List of adverse reactions

The adverse reactions in the adult ITP studies (N=763), paediatric ITP studies (N=171), the HCVstudies (N=1 520), the adult SAA study (N=43), the paediatric SAA study (N=51) and post-marketingreports are listed below by MedDRA system organ class and by frequency (Tables 4, 5 and 6). Withineach system organ class, the adverse drug reactions are ranked by frequency, with the most frequentreactions first. The corresponding frequency category for each adverse drug reaction is based on thefollowing convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon(≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); not known (cannot be estimated from the availabledata).

Table 4 Adverse reactions in the ITP study population

System organ class Frequency Adverse reaction

Infections and infestations Very Nasopharyngitis♦, upper respiratory tract infection♦common

Common Pharyngitis, influenza, oral herpes, pneumonia,sinusitis, tonsillitis, respiratory tract infection,gingivitis

Uncommon Skin infection

Neoplasms benign, Uncommon Rectosigmoid cancermalignant and unspecified(incl cysts and polyps)

Blood and lymphatic system Common Anaemia, eosinophilia, leukocytosis,disorders thrombocytopenia, haemoglobin decreased, whiteblood cell count decreased

Uncommon Anisocytosis, haemolytic anaemia, myelocytosis, bandneutrophil count increased, myelocyte present, plateletcount increased, haemoglobin increased

Immune system disorders Uncommon Hypersensitivity

Metabolism and nutrition Common Hypokalaemia, decreased appetite, blood uric aciddisorders increased

Uncommon Anorexia, gout, hypocalcaemia

Psychiatric disorders Common Sleep disorder, depression

Uncommon Apathy, mood altered, tearfulness

Nervous system disorders Common Paraesthesia, hypoaesthesia, somnolence, migraine

Uncommon Tremor, balance disorder, dysaesthesia, hemiparesis,migraine with aura, neuropathy peripheral, peripheralsensory neuropathy, speech disorder, toxic neuropathy,vascular headache

Eye disorders Common Dry eye, vision blurred, eye pain, visual acuity reduced

Uncommon Lenticular opacities, astigmatism, cataract cortical,lacrimation increased, retinal haemorrhage, retinalpigment epitheliopathy, visual impairment, visualacuity tests abnormal, blepharitis, keratoconjunctivitissicca

Ear and labyrinth disorders Common Ear pain, vertigo

Cardiac disorders Uncommon Tachycardia, acute myocardial infarction,cardiovascular disorder, cyanosis, sinus tachycardia,electrocardiogram QT prolonged

Vascular disorders Common Deep vein thrombosis, haematoma, hot flush

Uncommon Embolism, thrombophlebitis superficial, flushing

Respiratory, thoracic and Very Cough♦mediastinal disorders common

Common Oropharyngeal pain♦, rhinorrhoea♦

Uncommon Pulmonary embolism, pulmonary infarction, nasaldiscomfort, oropharyngeal blistering, sinus disorder,sleep apnoea syndrome

Gastrointestinal disorders Very Nausea, diarrhoeacommon

Common Mouth ulceration, toothache♦, vomiting, abdominalpain*, mouth haemorrhage, flatulence

* Very common in paediatric ITP

Uncommon Dry mouth, glossodynia, abdominal tenderness, faecesdiscoloured, food poisoning, frequent bowelmovements, haematemesis, oral discomfort

Hepatobiliary disorders Very Alanine aminotransferase increased†common

Common Aspartate aminotransferase increased†,hyperbilirubinaemia, hepatic function abnormal

Uncommon Cholestasis, hepatic lesion, hepatitis, drug-induced liverinjury

Skin and subcutaneous tissue Common Rash, alopecia, hyperhidrosis, pruritus generalised,disorders petechiae

Uncommon Urticaria, dermatosis, cold sweat, erythema, melanosis,pigmentation disorder, skin discolouration, skinexfoliation

Musculoskeletal and Very Back painconnective tissue disorders common

Common Myalgia, muscle spasm, musculoskeletal pain, bonepain

Uncommon Muscular weakness

Renal and urinary disorders Common Proteinuria, blood creatinine increased, thromboticmicroangiopathy with renal failure‡

Uncommon Renal failure, leukocyturia, lupus nephritis, nocturia,blood urea increased, urine protein/creatinine ratioincreased

Reproductive system and Common Menorrhagiabreast disorders

General disorders and Common Pyrexia*, chest pain, astheniaadministration site *Very common in paediatric ITPconditions Uncommon Feeling hot, vessel puncture site haemorrhage, feelingjittery, inflammation of wound, malaise, sensation offoreign body

Investigations Common Blood alkaline phosphatase increased

Uncommon Blood albumin increased, protein total increased, bloodalbumin decreased, pH urine increased

Injury, poisoning and Uncommon Sunburnprocedural complications♦ Additional adverse reactions observed in paediatric studies (aged 1 to 17 years).† Increase of alanine aminotransferase and aspartate aminotransferase may occur simultaneously, althoughat a lower frequency.‡ Grouped term with preferred terms acute kidney injury and renal failure.

Table 5 Adverse reactions in the HCV study population (in combination with anti-viralinterferon and ribavirin therapy)

System organ class Frequency Adverse reaction

Infections and infestations Common Urinary tract infection, upper respiratory tractinfection, bronchitis, nasopharyngitis, influenza, oralherpes

Uncommon Gastroenteritis, pharyngitis

Neoplasms benign, malignant Common Hepatic neoplasm malignantand unspecified (incl cysts andpolyps)

Blood and lymphatic system Very Anaemiadisorders common

Common Lymphopenia

Uncommon Haemolytic anaemia

Metabolism and nutrition Very Decreased appetitedisorders common

Common Hyperglycaemia, abnormal loss of weight

Psychiatric disorders Common Depression, anxiety, sleep disorder

Uncommon Confusional state, agitation

Nervous system disorders Very Headachecommon

Common Dizziness, disturbance in attention, dysgeusia, hepaticencephalopathy, lethargy, memory impairment,paraesthesia

Eye disorders Common Cataract, retinal exudates, dry eye, ocular icterus,retinal haemorrhage

Ear and labyrinth disorders Common Vertigo

Cardiac disorders Common Palpitations

Respiratory, thoracic and Very Coughmediastinal disorders common

Common Dyspnoea, oropharyngeal pain, dyspnoea exertional,productive cough

Gastrointestinal disorders Very Nausea, diarrhoeacommon

Common Vomiting, ascites, abdominal pain, abdominal painupper, dyspepsia, dry mouth, constipation, abdominaldistension, toothache, stomatitis, gastrooesophagealreflux disease, haemorrhoids, abdominal discomfort,varices oesophageal

Uncommon Oesophageal varices haemorrhage, gastritis, aphthousstomatitis

Hepatobiliary disorders Common Hyperbilirubinaemia, jaundice, drug-induced liverinjury

Uncommon Portal vein thrombosis, hepatic failure

Skin and subcutaneous tissue Very Pruritusdisorders common

Common Rash, dry skin, eczema, rash pruritic, erythema,hyperhidrosis, pruritus generalised, alopecia

Uncommon Skin lesion, skin discolouration, skinhyperpigmentation, night sweats

Musculoskeletal and Very Myalgiaconnective tissue disorder common

Common Arthralgia, muscle spasms, back pain, pain inextremity, musculoskeletal pain, bone pain

Renal and urinary disorders Uncommon Thrombotic microangiopathy with acute renalfailure†, dysuria

General disorders and Very Pyrexia, fatigue, influenza-like illness, asthenia, chillsadministration site conditions common

Common Irritability, pain, malaise, injection site reaction, non-cardiac chest pain, oedema, oedema peripheral

Uncommon Injection site pruritus, injection site rash, chestdiscomfort

Investigations Common Blood bilirubin increased, weight decreased, whiteblood cell count decreased, haemoglobin decreased,neutrophil count decreased, international normalisedratio increased, activated partial thromboplastin timeprolonged, blood glucose increased, blood albumindecreased

Uncommon Electrocardiogram QT prolonged† Grouped term with preferred terms oliguria, renal failure and renal impairment.

