Revolade is used for the following indications:

•           For the treatment of adult patients with immune (idiopathic) thrombocytopenic purpura (ITP) lasting at least 6 months from diagnosis who have not responded sufficiently to other treatment options (e.g. corticosteroids, immunoglobulins or splenectomy) when there is an increased risk of bleeding due to pronounced thrombocytopenia.

•           For the treatment of paediatric patients (aged 1 year and older) with immune (idiopathic) thrombocytopenic purpura (ITP) lasting at least 6 months from diagnosis and a significant tendency to bleed who have not responded to an established treatment (e.g. IVIG, corticosteroids) and for whom splenectomy is not a treatment option.

•           For the treatment of thrombocytopenia in adult patients aged 18 years and older with chronic hepatitis C virus (HCV) infection, where the degree of thrombocytopenia prevents the initiation of interferon-based therapy and/or the ability to optimally maintain it.

Revolade has not been tested in combination with HCV protease inhibitors (boceprevir, telaprevir).

•           For the treatment of cytopenias in adult patients with acquired severe aplastic anaemia (SAA) who are either treatment-refractory or who have undergone considerable prior therapy and who are not eligible for a haematopoietic stem cell transplant at the time of indication.

•           For the first-line treatment of acquired severe aplastic anaemia (SAA) in combination with standard immunosuppressive therapy in adult and paediatric patients aged 2 years and over who are unsuitable for haematopoietic stem cell transplantation at the time of diagnosis.

Revolade dosage regimens must be individualised based on the patient’s platelet count.

The lowest effective dosage regimen to maintain platelet counts should always be used, as clinically indicated.

After any Revolade dose adjustment platelet counts should be monitored at least weekly for two to three weeks. Any new dose adjustment can only be considered after waiting at least two weeks, once the effect of the previous adjustment on the patient’s platelet count has become apparent.

The tablets and suspension are taken orally.

Revolade should be taken at least two hours before or at least four hours after products such as antacids, dairy products or mineral supplements containing polyvalent cations (e.g. aluminium, calcium, iron, magnesium, selenium and zinc). Revolade may be taken with food that does not contain calcium or that only contains a small amount of calcium (<50 mg) (see “Interactions” and “Pharmacokinetics”).

Immune (idiopathic) thrombocytopenic purpura (ITP)

To reduce the risk of bleeding, after the start of treatment adjust the dose to achieve and maintain a platelet count of ³50,000/ml.

Dose adjustments are based on the platelet count response.

A dose of 75 mg once daily should not be exceeded. Revolade should only be used in patients with an increased bleeding risk due to pronounced thrombocytopenia. The platelet count should only be increased to a value required to avoid bleeding events and not to the physiological range.

Patients should be clinically assessed periodically and a decision taken by the treating physician on a case-by-case basis about whether to continue the treatment. Recurrence of thrombocytopenia is possible following discontinuation of treatment.

The treatment of ITP with Revolade must be stopped if, after four weeks of therapy with 75 mg/day, platelet counts do not increase sufficiently.

Adults

Starting dose

The recommended starting dose of Revolade in ITP is 50 mg once daily. For patients of Asian descent and for patients with hepatic impairment the starting dose should be reduced to 25 mg (see “Special patient populations”).

Monitoring and dose adjustment

The standard dose adjustment is by 25 mg increments/decrements. However, in some ITP patients a combination of different tablet strengths on different days may be required.

Table 1: Dose adjustment of Revolade in adult ITP patients

Paediatric patients

The recommended starting dose of Revolade in ITP is based on body weight (BW) and ethnicity.

The dose adjustment should be carried out taking into consideration the clinical necessity and depending on any planned measures (e.g. neurosurgical procedures). The target platelet count is >50‘000/µl and should be titrated as clinically necessary.