Table 6 Adverse reactions in the SAA study population

System organ class Frequency Adverse reaction

Blood and lymphatic system Common Neutropenia, splenic infarctiondisorders

Metabolism and nutrition Common Iron overload, decreased appetite, hypoglycaemia,disorders increased appetite

Psychiatric disorders Common Anxiety, depression

Nervous system disorders Very Headache, dizzinesscommon

Common Syncope

Eye disorders Common Dry eye, cataract, ocular icterus, vision blurred,visual impairment, vitreous floaters

Respiratory, thoracic and Very Cough, oropharyngeal pain, rhinorrhoeamediastinal disorders common

Common Epistaxis

Gastrointestinal disorders Very Diarrhoea, nausea, abdominal paincommon

Common Oral mucosal blistering, oral pain, vomiting,abdominal discomfort, constipation, gingivalbleeding, abdominal distension, dysphagia, faecesdiscoloured, swollen tongue, gastrointestinal motilitydisorder, flatulence

Hepatobiliary disorders Very Transaminases increasedcommon

Common Blood bilirubin increased (hyperbilirubinemia),jaundice

Not known Drug-induced liver injury

Skin and subcutaneous tissue Common Petechiae, rash, pruritus, urticaria, skin lesion, rashdisorders macular

Not known Skin discolouration, skin hyperpigmentation

Musculosketal and connective Very Arthralgia, pain in extremity, muscle spasmstissue disorders common

Common Back pain, myalgia, bone pain

Renal and urinary disorders Common Chromaturia

General disorders and Very Fatigue, pyrexia, chillsadministration site conditions common

Common Asthenia, oedema peripheral, malaise

Investigations Common Blood creatine phosphokinase increased

Thrombotic/thromboembolic events (TEEs)

In 3 controlled and 2 uncontrolled clinical studies among adult ITP patients receiving eltrombopag(n=446), 17 patients experienced a total of 19 TEEs, which included (in descending order ofoccurrence) 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 (n=288, Safety population), following 2 weeks’ treatment in preparationfor invasive procedures, 6 of 143 (4%) adult patients with chronic liver disease receiving eltrombopagexperienced 7 TEEs of the portal venous system and 2 of 145 (1%) patients in the placebo groupexperienced 3 TEEs. Five of the 6 patients treated with eltrombopag experienced the TEE at a plateletcount >200 000/µl

No specific risk factors were identified in those patients who experienced a TEE with the exception ofplatelet counts ≥200 000/µl (see section 4.4).

In controlled studies in thrombocytopenic patients with HCV (n=1 439), 38 out of 955 patients (4%)treated with eltrombopag experienced a TEE and 6 out of 484 patients (1%) in the placebo groupexperienced TEEs. Portal vein thrombosis was the most common TEE in both treatment groups (2% inpatients treated with eltrombopag versus < 1% for placebo) (see section 4.4). Patients with lowalbumin levels (≤ 35 g/l) or MELD ≥10 had a 2-fold greater risk of TEEs than those with higheralbumin levels; those aged ≥60 years had a 2-fold greater risk of TEEs compared to younger patients.

Hepatic decompensation (use with interferon)

Chronic HCV patients with cirrhosis may be at risk of hepatic decompensation when receiving alfainterferon therapy. In 2 controlled clinical studies in thrombocytopenic patients with HCV, hepaticdecompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterialperitonitis) was reported more frequently in the eltrombopag arm (11%) than in the placebo arm (6%).

In patients with low albumin levels (≤35 g/l) or MELD score ≥10 at baseline, there was a 3-foldgreater risk of hepatic decompensation and an increase in the risk of a fatal adverse event compared tothose with less advanced liver disease. Eltrombopag should only be administered to such patients aftercareful consideration of the expected benefits in comparison with the risks. Patients with thesecharacteristics should be closely monitored for signs and symptoms of hepatic decompensation (seesection 4.4).

In the controlled clinical studies in chronic ITP with eltrombopag, increases in serum ALT, AST andbilirubin were observed (see section 4.4).

These findings were mostly mild (Grade 1-2), reversible and not accompanied by clinically significantsymptoms that would indicate an impaired liver function. Across the 3 placebo-controlled studies inadults with chronic ITP, 1 patient in the placebo group and 1 patient in the eltrombopag groupexperienced a Grade 4 liver test abnormality. In two placebo-controlled studies in paediatric patients(aged 1 to 17 years) with chronic ITP, ALT 3 x ULN was reported in 4.7% and 0% of theeltrombopag and placebo groups, respectively.

In 2 controlled clinical studies in patients with HCV, ALT or AST 3 x ULN was reported in 34% and38% of the eltrombopag and placebo groups, respectively. Most patients receiving eltrombopag incombination with peginterferon/ribavirin therapy will experience indirect hyperbilirubinaemia.

Overall, total bilirubin ≥1.5 x ULN was reported in 76% and 50% of the eltrombopag and placebogroups, respectively.

In the single-arm phase II monotherapy refractory SAA study, concurrent ALT or AST >3 x ULNwith total (indirect) bilirubin >1.5 x ULN were reported in 5% of patients. Total bilirubin >1.5 x ULNoccurred in 14% of patients.

Thrombocytopenia following discontinuation of treatment

In the 3 controlled clinical ITP studies, transient decreases in platelet counts to levels lower thanbaseline were observed following discontinuation of treatment in 8% and 8% of the eltrombopag andplacebo groups, respectively (see section 4.4).

Across the programme, no patients had evidence of clinically relevant bone marrow abnormalities orclinical findings that would indicate bone marrow dysfunction. In a small number of ITP patients,eltrombopag treatment was discontinued due to bone marrow reticulin (see section 4.4).

Cytogenetic abnormalities

In the phase II refractory SAA clinical study with eltrombopag with a starting dose of 50 mg/day(escalated every 2 weeks to a maximum of 150 mg/day) (ELT112523), the incidence of newcytogenetic abnormalities was observed in 17.1% of adult patients [7/41 (where 4 of them had changesin chromosome 7)]. The median time on study to a cytogenetic abnormality was 2.9 months.

In the phase II refractory SAA clinical study with eltrombopag at a dose of 150 mg/day (with ethnic orage related modifications as indicated) (ELT116826), the incidence of new cytogenetic abnormalitieswas observed in 22.6% of adult patients [7/31 (where 3 of them had changes in chromosome 7)]. All7 patients had normal cytogenetics at baseline. Six patients had cytogenetic abnormality at Month 3 ofeltrombopag therapy and one patient had cytogenetic abnormality at Month 6.

Haematologic malignancies

In the single-arm, open-label study in SAA, three (7%) patients were diagnosed with MDS followingtreatment with eltrombopag, in the two ongoing studies (ELT116826 and ELT116643), 1/28 (4%) and1/62 (2%) patient has been diagnosed with MDS or AML in each study.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In the event of overdose, platelet counts may increase excessively and result inthrombotic/thromboembolic complications. In case of an overdose, consideration should be given tooral administration of a metal cation-containing preparation, such as calcium, aluminium, ormagnesium preparations to chelate eltrombopag and thus limit absorption. Platelet counts should beclosely monitored. Treatment with eltrombopag should be reinitiated in accordance with dosing andadministration recommendations (see section 4.2).

In the clinical studies there was one report of overdose where the patient ingested 5 000 mg ofeltrombopag. Reported adverse reactions included mild rash, transient bradycardia, ALT and ASTelevation, and fatigue. Liver enzymes measured between Days 2 and 18 after ingestion peaked at a1.6-fold ULN in AST, a 3.9-fold ULN in ALT, and a 2.4-fold ULN in total bilirubin. The plateletcounts were 672 000/µl on Day 18 after ingestion and the maximum platelet count was 929 000/µl. Allevents 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 ofeltrombopag.

Pharmacotherapeutic group: Antihemorrhagics, other systemic hemostatics. ATC code: B02BX 05.

TPO is the main cytokine involved in regulation of megakaryopoiesis and platelet production, and isthe endogenous ligand for the TPO-R. Eltrombopag interacts with the transmembrane domain of thehuman TPO-R and initiates signalling cascades similar but not identical to that of endogenousthrombopoietin (TPO), inducing proliferation and differentiation from bone marrow progenitor cells.

Immune (primary) thrombocytopenia (ITP) 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 ITP. Overall,eltrombopag was administered to 277 ITP patients for at least 6 months and 202 patients for at least1 year. The single-arm phase II study TAPER (CETB115J2411) evaluated the safety and efficacy ofeltrombopag and its ability to induce sustained response after treatment discontinuation in 105 adult

ITP patients who relapsed or failed to respond to first-line corticosteroid treatment.

Double-blind placebo-controlled studies

RAISE:

197 ITP patients were randomised 2:1, eltrombopag (n=135) to placebo (n=62), and randomisationwas stratified based upon splenectomy status, use of ITP medicinal products at baseline and baselineplatelet count. The dose of eltrombopag was adjusted during the 6-month treatment period based onindividual platelet counts. All patients initiated treatment with eltrombopag 50 mg. From Day 29 tothe end of treatment, 15 to 28% of eltrombopag-treated patients were maintained on ≤25 mg and 29 to53% received 75 mg.

In addition, patients could taper off concomitant ITP medicinal products and receive rescue treatmentsas dictated by local standard of care. More than half of all patients in each treatment group had ≥3prior ITP therapies and 36% had a prior splenectomy.

Median platelet counts at baseline were 16 000/l for both treatment groups and in the eltrombopaggroup were maintained above 50 000/µl at all on-therapy visits starting at Day 15; in contrast, medianplatelet counts in the placebo group remained <30 000/µl throughout the study.

Platelet count response between 50 000-400 000/l in the absence of rescue treatment was achieved bysignificantly more patients in the eltrombopag treated group during the 6-month treatment period,p <0.001 (Table 7). Fifty-four percent of the eltrombopag-treated patients and 13% of placebo-treatedpatients achieved this level of response after 6 weeks of treatment. A similar platelet response wasmaintained throughout the study, with 52% and 16% of patients responding at the end of the 6-monthtreatment period.

Table 7 Secondary efficacy results from RAISE

Eltrombopag Placebo

N=135 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 51 (38) 4 (7)400 000/l), n (%)<0.001p-value a

Patients with bleeding (WHO Grades 1-4) at any time during 106 (79) 56 (93)6 months, n (%) 0.012p-value a

Patients with bleeding (WHO Grades 2-4) at any time during 44 (33) 32 (53)6 months, n (%)0.002p-value a

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 37 (59) 10 (32)therapy, n (%)ba 0.016p-valuea Logistic regression model adjusted for randomisation stratification variables.b 21 out of 63 (33%) patients treated with eltrombopag who were taking an ITP medicinal product atbaseline permanently discontinued all baseline ITP medicinal products.

At baseline, more than 70% of ITP 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) andclinically 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 ITP patients who had anincrease in platelet counts to 50 000/l at Day 43 from a baseline of <30 000/l; patients whowithdrew prematurely due to a platelet count 200 000/l were considered responders, those thatdiscontinued for any other reason were considered non-responders irrespective of platelet count. Atotal of 114 patients with previously treated ITP were randomised 2:1 eltrombopag (n=76) to placebo(n=38) (Table 8).

Table 8 Efficacy results from TRA100773B

Eltrombopag Placebo

N=76 N=38

Key primary endpoints

Eligible for efficacy analysis, n 73 37

Patients with platelet count 50 000/l after up to 42 days 43 (59) 6 (16)of dosing (compared to a baseline count of <30 000/l), n(%)<0.001p-valuea

Key secondary endpoints

Patients with a Day 43 bleeding assessment, n 51 30

Bleeding (WHO Grades 1-4) n (%) 20 (39) 18 (60)a 0.029p-valuea Logistic regression model adjusted for randomisation stratification variables.

In both RAISE and TRA100773B the response to eltrombopag relative to placebo was similarirrespective of ITP medicinal product use, splenectomy status and baseline platelet count (≤15 000/µl,>15 000/µl) at randomisation.

In RAISE and TRA100773B studies, in the subgroup of ITP patients with baseline platelet count≤15 000/μl the median platelet counts did not reach the target level (>50 000/l), although in bothstudies 43% of these patients treated with eltrombopag responded after 6 weeks of treatment. Inaddition, in the RAISE study, 42% of patients with baseline platelet count ≤15 000/μl treated witheltrombopag responded at the end of the 6-month treatment period. Forty-two to 60% of theeltrombopag-treated patients in the RAISE study were receiving 75 mg from Day 29 to the end oftreatment.

Open-label non-controlled studies

REPEAT (TRA108057):

This open-label, repeat-dose study (3 cycles of 6 weeks of treatment, followed by 4 weeks offtreatment) showed that episodic use with multiple courses of eltrombopag has demonstrated no loss ofresponse.

EXTEND (TRA105325):

Eltrombopag was administered to 302 ITP patients in this open-label extension study, 218 patientscompleted 1 year, 180 completed 2 years, 107 completed 3 years, 75 completed 4 years, 34 completed5 years and 18 completed 6 years. The median baseline platelet count was 19 000/l prior toeltrombopag administration. Median platelet counts at 1, 2, 3, 4, 5, 6 and 7 years on study were85 000/l, 85 000/l, 105 000/l, 64 000/l, 75 000/l, 119 000/l and 76 000/l, respectively.

TAPER (CETB115J2411):

This was a single-arm phase II study including ITP patients treated with eltrombopag after first-linecorticosteroid failure irrespective of time since diagnosis. A total of 105 patients were enrolled on thestudy and started eltrombopag treatment on 50 mg once daily (25 mg once daily for patients of East-/Southeast-Asian ancestry). The dose of eltrombopag was adjusted during the treatment period basedon individual platelet counts with the goal to achieve a platelet count ≥100 000/l.

Of the 105 patients who were enrolled in the study and who received at least one dose of eltrombopag,69 patients (65.7%) completed treatment and 36 patients (34.3%) discontinued treatment early.

Analysis of sustained response off treatment

The primary endpoint was the proportion of patients with sustained response off treatment until

Month 12. Patients who reached a platelet count of ≥100 000/µl and maintained platelet counts around100 000/µl for 2 months (no counts below 70 000/µl) were eligible for tapering off eltrombopag andtreatment discontinuation. To be considered as having achieved a sustained response off treatment, apatient had to maintain platelet counts ≥30 000/µl, in the absence of bleeding events or the use ofrescue therapy, both during the treatment tapering period and following discontinuation of treatmentuntil Month 12.

The duration of tapering was individualised depending on the starting dose and the response of thepatient. The tapering schedule recommended dose reductions of 25 mg every 2 weeks if the plateletcounts were stable. After the daily dose was reduced to 25 mg for 2 weeks, the dose of 25 mg was thenonly administered on alternate days for 2 weeks until treatment discontinuation. The tapering wasdone in smaller decrements of 12.5 mg every second week for patients of East-/Southeast-Asianancestry. If a relapse (defined as platelet count <30 000/µl) occurred, patients were offered a newcourse of eltrombopag at the appropriate starting dose.

Eighty-nine patients (84.8%) achieved a complete response (platelet count ≥100 000/µl) (Step 1,

Table 9) and 65 patients (61.9%) maintained the complete response for at least 2 months with noplatelet counts below 70 000/µl (Step 2, Table 9). Forty-four patients (41.9%) were able to be taperedoff eltrombopag until treatment discontinuation while maintaining platelet counts ≥30 000/µl in theabsence of bleeding events or the use of rescue therapy (Step 3, Table 9).