Paediatric patients aged 6 to 17 years

Starting dose

Non-Asian descent, BW >27 kg: 50 mg once daily

Non-Asian descent, BW <27 kg: 37.5 mg once daily

Asian descent, no weight data: 25 mg once daily

For patients with hepatic impairment the starting dose should be reduced to 25 mg (see “Special patient populations”).

Monitoring and dose adjustment

The standard dose adjustment is by 25 mg increments/decrements. However, in some ITP patients a combination of different tablet strengths on different days may be required.

Table 2: Dose adjustment of Revolade in paediatric ITP patients aged 6 to 17 years

Chronic hepatitis C (HCV) associated thrombocytopenia

When Revolade is given in combination with peginterferon-based antiviral therapy regimens, the dosage instructions in the prescribing information of all co-administered medicinal products should be observed.

Inducing a platelet count that would allow peginterferon-based anti-HCV therapy should begin with the lowest possible Revolade dose and the QT interval should be monitored via ECG (see “Warnings/precautions”). For a daily dose of less than 25 mg Revolade consideration of a 25 mg dose every other day is recommended.

During antiviral therapy the therapeutic target should be to maintain the platelet count at a level that keeps the risk of bleeding and thrombosis low but is also compatible with full-dose peginterferon therapy (Table 6).

In clinical studies platelet counts generally increased within one week of starting treatment with Revolade.

Revolade should only be used in patients with an increased bleeding risk due to pronounced thrombocytopenia. The platelet count should only be increased to a value required to avoid bleeding events and not to the physiological range.

Starting dose

Initiate Revolade therapy in HCV patients at a dose of 25 mg once daily.

Monitoring and dose adjustment

Dose adjustments are based on the platelet count response. Adjust the Revolade dose in 25 mg increments at two‑week intervals until the platelet count required to initiate antiviral therapy is achieved.

Platelet count stabilisation during antiviral therapy:

To avoid a peginterferon dose reduction during antiviral therapy, the Revolade dose must also be adjusted continuously during antiviral therapy while monitoring the platelet count. It is recommended that complete blood counts are performed every two weeks. Platelet counts should be monitored weekly in the event of unstable platelet counts during antiviral therapy.

The Revolade dose should be adjusted as per Table 6. The target platelet count range is between 75,000 and 100,000/μl.

A dose of 100 mg once daily should not be exceeded.

Table 6: Dose adjustment of Revolade in HCV patients during antiviral therapy

*For patients taking 25 mg Revolade/Promacta once daily a dose of 12.5 mg once daily, or alternatively a dose of 25 mg once every other day, should be considered.

Discontinuation of therapy

Revolade treatment should be terminated when antiviral therapy is discontinued. Excessive platelet count responses and increased liver values may require discontinuation of Revolade (see “Warnings and precautions”).

For patients with genotype 1/4/6 HCV discontinuation of Revolade should be considered independently of the decision on continuation of antiviral therapy if a patient has achieved no virological response (= reduction of HCV RNA in the blood by a factor of >100) by week 12. If HCV RNA is still detectable after 24 weeks of therapy, Revolade should be discontinued (see “Warnings and precautions”).

First-line therapy in severe aplastic anaemia

Eltrombopag should be initiated concurrently with standard immunosuppressive therapy.

The initial dose of eltrombopag must not be exceeded.

Starting dose

Adults and adolescents aged 12 to 17 years

The recommended starting dose of eltrombopag is 150 mg once daily for 6 months.

In adult and adolescent SAA patients of Asian descent (such as Chinese, Japanese, Taiwanese, Korean or Thai patients) eltrombopag should be initiated at a dose of 75 mg once daily for 6 months.

Paediatric patients aged 6 to 11 years

The recommended starting dose of eltrombopag is 75 mg once daily for 6 months.

In paediatric SAA patients of Asian descent (such as Chinese, Japanese, Taiwanese, Korean or Thai patients) aged 6 to 11 years eltrombopag should be initiated at a dose of 37.5 mg once daily for 6 months.