The study met the primary objective by demonstrating that eltrombopag was able to induce sustainedresponse off treatment, in the absence of bleeding events or the use of rescue therapy, by Month 12 in32 of the 105 enrolled patients (30.5%; p<0.0001; 95% CI: 21.9, 40.2) (Step 4, Table 9). By Month 24,20 of the 105 enrolled patients (19.0%; 95% CI: 12.0, 27.9) maintained sustained response offtreatment in the absence of bleeding events or the use of rescue therapy (Step 5, Table 9).

The median duration of sustained response after treatment discontinuation to Month 12 was33.3 weeks (min-max: 4-51), and the median duration of sustained response after treatmentdiscontinuation to Month 24 was 88.6 weeks (min-max: 57-107).

After tapering off and discontinuation of eltrombopag treatment, 12 patients had a loss of response, 8of them re-started eltrombopag and 7 had a recovery response.

During the 2-year follow-up, 6 out of 105 patients (5.7%) experienced thromboembolic events, ofwhich 3 patients (2.9%) experienced deep vein thrombosis, 1 patient (1.0%) experienced superficialvein thrombosis, 1 patient (1.0%) experienced cavernous sinus thrombosis, 1 patient (1.0%)experienced cerebrovascular accident and 1 patient (1.0%) experienced pulmonary embolism. Of the6 patients, 4 patients experienced thromboembolic events that were reported at or greater than

Grade 3, and 4 patients experienced thromboembolic event that were reported as serious. No fatalcases were reported.

Twenty out of 105 patients (19.0%) experienced mild to severe haemorrhage events on treatmentbefore tapering started. Five out of 65 patients (7.7%) who started tapering experienced mild tomoderate haemorrhage events during tapering. No severe haemorrhage event occurred during tapering.

Two out of 44 patients (4.5%) who tapered off and discontinued eltrombopag treatment experiencedmild to moderate haemorrhage events after treatment discontinuation until Month 12. No severehaemorrhage event occurred during this period. None of the patients who discontinued eltrombopagand entered the second year follow-up experienced haemorrhage event during the second year. Twofatal intracranial haemorrhage events were reported during the 2-year follow-up. Both events occurredon treatment, not in the context of tapering. The events were not considered to be related to studytreatment.

The overall safety analysis is consistent with previously reported data and the risk-benefit assessmentremained unchanged for the use of eltrombopag in patients with ITP.

Table 9 Proportion of patients with sustained response off treatment at Month 12 and at

Month 24 (full analysis set) in TAPER

All patients Hypothesis testing

N=105n (%) 95% CI p-value Reject H0

Step 1: Patients who reached platelet count ≥100 000/µl at least 89 (84.8) (76.4, 91.0)once

Step 2: Patients who maintained stable platelet count for 65 (61.9) (51.9, 71.2)2 months after reaching 100 000/µl (no counts<70 000/µl)

Step 3: Patients who were able to be tapered off eltrombopag 44 (41.9) (32.3, 51.9)until treatment discontinuation, maintaining platelet count≥30 000/µl in the absence of bleeding events or use ofany rescue therapy

Step 4: Patients with sustained response off treatment until 32 (30.5) (21.9, 40.2) <0.0001* Yes

Month 12, with platelet count maintained ≥30 000/µl inthe absence of bleeding events or use of any rescuetherapy

Step 5: Patients with sustained response off treatment from 20 (19.0) (12.0, 27.9)

Month 12 to Month 24, maintaining platelet count≥30 000/µl in the absence of bleeding events or use ofany rescue therapy

N: The total number of patients in the treatment group. This is the denominator for percentage (%) calculation.

n: Number of patients in the corresponding category.

The 95% CI for the frequency distribution was computed using Clopper-Pearson exact method. Clopper-Pearson test was usedfor testing whether the proportion of responders was >15%. CI and p-values are reported.

* Indicates statistical significance (one-sided) at the 0.05 level.

Results of response on treatment analysis by time since ITP diagnosis

An ad-hoc analysis was conducted on the n=105 patients by time since ITP diagnosis to assess theresponse to eltrombopag across four different ITP categories by time since diagnosis (newly diagnosed

ITP <3 months, persistent ITP 3 to <6 months, persistent ITP 6 to ≤12 months, and chronic ITP>12 months). 49% of patients (n=51) had an ITP diagnosis of <3 months, 20% (n=21) of 3 to<6 months, 17% (n=18) of 6 to ≤12 months and 14% (n=15) of >12 months.

Until the cut-off date (22-Oct-2021), patients were exposed to eltrombopag for a median (Q1-Q3)duration of 6.2 months (2.3-12.0 months). The median (Q1-Q3) platelet count at baseline was16 000/l (7 800-28 000/l).

Platelet count response, defined as a platelet count ≥50 000/l at least once by Week 9 without rescuetherapy, was achieved in 84% (95% CI: 71% to 93%) of newly diagnosed ITP patients, 91% (95% CI:

70% to 99%) and 94% (95% CI: 73% to 100%) of persistent ITP patients (i.e. with ITP diagnosis 3 to<6 months and 6 to ≤12 months, respectively), and in 87% (95% CI: 60% to 98%) of chronic ITPpatients.

The rate of complete response, defined as platelet count ≥100 000/l at least once by Week 9 withoutrescue therapy, was 75% (95% CI: 60% to 86%) in newly diagnosed ITP patients, 76% (95% CI: 53%to 92%) and 72% (95% CI: 47% to 90%) in persistent ITP patients (ITP diagnosis 3 to <6 months and6 to ≤12 months, respectively), and 87% (95% CI: 60% to 98%) in chronic ITP patients.

The rate of durable response, defined as a platelet count ≥50 000/l for at least 6 out of 8 consecutiveassessments without rescue therapy during the first 6 months on study, was 71% (95% CI: 56% to 83%)in newly diagnosed ITP patients, 81% (95% CI: 58% to 95%) and 72% (95% CI: 47% to 90.3%) inpersistent ITP patients (ITP diagnosis 3 to <6 months and 6 to ≤12 months, respectively), and 80% (95%

CI: 52% to 96%) in chronic ITP patients.

When assessed with the WHO Bleeding Scale, the proportion of newly diagnosed and persistent ITPpatients without bleeding at Week 4 ranged from 88% to 95% compared to 37% to 57% at baseline.

For chronic ITP patients it was 93% compared to 73% at baseline.

The safety of eltrombopag was consistent across all ITP categories and in line with its known safetyprofile.

Clinical studies comparing eltrombopag to other treatment options (e.g. splenectomy) have not beenconducted. The long-term safety of eltrombopag should be considered prior to starting therapy.

Paediatric population (aged 1 to 17 years)

The safety and efficacy of eltrombopag in paediatric patients have been investigated in two studies.

TRA115450 (PETIT2):

The primary endpoint was a sustained response, defined as the proportion of patients receivingeltrombopag, compared to placebo, achieving platelet counts ≥50 000/µl for at least 6 out of 8 weeks(in the absence of rescue therapy), between weeks 5 to 12 during the double-blind randomised period.

Patients were diagnosed with chronic ITP for at least 1 year and were refractory or relapsed to at leastone prior ITP therapy or unable to continue other ITP treatments for a medical reason and had plateletcount <30 000/µl. Ninety-two patients were randomised by three age cohort strata (2:1) toeltrombopag (n=63) or placebo (n=29). The dose of eltrombopag could be adjusted based onindividual platelet counts.

Overall, a significantly greater proportion of eltrombopag patients (40%) compared with placebopatients (3%) achieved the primary endpoint (Odds Ratio: 18.0 [95% CI: 2.3, 140.9] p <0.001) whichwas similar across the three age cohorts (Table 10).

Table 10 Sustained platelet response rates by age cohort in paediatric patients with chronic

ITP

Eltrombopag Placebon/N (%) n/N (%)[95% CI] [95% CI]

Cohort 1 (12 to 17 years) 9/23 (39%) 1/10 (10%)[20%, 61%] [0%, 45%]

Cohort 2 (6 to 11 years) 11/26 (42%) 0/13 (0%)[23%, 63%] [N/A]

Cohort 3 (1 to 5 years) 5/14 (36%) 0/6 (0%)[13%, 65%] [N/A]

Statistically fewer eltrombopag patients required rescue treatment during the randomised periodcompared to placebo patients (19% [12/63] vs. 24% [7/29], p=0.032).