Table 7:            Dose of standard immunosuppressive therapy administered with eltrombopag in the pivotal study (see “Properties/Actions”)

Monitoring and dose adjustment

Clinical haematology and liver function tests should be performed regularly throughout therapy with eltrombopag and the dosage regimen of eltrombopag should be modified based on platelet counts as outlined in Table 8.

Table 9 summarises the recommendations for dose interruption, reduction or discontinuation of eltrombopag in the management of hepatic impairment and thrombosis/embolism events.

Table 8:            Dose adjustments of eltrombopag in first-line therapy in severe aplastic anaemia

Table 9:            Recommended dose modification for hepatic impairment and thrombosis/embolism

Discontinuation of therapy

The total duration of eltrombopag treatment is 6 months. Excessive platelet count responses (as outlined in Table 8) or certain adverse events (as outlined in Table 9) also necessitate discontinuation of eltrombopag.

Refractory severe aplastic anaemia (SAA)

Starting dose

Initiate treatment with Revolade at a dose of 50 mg once daily. For patients of Asian descent and for patients with hepatic impairment the starting dose should be reduced to 25 mg (see “Special patient populations”). Treatment should not be initiated if patients have existing cytogenetic abnormalities affecting chromosome 7.

Monitoring and dose adjustment

Haematological response may take up to 16 weeks after starting Revolade treatment and may require dose escalation. This involves increasing the Revolade dose in 25 mg increments every 2 weeks until the target platelet count of ≥50,000/µl is achieved. A dose of 150 mg once daily should not be exceeded. Clinical/haematological parameters and liver values should be monitored regularly throughout therapy with Revolade. The dosage of Revolade should be adjusted based on platelet counts as shown in Table . Bone marrow examinations with aspirations for cytogenetics are recommended prior to initiation of Revolade therapy, 3 months after treatment initiation and 6 months after discontinuation. If new cytogenetic abnormalities are detected, it must be carefully reconsidered whether continuation of therapy is appropriate.

Table 10: Dose adjustments of Revolade in patients with severe aplastic anaemia

Tapering for trilineage (white blood cells, red blood cells and platelets) responders

Once platelet count >50,000/µl, haemoglobin >10 g/dl in the absence of red blood cell (RBC) transfusion and absolute neutrophil count (ANC) >1 x 10⁹/l for more than 8 weeks, the Revolade dose should be reduced by 50%. If values remain stable after 8 weeks at the reduced dose, treatment with Revolade must be discontinued and the blood count monitored. If platelet count drops to <30,000/µl, haemoglobin concentration to <9 g/dl or ANC to <0.5 x 10⁹/l, Revolade may be reinitiated at the previous dose.

Discontinuation of therapy

If no haematological response has occurred after 16 weeks of therapy with Revolade, therapy should be discontinued. If new cytogenetic abnormalities are detected, it must be carefully re-evaluated whether continuation of Revolade is appropriate (see “Warnings and precautions”). Excessive platelet count responses or hepatic impairment may also require discontinuation of Revolade therapy (see “Warnings and precautions”).

Special populations

Children and adolescents

Revolade is not recommended in children under one year of age with ITP lasting at least 6 months due to a lack of sufficient data on safety and efficacy.

The safety and efficacy of eltrombopag in the treatment of children and adolescents with thrombocytopenia in the case of chronic HCV infection, refractory SAA and definitive immunosuppressive therapy-naive SAA who are younger than 2 years of age have not been established..

No data are available in any indication on children and adolescents with renal or hepatic impairment. No therapy recommendations can be given.

Elderly patients

There are limited data on the use of Revolade in patients aged 65 years and over.

In the clinical ITP studies no overall clinically significant difference in the safety of eltrombopag was observed between patients aged 65 years and above and younger patients.

For HCV patients, however, there is evidence of more frequent serious adverse events during treatment with Revolade in elderly patients, in particular gastrointestinal bleeding (see “Warnings and precautions”), with simultaneously limited efficacy in this subgroup (see “Properties/Actions”).