At baseline, 71% of patients in the eltrombopag group and 69% in the placebo group reported anybleeding (WHO Grades 1-4). At Week 12, the proportion of eltrombopag patients reporting anybleeding was decreased to half of baseline (36%). In comparison, at Week 12, 55% of placebo patientsreported any bleeding.

Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phaseof the study and 53% (8/15) of patients were able to reduce (n=1) or discontinue (n=7) baseline ITPtherapy, mainly corticosteroids, without needing rescue therapy.

TRA108062 (PETIT):

The primary endpoint was the proportion of patients achieving platelet counts ≥50 000/µl at least oncebetween weeks 1 and 6 of the randomised period. Patients were diagnosed with ITP for at least6 months and were refractory or relapsed to at least one prior ITP therapy with a platelet count<30 000/µl (n=67). During the randomised period of the study, patients were randomised by three agecohort strata (2:1) to eltrombopag (n=45) or placebo (n=22). The dose of eltrombopag could beadjusted based on individual platelet counts.

Overall, a significantly greater proportion of eltrombopag patients (62%) compared with placebopatients (32%) met the primary endpoint (Odds Ratio: 4.3 [95% CI: 1.4, 13.3] p=0.011).

Sustained response was seen in 50% of the initial responders during 20 out of 24 weeks in the

PETIT 2 study and 15 out of 24 weeks in the PETIT study.

Chronic hepatitis C associated thrombocytopenia studies

The efficacy and safety of eltrombopag for the treatment of thrombocytopenia in patients with HCVinfection were evaluated in two randomised, double-blind, placebo-controlled studies. ENABLE 1utilised peginterferon alfa-2a plus ribavirin for antiviral treatment and ENABLE 2 utilisedpeginterferon alfa-2b plus ribavirin. Patients did not receive direct acting antiviral agents. In bothstudies, patients with a platelet count of <75 000/µl were enrolled and stratified by platelet count(<50 000/µl and ≥50 000/µl to <75 000/µl), screening HCV RNA (<800 000 IU/ml and≥800 000 IU/ml), and HCV genotype (genotype 2/3, and genotype 1/4/6).

Baseline disease characteristics were similar in both studies and were consistent with compensatedcirrhotic HCV patient population. The majority of patients were HCV genotype 1 (64%) and hadbridging fibrosis/cirrhosis. Thirty-one percent of patients had been treated with prior HCV therapies,primarily pegylated interferon plus ribavirin. The median baseline platelet count was 59 500/µl in bothtreatment groups: 0.8%, 28% and 72% of the patients recruited had platelet counts <20 000/µl,<50 000/µl and ≥50 000/µl respectively.

The studies consisted of two phases - a pre-antiviral treatment phase and an antiviral treatment phase.

In the pre-antiviral treatment phase, patients received open-label eltrombopag to increase the plateletcount to ≥90 000/µl for ENABLE 1 and ≥100 000/µl for ENABLE 2. The median time to achieve thetarget platelet count ≥90 000/µl (ENABLE 1) or ≥100 000/µl (ENABLE 2) was 2 weeks.

The primary efficacy endpoint for both studies was sustained virologic response (SVR), defined as thepercentage of patients with no detectable HCV-RNA at 24 weeks after completion of the plannedtreatment period.

In both HCV studies, a significantly greater proportion of patients treated with eltrombopag (n=201,21%) achieved SVR compared to those treated with placebo (n=65, 13%) (see Table 11). Theimprovement in the proportion of patients who achieved SVR was consistent across all subgroups inthe randomisation strata (baseline platelet counts (<50 000 vs. >50 000), viral load (<800 000 IU/mlvs. ≥800 000 IU/ml) and genotype (2/3 vs. 1/4/6)).

Table 11 Virologic response in HCV patients in ENABLE 1 and ENABLE 2

Pooled data ENABLE 1a ENABLE 2b

Patients achievingtarget platelet counts 1 439/1 520 (95%) 680/715 (95%) 759/805 (94%)and initiating antiviraltherapy c

Eltrombopag Placebo Eltrombopag Placebo Eltrombopag Placebo

Total number of n=956 n=485 n=450 n=232 n=506 n=253patients enteringantiviral treatmentphase% patients achieving virologic response

Overall SVR d 21 13 23 14 19 13

HCV RNA Genotype

Genotype 2/3 35 25 35 24 34 25

Genotype 1/4/6e 15 8 18 10 13 7

Albumin levels f≤ 35g/l 11 8> 35g/l 25 16

MELD scoref≥ 10 18 10< 10 23 17a Eltrombopag given in combination with peginterferon alfa-2a (180 μg once weekly for 48 weeks forgenotypes 1/4/6; 24 weeks for genotype 2/3) plus ribavirin (800 to 1 200 mg daily in 2 divided dosesorally)b Eltrombopag given in combination with peginterferon alfa-2b (1.5 μg/kg once weekly for 48 weeks forgenotype 1/4/6; 24 weeks for genotype 2/3) plus ribavirin (800 to 1 400 mg orally in 2 divided doses)c Target platelet count was 90 000/µl for ENABLE 1 and 100 000/µl for ENABLE 2. For ENABLE 1,682 patients were randomised to the antiviral treatment phase; however 2 patients then withdrewconsent prior to receiving antiviral therapyd p-value <0.05 for eltrombopag versus placeboe 64% patients participating in ENABLE 1 and ENABLE 2 were genotype 1f Post-hoc analyses

Other secondary findings of the studies included the following: significantly fewer patients treatedwith eltrombopag prematurely discontinued antiviral therapy compared to placebo (45% vs. 60%,p<0.0001). A greater proportion of patients on eltrombopag did not require any antiviral dosereduction as compared to placebo (45% vs. 27%). Eltrombopag treatment delayed and reduced thenumber of peginterferon dose reductions.

The European Medicines Agency has waived the obligation to submit the results of studies witheltrombopag in all subsets of the paediatric population in secondary thrombocytopenia (see section 4.2for information on paediatric use).

Severe aplastic anaemia

Eltrombopag was studied in a single-arm, single-centre, open-label study in 43 patients with SAA withrefractory thrombocytopenia following at least one prior immunosuppressive therapy (IST) and whohad a platelet count ≤30 000/µl.

The majority of patients, 33 (77%), were considered to have ‘primary refractory disease’, defined ashaving no prior adequate response to IST in any lineage. The remaining 10 patients had insufficientplatelet response to prior therapies. All 10 had received at least 2 prior IST regimens and 50% hadreceived at least 3 prior IST regimens. Patients with diagnosis of Fanconi anaemia, infection notresponding to appropriate therapy, PNH clone size in neutrophils of ≥50%, where excluded fromparticipation.

At baseline the median platelet count was 20 000/µl, haemoglobin was 8.4 g/dl, ANC was 0.58 x 109/land absolute reticulocyte count was 24.3 x 109/l. Eighty-six percent of patients were RBC transfusiondependent, and 91% were platelet transfusion dependent. The majority of patients (84%) had receivedat least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline.

The primary endpoint was haematological response assessed after 12 weeks of eltrombopag treatment.

Haematological response was defined as meeting one or more of the following criteria: 1) plateletcount increases to 20 000/µl above baseline or stable platelet counts with transfusion independence fora minimum of 8 weeks; 2) haemoglobin increase by >1.5g/dl, or a reduction in ≥4 units of red bloodcell (RBC) transfusions for 8 consecutive weeks; 3) absolute neutrophil count (ANC) increase of100% or an ANC increase >0.5 x 109/l.

The haematological response rate was 40% (17/43 patients; 95% CI 25, 56), the majority wereunilineage responses (13/17, 76%) whilst there were 3 bilineage and 1 trilineage responses at week 12.

Eltrombopag was discontinued after 16 weeks if no haematological response or transfusionindependence was observed. Patients who responded continued therapy in an extension phase of thestudy. A total of 14 patients entered the extension phase of the trial. Nine of these patients achieved amulti-lineage response, 4 of the 9 remain on treatment and 5 tapered off treatment with eltrombopagand maintained the response (median follow up: 20.6 months, range: 5.7 to 22.5 months). Theremaining 5 patients discontinued treatment, three due to relapse at the month 3 extension visit.

During treatment with eltrombopag 59% (23/39) became platelet transfusion independent (28 dayswithout platelet transfusion) and 27% (10/37) became RBC transfusion independent (56 days without

RBC transfusion). The longest platelet transfusion-free period for non-responders was 27 days(median). The longest platelet transfusion-free period for responders was 287 days (median). Thelongest RBC transfusion-free period for non-responders was 29 days (median). The longest RBCtransfusion-free period for responders was 266 days (median).

Over 50% of responders who were transfusion-dependent at baseline, had >80% reduction in bothplatelet and RBC transfusion requirements compared to baseline.

Preliminary results from a supportive study (Study ELT116826), an ongoing non-randomised,phase II, single-arm, open-label study in refractory SAA patients, showed consistent results. Data arelimited to 21 out of the planned 60 patients with haematological responses reported by 52% of patientsat 6 months. Multilineage responses were reported by 45% of patients.

The efficacy of oral eltrombopag in paediatric patients aged 2 to 17 years with refractory/relapsed(cohort A; n=14) or treatment-naive (cohort B; n=37) SAA was assessed in an open-label,uncontrolled, intra-patient dose escalation study (total N=51) (study CETB115E2201) (see alsosection 4.2). Cohort A consisted of 14 patients with refractory (6 patients) or relapsed (8 patients)

SAA. These 14 patients received one of two treatment regimens: 1) eltrombopag plus horse anti-thymocyte globulin (hATG)/cyclosporine A (CsA) or 2) eltrombopag plus CsA. In cohort B, 37 IST-naive SAA patients were treated with hATG and CsA in addition to eltrombopag. The treatmentduration was 26 weeks with an additional 52-week follow-up period and long-term follow-up of up tothree years.

Eltrombopag starting doses were 25 mg daily in patients aged from 1 to <6 years and 50 mg daily inpatients aged 6 to <18 years, regardless of ethnicity. Intra-patient dose escalations were permittedevery 2 weeks until the patient had either achieved the targeted platelet count or reached the maximumdose (150 mg), whichever occurred first.

The primary objective was to characterise the PK of eltrombopag at the highest individual steady-statedose (see section 5.2). Secondary efficacy objectives were to assess the overall response rate (ORR)and platelet response rate (PRR), and to evaluate platelet and red blood cell transfusion independence.

ORR was defined as the proportion of patients who had either a complete response (CR) or a partialresponse (PR). CR was defined as meeting the criteria platelet and red blood cell transfusionindependence, normal age-adjusted haemoglobin, platelet count >100 x 109/l, and absolute neutrophilcount >1.5 x 109/l. PR was defined as meeting at least two or more of the following criteria: absolutereticulocyte count >30 x 109/l, platelet count >30 x 109/l, absolute neutrophil count >0.5 x 109/l abovebaseline with transfusion independence for at least 28 days for platelet transfusion and 56 days for redblood cell (RBC) transfusion. PRR was also defined as the proportion of patients who had either acomplete response (CR) or a partial response (PR). CR was defined as meeting the criteria plateletcount >100 x 109/l. PR was defined as meeting the criteria platelet count >30 x 109/l.

The median age of the overall population was 10 years old (range: 2 to 17 years), 54.9% of patientswere male, and 58.8% of patients were Caucasian. The median body-mass index (BMI) was17.9 kg/m2. There were 12 patients aged <6 years and 39 patients aged 6 to <18 years.

The ORR was 19.6% at Week 12, 52.9% at Week 26, 45.1% at Week 52, and 45.1% at Week 78 forall patients. The ORR was generally higher in Cohort A than in Cohort B (e.g. 71.4% vs. 45.9% at

Week 26). The PRR was 47.1% at Week 12, 56.9% at Week 26, 51.0% at Week 52, and 49.0% at

Week 78.

Twenty-eight (7 patients in Cohort A and 21 patients in Cohort B) of the 42 patients who were RBCtransfusion-dependent at baseline achieved transfusion independence for at least 56 days during thestudy. The median of the longest RBC transfusion-free period was 266 days for 34 patients (range: 58to 1 637), 321 days (range: 185 to 1 637 days) for Cohort A, and 262 days (range: 58 to 1 296 days)for Cohort B. Thirty-three (8 patients in Cohort A and 25 patients in Cohort B) of the 43 patients whowere platelet transfusion-dependent at baseline achieved transfusion independence for at least 28 daysduring the study. The median of the longest platelet transfusion-free period was 263 days (range: 34 to1 637 days) for 40 patients, 268 days (range: 36 to 1 637 days) for Cohort A, and 250 days (range: 34to 1 289 days) for Cohort B.

Safety results were consistent with the known safety profile of eltrombopag (see section 4.8).

Efficacy results were not sufficient to conclude on the efficacy of eltrombopag in paediatric patientswith SAA.

Pharmacokinetics

The plasma eltrombopag concentration-time data collected in 88 patients with ITP in studies

TRA100773A and TRA100773B were combined with data from 111 healthy adult subjects in apopulation PK analysis. Plasma eltrombopag AUC(0-) and Cmax estimates for ITP patients arepresented (Table 12).

Table 12 Geometric mean (95% confidence intervals) of steady-state plasma eltrombopagpharmacokinetic parameters in adults with ITP

Eltrombopag dose, N AUC a,(0-) g.h/ml C amax , g/mlonce daily30 mg 28 47 (39, 58) 3.78 (3.18, pct. 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-) and Cmax based on population PK post-hoc estimates.

Plasma eltrombopag concentration-time data collected in 590 patients with HCV enrolled in phase IIIstudies TPL103922/ENABLE 1 and TPL108390/ENABLE 2 were combined with data from patientswith HCV enrolled in the phase II study TPL102357 and healthy adult subjects in a population PKanalysis. Plasma eltrombopag Cmax and AUC(0-) estimates for adult patients with HCV enrolled in thephase III studies are presented for each dose studied in Table 13.

Table 13 Geometric mean (95% CI) steady-state plasma eltrombopag pharmacokineticparameters in patients with chronic HCV

Eltrombopag dose N AUC(0-) Cmax(once daily) (g.h/ml) (g/ml)25 mg 330 118 6.40(109, 128) (5.97, 6.86)50 mg 119 166 9.08(143, 192) (7.96, 10.35)75 mg 45 301 16.71(250, 363) (14.26, 19.58)100 mg 96 354 19.19(304, 411) (16.81, 21.91)

AUC(0-) and Cmax based on population PK post-hoc estimates at the highest dose in the data foreach patient.

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 polyvalentcations such as dairy products and mineral supplements significantly reduces eltrombopag exposure(see section 4.2). In a relative bioavailability study in adults, the eltrombopag powder for oralsuspension delivered 22% higher plasma AUC(0-) than the film-coated tablet formulation. Theabsolute 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-relatedmaterial following administration of a single 75 mg eltrombopag solution dose was estimated to be atleast 52%.

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.

Eltrombopag is primarily metabolised through cleavage, oxidation and conjugation with glucuronicacid, glutathione, or cysteine. In a human radiolabel study, eltrombopag accounted for approximately64% of plasma radiocarbon AUC0-. Minor metabolites due to glucuronidation and oxidation werealso detected. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for oxidativemetabolism of eltrombopag. Uridine diphosphoglucuronyl transferase UGT1A1 and UGT1A3 areresponsible for glucuronidation, and bacteria in the lower gastrointestinal tract may be responsible forthe cleavage pathway.

Absorbed eltrombopag is extensively metabolised. The predominant route of eltrombopag excretion isvia 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 forapproximately 20% of the dose. The plasma elimination half-life of eltrombopag is approximately 21-32 hours.