Asian adult patients

In patients of Asian descent (such as Chinese, Japanese, Taiwanese or Korean patients), including those with hepatic impairment, Revolade should be initiated at a dose of 25 mg once daily (see “Pharmacokinetics in special populations”).

Further dose adjustments should be based on the standard criteria (Table 1, Table 2,Table 5,Table 6, Table 10) and accompanied by continuous monitoring of the platelet count.

Adult patients with renal impairment

Caution and close monitoring are required for the use of Revolade in adult patients with renal impairment due to the absence of clinical experience.

Adult patients with hepatic impairment

Adult ITP patients with liver cirrhosis should use Revolade with caution and should be closely monitored. An interval of at least three weeks must be observed before adjusting the dose (see “Warnings and precautions”). For patients with a Child‑Pugh score ≥5 the starting dose should be reduced to 25 mg Revolade daily.

Adult patients with chronic HCV infection and hepatic impairment and refractory severe aplastic anaemia patients with hepatic impairment should be administered the standard starting dose of 25 mg once daily. Any further dose adjustments should be undertaken subject to continuous monitoring of the platelet count in line with the standard criteria (Table 1, Table 2, Table 5, Table 6, Table ) (see “Pharmacokinetics in special patient populations” under “Pharmacokinetics”). Patients with a Child‑Pugh score >9 were not investigated in the studies on HCV, ITP and SAA patients.

In a clinical study on definitive immunosuppressive therapy-naive severe aplastic anaemia, patients with baseline AST/ALT >5 x ULN were ineligible to participate. The initial dose of eltrombopag in patients with hepatic impairment in the first-line setting should be determined as necessary based on clinical judgement, tolerability and close monitoring of liver function.

The efficacy and safety of eltrombopag have not been established for use in other thrombocytopenic conditions such as chemotherapy-induced thrombocytopenia or myelodysplastic syndrome (MDS).

In the SAA indication there is only limited safety data from one open-label study. Due to the higher exposure in this indication a higher frequency and/or greater severity of the adverse effects described below (particularly of hepatotoxicity and thromboembolic events) cannot be ruled out. This also applies to drug interactions (see “Interactions”).

This medicinal product contains less than 1 mmol (23 mg) of sodium per film-coated tablet, making it practically “sodium-free”.

Grade 4 neutropenia (<500/µl) and blood count monitoring for paediatric ITP patients

In two placebo-controlled studies (PETIT and PETIT2) with paediatric patients (between 1 and 17 years of age) with ITP lasting at least 6 months 3 cases (2.8%) of grade 4 neutropenia (<500/µl) were observed on eltrombopag and 0 cases on placebo. There was one case of fungal pneumonia. Neutropenia of all grades occurred in 15.9% of patients on eltrombopag and 10.0% of patients on placebo. During treatment of paediatric patients with eltrombopag regular blood counts must be performed (as well as additional blood counts in the event of fever). Patients and their parents must be advised to seek immediate medical treatment in the event of a fever.

Cases of death in thrombocytopenic patients with hepatitis C

In two controlled studies in thrombocytopenic patients with hepatitis C (ENABLE 1 and ENABLE 2) peginterferon-based antiviral therapy in patients with HCV genotype 1/4/6 infections and/or advanced liver damage (MELD (Model for End-Stage Liver Disease) score ≥10, FibroScan fibrosis stage F3 or F4, albumin <3.5 g/dl) resulted in more frequently observed cases of death in patients treated with eltrombopag. Overall, 3% of patients in the eltrombopag group died compared to 2% in the placebo group. The causes of death were mainly hepatic decompensation and bleeding, including bleeding oesophageal varices.

Hepatic impairment and hepatotoxicity

Eltrombopag inhibits UGT1A1 and OATP1B1, which may lead to indirect hyperbilirubinaemia.