Based on a human study with radiolabelled eltrombopag, glucuronidation plays a minor role in themetabolism of eltrombopag. Human liver microsome studies identified UGT1A1 and UGT1A3 as theenzymes responsible for eltrombopag glucuronidation. Eltrombopag was an inhibitor of a number of

UGT enzymes in vitro. Clinically significant drug interactions involving glucuronidation are notanticipated due to limited contribution of individual UGT enzymes in the glucuronidation ofeltrombopag.

Approximately 21% of an eltrombopag dose could undergo oxidative metabolism. Human livermicrosome studies identified CYP1A2 and CYP2C8 as the enzymes responsible for eltrombopagoxidation. 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 aninhibitor of the BCRP transporter and eltrombopag increased exposure of the OATP1B1 and BCRPsubstrate rosuvastatin in a clinical drug interaction study (see section 4.5). In clinical studies witheltrombopag, a dose reduction of statins by 50% was recommended.

Eltrombopag chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, seleniumand zinc (see sections 4.2 and 4.5).

In vitro studies demonstrated that eltrombopag is not a substrate for the organic anion transporterpolypeptide, OATP1B1, but is an inhibitor of this transporter (IC50 value of 2.7 μM [1.2 μg/ml]). Invitro studies also demonstrated that eltrombopag is a breast cancer resistance protein (BCRP) substrateand inhibitor (IC50 value of 2.7 μM [1.2 μg/ml]).

The pharmacokinetics of eltrombopag have been studied after administration of eltrombopag to adultpatients with renal impairment. Following administration of a single 50 mg dose, the AUC0- ofeltrombopag was 32% to 36% lower in patients with mild to moderate renal impairment, and 60%lower in patients with severe renal impairment compared with healthy volunteers. There wassubstantial variability and significant overlap in exposures between patients with renal impairment andhealthy volunteers. Unbound eltrombopag (active) concentrations for this highly protein-boundmedicinal product were not measured. Patients with impaired renal function should use eltrombopagwith caution and close monitoring, for example by testing serum creatinine and/or urine analysis (seesection 4.2). The efficacy and safety of eltrombopag have not been established in patients with bothmoderate to severe renal impairment and hepatic impairment.

The pharmacokinetics of eltrombopag have been studied after administration of eltrombopag to adultpatients with hepatic impairment. Following the administration of a single 50 mg dose, the AUC0- ofeltrombopag was 41% higher in patients with mild hepatic impairment and 80% to 93% higher inpatients with moderate to severe hepatic impairment compared with healthy volunteers. There wassubstantial variability and significant overlap in exposures between patients with hepatic impairmentand healthy volunteers. Unbound eltrombopag (active) concentrations for this highly protein-boundmedicinal product were not measured.

The influence of hepatic impairment on the pharmacokinetics of eltrombopag following repeatadministration was evaluated using a population pharmacokinetic analysis in 28 healthy adults and714 patients with hepatic impairment (673 patients with HCV and 41 patients with chronic liverdisease of other aetiology). Of the 714 patients, 642 were with mild hepatic impairment, 67 withmoderate hepatic impairment, and 2 with severe hepatic impairment. Compared to healthy volunteers,patients with mild hepatic impairment had approximately 111% (95% CI: 45% to 283%) higherplasma eltrombopag AUC(0-) values and patients with moderate hepatic impairment hadapproximately 183% (95% CI: 90% to 459%) higher plasma eltrombopag AUC(0-) values.

Therefore, eltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score≥5) unless the expected benefit outweighs the identified risk of portal venous thrombosis (seesections 4.2 and 4.4). For patients with HCV initiate eltrombopag at a dose of 25 mg once daily (seesection 4.2).

The influence of East-Asian ethnicity on the pharmacokinetics of eltrombopag was evaluated using apopulation 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 ITPpatients had approximately 49% higher plasma eltrombopag AUC(0-) values as compared to non-East-

Asian patients who were predominantly Caucasian (see section 4.2).

The influence of East-/Southeast-Asian ethnicity on the pharmacokinetics of eltrombopag wasevaluated using a population pharmacokinetic analysis in 635 patients with HCV (145 East-Asians and69 Southeast-Asians). Based on estimates from the population pharmacokinetic analysis, East-/Southeast-Asian patients had approximately 55% higher plasma eltrombopag AUC(0-) values ascompared to patients of other races who were predominantly Caucasian (see section 4.2).

The influence of gender on the pharmacokinetics of eltrombopag was evaluated using a populationpharmacokinetic 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 hadapproximately 23% higher plasma eltrombopag AUC(0-) as compared to male patients, withoutadjustment for body weight differences.

The influence of gender on eltrombopag pharmacokinetics was evaluated using populationpharmacokinetics analysis in 635 patients with HCV (260 females). Based on model estimate, female

HCV patient had approximately 41% higher plasma eltrombopag AUC(0-) as compared to malepatients.

The influence of age on eltrombopag pharmacokinetics was evaluated using populationpharmacokinetics analysis in 28 healthy subjects, 673 patients with HCV, and 41 patients with chronicliver disease of other aetiology ranging from 19 to 74 years old. There are no PK data on the use ofeltrombopag in patients ≥75 years. Based on model estimate, elderly (≥65 years) patients hadapproximately 41% higher plasma eltrombopag AUC(0-) as compared to younger patients (seesection 4.2).

Paediatric population (aged 1 to 17 years)

The pharmacokinetics of eltrombopag have been evaluated in 168 paediatric ITP patients dosed oncedaily in two studies, TRA108062/PETIT and TRA115450/PETIT-2. Plasma eltrombopag apparentclearance following oral administration (CL/F) increased with increasing body weight. The effects ofrace and sex on plasma eltrombopag CL/F estimates were consistent between paediatric and adultpatients. East-/Southeast-Asian paediatric ITP patients had approximately 43% higher plasmaeltrombopag AUC(0-) values as compared to non-Asian patients. Female paediatric ITP patients hadapproximately 25% higher plasma eltrombopag AUC(0-) values as compared to male patients.

The pharmacokinetic parameters of eltrombopag in paediatric patients with ITP are shown in

Table 14.

Table 14 Geometric mean (95% CI) steady-state plasma eltrombopag pharmacokineticparameters in paediatric patients with ITP (50 mg once daily dosing regimen)

Age Cmax AUC(0-τ)(µg/ml) (µg.hr/ml)12 to 17 years (n=62) 6.80 103(6.17, 7.50) (91.1, 116)6 to 11 years (n=68) 10.3 153(9.42, 11.2) (137, 170)1 to 5 years (n=38) 11.6 162(10.4, 12.9) (139, 187)

Data presented as geometric mean (95%CI). AUC(0-) and Cmax based on population PK post-hocestimates.

Plasma eltrombopag PK data collected at the highest individual steady state dose from 38 paediatricpatients with first-line (cohort B) or second-line (cohort A) SAA enrolled in study CETB115E2201 arepresented after adjustment to a common 50 mg dose in Table 15. Overall, eltrombopag clearance waslower and eltrombopag plasma exposure was higher for patients aged 2 to <6 years of age compared topatients aged 6 to <18 years.

Table 15 Eltrombopag steady-state PK parameters in CETB115E2201, adjusted to a 50 mgdose, at the highest individual dose (Week 12 or later) by cohort and age group

Treatment Age group Statistic AUC(0-τ) Cmax(µg.hr/ml) (µg/ml)

Cohort A (N=11) 2 to <6 years n 1 1

Geo-mean 272 16.1

Geo-CV%6 to <18 years n 5 7

Geo-mean 306 14.5

Geo-CV% 63.8 58.2

Cohort B (N=27) 2 to <6 years n 6 8

Geo-mean 502 27.1

Geo-CV% 65.6 40.66 to <18 years n 10 15

Geo-mean 275 15.6

Geo-CV% 52.6 47.2

Total patients (N=38) 2 to <6 years n 7 9

Geo-mean 460 25.6

Geo-CV% 64.9 42.26 to < 18 years n 15 22

Geo-mean 285 15.2

Geo-CV% 54.2 49.5

Cohort A: eltrombopag administered as second-line treatment, Cohort B: eltrombopag administered as first-line treatment

Safety pharmacology and repeat-dose toxicity

Eltrombopag does not stimulate platelet production in mice, rats or dogs because of unique TPOreceptor specificity. Therefore, data from these animals do not fully model potential adverse effectsrelated to the pharmacology of eltrombopag in humans, including the reproduction and carcinogenicitystudies.

Treatment-related cataracts were detected in rodents and were dose and time-dependent. At ≥6 timesthe human clinical exposure in adult ITP patients at 75 mg/day and 3 times the human clinicalexposure in adult HCV patients at 100 mg/day, based on AUC, cataracts were observed in mice after6 weeks and rats after 28 weeks of dosing. At 4 times the human clinical exposure in ITP patients at75 mg/day and 2 times the human exposure in HCV patients at 100 mg/day, based on AUC, cataractswere observed in mice after 13 weeks and in rats after 39 weeks of dosing. At non-tolerated doses inpre-weaning juvenile rats dosed from Days 4-32 (approximately equating to a 2-year-old human at theend of the dosing period), ocular opacities were observed (histology not performed) at 9 times themaximum human clinical exposure in paediatric ITP patients at 75 mg/day, based on AUC. However,cataracts were not observed in juvenile rats given tolerated doses at 5 times the human clinicalexposure in paediatric ITP patients, based on AUC. Cataracts have not been observed in adult dogsafter 52 weeks of dosing at 2 times the human clinical exposure in adult or paediatric ITP patients at75 mg/day and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on

AUC).

Renal tubular toxicity was observed in studies of up to 14 days duration in mice and rats at exposuresthat 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 severeat lower doses and were characterised by a spectrum of regenerative changes. The exposure at thelowest dose was 1.2 or 0.8 times the human clinical exposure based on AUC in adult or paediatric ITPpatients at 75 mg/day and 0.6 times the human clinical exposure in HCV patients at 100 mg/day, basedon AUC. Renal effects were not observed in rats after 28 weeks or in dogs after 52 weeks at exposures4 and 2 times the human clinical exposure in adult ITP patients and 3 and 2 times the human clinicalexposure in paediatric ITP patients at 75 mg/day and 2 times and equivalent to the human clinicalexposure in HCV patients at 100 mg/day, based on AUC.

Hepatocyte degeneration and/or necrosis, often accompanied by increased serum liver enzymes, wasobserved in mice, rats and dogs at doses that were associated with morbidity and mortality or werepoorly tolerated. No hepatic effects were observed after chronic dosing in rats (28 weeks) and in dogs(52 weeks) at 4 or 2 times the human clinical exposure in adult ITP patients and 3 or 2 times thehuman clinical exposure in paediatric ITP patients at 75 mg/day and 2 times or equivalent to thehuman clinical exposure in HCV patients at 100 mg/day, based on AUC.

At poorly tolerated doses in rats and dogs (>10 or 7 times the human clinical exposure in adult orpaediatric ITP patients at 75 mg/day and>4 times the human clinical exposure in HCV patients at100 mg/day, based on AUC), decreased reticulocyte counts and regenerative bone marrow erythroidhyperplasia (rats only) were observed in short-term studies. There were no effects of note on red cellmass or reticulocyte counts after dosing for up to 28 weeks in rats, 52 weeks in dogs and 2 years inmice or rats at maximally tolerated doses which were 2 to 4 times human clinical exposure in adult orpaediatric ITP patients at 75 mg/day and ≤2 times the human clinical exposure in HCV patients at100 mg/day, based on AUC.

Endosteal hyperostosis was observed in a 28-week toxicity study in rats at a non-tolerated dose of60 mg/kg/day (6 times or 4 times the human clinical exposure in adult or paediatric ITP patients at75 mg/day and 3 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC).

There were no bone changes observed in mice or rats after lifetime exposure (2 years) at 4 times or2 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 2 times thehuman clinical exposure in HCV patients at 100 mg/day, based on AUC.

Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to40 mg/kg/day (exposures up to 4 or 2 times the human clinical exposure in adult or paediatric ITPpatients at 75 mg/day and 2 times the human clinical exposure in HCV patients at 100 mg/day, basedon AUC). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two invivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times or 8 times the humanclinical exposure in adult or paediatric ITP patients at 75 mg/day and 7 times the human clinicalexposure in HCV patients at 100 mg/day, based on Cmax). In the in vitro mouse lymphoma assay,eltrombopag was marginally positive (<3-fold increase in mutation frequency). These in vitro and invivo findings suggest that eltrombopag does not pose a genotoxic risk to humans.

Eltrombopag did not affect female fertility, early embryonic development or embryofoetaldevelopment in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure in adult oradolescent (12-17 years old) ITP patients at 75 mg/day and equivalent to the human clinical exposurein HCV patients at 100 mg/day, based on AUC). Also there was no effect on embryofoetaldevelopment in rabbits at doses up to 150 mg/kg/day, the highest dose tested (0.3 to 0.5 times thehuman clinical exposure in ITP patients at 75 mg/day and HCV patients at 100 mg/day, based on

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

ITP patients at 75 mg/day and 3 times the human clinical exposure in HCV patients at 100 mg/day,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 femalefertility study and a low incidence of cervical ribs and reduced foetal body weight in the embryofoetaldevelopment study. Eltrombopag should be used during pregnancy only if the expected benefitjustifies the potential risk to the foetus (see section 4.6). Eltrombopag did not affect male fertility inrats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure in ITPpatients at 75 mg/day and 2 times the human clinical exposure in HCV patients at 100 mg/day, basedon AUC). In the pre- and post-natal development study in rats, there were no undesirable effects onpregnancy, parturition or lactation of F0 female rats at maternally non-toxic doses (10 and20 mg/kg/day) and no effects on the growth, development, neurobehavioural or reproductive functionof the offspring (F1). Eltrombopag was detected in the plasma of all F1 rat pups for the entire 22 hoursampling period following administration of medicinal product to the F0 dams, suggesting that rat pupexposure to eltrombopag was likely via lactation.

In vitro studies with eltrombopag suggest a potential phototoxicity risk; however, in rodents there wasno evidence of cutaneous phototoxicity (10 or 7 times the human clinical exposure in adult orpaediatric ITP patients at 75 mg/day and 5 times the human clinical exposure in HCV patients at100 mg/day, based on AUC) or ocular phototoxicity (4 times the human clinical exposure in adult orpaediatric ITP patients at 75 mg/day and 3 times the human clinical exposure in HCV patients at100 mg/day, based on AUC). Furthermore, a clinical pharmacology study in 36 subjects showed noevidence that photosensitivity was increased following administration of eltrombopag 75 mg. This wasmeasured by delayed phototoxic index. Nevertheless, a potential risk of photoallergy cannot be ruledout since no specific preclinical study could be performed.

At non-tolerated doses in pre-weaning rats, ocular opacities were observed. At tolerated doses, noocular opacities were observed (see above subsection ‘Safety pharmacology and repeat-dose toxicity’).

In conclusion, taking into account the exposure margins based on AUC, a risk of eltrombopag-relatedcataracts in paediatric patients cannot be excluded. There are no findings in juvenile rats to suggest agreater risk of toxicity with eltrombopag treatment in paediatric vs. adult ITP patients.

Revolade 12.5 mg film-coated tablets

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3 years.

This medicinal product does not require any special storage conditions.

Aluminum blisters (PA/Alu/PVC/Alu) in a carton containing 14 or 28 film-coated tablets andmultipacks containing 84 (3 packs of 28) film-coated tablets.

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Revolade 12.5 mg film-coated tablets

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Revolade 25 mg film-coated tablets

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Date of first authorisation: 11 March 2010

Date of latest renewal: 15 January 2015

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