Treatment with Revolade may lead to changes in hepatobiliary laboratory values, to severe hepatotoxicity and to potentially fatal liver damage.

Revolade should be used with caution in patients with hepatic disease. Monitoring of laboratory values is obligatory (see below).

Clinical data

In clinical studies with eltrombopag an increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and indirect bilirubin was observed. This occurred approximately three months after the start of treatment. The hepatic changes were reversible after discontinuation of eltrombopag.

ITP patients

In clinical studies in ITP lasting at least 6 months this increase was mostly mild (grade 1‑2), reversible and not accompanied by any clinically significant symptoms that would indicate hepatic impairment. In two placebo-controlled studies in adult patients with ITP lasting at least 6 months from diagnosis an increase in ALT was reported in 5.7% of patients on eltrombopag and 4.0% of patients on placebo.

In the paediatric study PETIT2 increased ALT values ≥3x ULN were reported on eltrombopag in 4 of 26 patients in cohort 2 (6‑11 years of age; both in the randomised period) and in 1 of 14 patients in cohort 3 (1‑5 years of age) compared to 0 cases on placebo. No such cases were reported in cohort 1 (12‑17 years of age).

In the paediatric studies changes in hepatobiliary laboratory values (patients with events that fulfilled at least one criterion) occurred in 7.5% of patients on eltrombopag versus 2% of patients on placebo, with hepatobiliary events occurring in 6.5% and 0% of patients on eltrombopag and placebo, respectively.

SAA patients

In the open-label SAA study an increase in ALT was reported in 19% of patients on eltrombopag.

In a single-arm, open-label clinical study in definitive immunosuppressive therapy-naive SAA patients who received eltrombopag concurrently with h‑ATG and ciclosporin, ALT or AST >3 x ULN with total bilirubin >1.5 x ULN was reported in 40/92 patients. None of these increases resulted in discontinuation.

Dose adjustment

In patients with ITP, HCV and refractory SAA, serum ALT, AST and bilirubin should be determined prior to initiation of Revolade treatment, every two weeks during the dose adjustment phase and monthly following achievement of a stable dose. Direct and indirect bilirubin fractions should be determined in the case of elevated total bilirubin levels. In the event of abnormal liver values repeat the tests within 3 to 5 days. If the abnormalities are confirmed, monitor serum liver values until the abnormalities resolve, stabilise or return to baseline levels. Discontinue Revolade if ALT levels increase to ≥3x ULN in patients with normal liver function or to ≥3x baseline (or to >5x ULN, if this value is lower) in patients with elevations in liver values before treatment and this increase: 

·           is progressive or

·           persists for 4 weeks or

·           is accompanied by increased direct bilirubin or

·           is accompanied by clinical symptoms of liver damage or evidence of hepatic impairment.

Gilbert’s syndrome should be ruled out before initiating treatment (see “Pharmacokinetics”).

In the first-line treatment of severe aplastic anaemia, ALT, AST and bilirubin should be measured prior to initiation of eltrombopag. During treatment increases in ALT levels should be managed as recommended in Table 9.

Hepatic impairment and hepatic decompensation in thrombocytopenic patients with hepatitis C

In two controlled clinical studies on thrombocytopenic patients with chronic HCV infection (ENABLE 1 and ENABLE 2) more frequent cases of hepatic decompensation (13% versus 7%) were observed on peginterferon-based antiviral therapy and concomitant treatment with eltrombopag versus placebo. These were associated with symptoms such as jaundice, ascites, hepatic encephalopathy, hepatorenal syndrome and bleeding oesophageal varices, some of which were fatal.

In patients with advanced liver disease at baseline (albumin <3.5 g/dl, MELD score ≥10 and/or FibroScan/elastography score F3 or F4) the risk of hepatic decompensation and of fatal incidents was increased. These at-risk patients must be closely monitored for signs associated with potential hepatic decompensation. The appropriate discontinuation criteria for Revolade (see “Dosage/Administration”) and for the antiviral medicinal products (in the respective prescribing information) must be observed.

Thrombotic/thromboembolic complications and portal vein thrombosis

If platelet counts are above the normal range, there is a risk of thromboembolic complications. The platelet count should be closely monitored. The dose should be reduced or treatment discontinued if the platelet count exceeds the desired value.

In studies in ITP patients thromboembolic events (TEEs) such as deep vein thrombosis in the leg, pulmonary embolism, transient ischaemic attack, myocardial infarction, ischaemic stroke or suspected PRIND (prolonged reversible ischaemic neurological deficit) were observed in 3.8% of patients.

Thromboembolic events were also observed at low and normal platelet counts. Use particular caution when administering Revolade to patients with known risk factors of thromboembolism (e.g. Factor V Leiden, ATIII deficiency, antiphospholipid syndrome).

ITP patients with hepatic impairment (Child‑Pugh score ≥5) and/or liver cirrhosis are at increased risk of portal vein thrombosis during therapy with eltrombopag. The expected benefit must be carefully assessed in relation to this risk in this at-risk population and Revolade must be used with increased caution in patients with hepatic impairment (see “Dosage/Administration” and “Adverse effects”).

Revolade is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease for whom invasive procedures are planned. In a controlled study in this patient population (n = 288) the risk of portal vein thrombosis/thrombotic events was increased in patients who were given 75 mg eltrombopag once daily for 14 days. In adult patients with chronic liver disease TEEs occurred in 4% of patients on eltrombopag (all in the portal vein system) and in 1% of patients on placebo (1 TEE in the portal vein system, 1 myocardial infarction). In five of the patients treated with eltrombopag the TEE occurred within 14 days of the end of eltrombopag therapy and at a platelet count of >200,000/µl.

In two controlled studies in thrombocytopenic patients with hepatitis C (ENABLE 1 and ENABLE 2), during peginterferon-based antiviral therapy 3% of patients in the group co-administered eltrombopag suffered a TEE compared to 1% in the placebo group, with portal vein thrombosis occurring most frequently.

Gastrointestinal bleeding in thrombocytopenic patients with hepatitis C:

During peginterferon-based antiviral therapy severe gastrointestinal bleeding, sometimes with a fatal outcome, was observed during treatment with eltrombopag; patients must be closely monitored for this.

Bleeding following discontinuation of eltrombopag

Following discontinuation of eltrombopag in ITP and HCV platelet counts return to baseline levels within two weeks in the majority of patients, which increases the risk of bleeding and, in some cases, may lead to bleeding. Platelet counts must be monitored weekly for four weeks following discontinuation of Revolade.

Prolonged QT interval

In two controlled clinical studies (ENABLE 1 and ENABLE 2) in thrombocytopenic patients with hepatitis C QT intervals above 500 ms were observed more frequently with eltrombopag compared to placebo (13/955 vs 2/484). QT prolongation may result in an increased risk of ventricular arrhythmias (including torsade de pointes) and cardiac arrest.

The extent of the QT prolongation increases with the dose. In patients with severe aplastic anaemia clinically relevant QT prolongation cannot be ruled out due to the higher exposure compared to healthy subjects and patients with other indications (see “Pharmacokinetics”) and due to the large number of co-medications. Therefore, the lowest effective dose should be administered. ECG monitoring must be performed and the QT interval checked before the first Revolade dose and once steady state has been reached after 3‑4 weeks as well as at the time of the first dose and after every dose increase. Close monitoring of relevant electrolytes is also indicated. In the event of QT prolongations the dose must be reduced or Revolade discontinued. Caution is required where there are also other risk factors for arrhythmia, i.e. electrolyte disturbances (such as hypokalaemia or hypomagnesaemia), congenital or acquired long QT syndrome, pronounced bradycardia, recent acute myocardial infarction or decompensated heart failure and in case of concomitant treatment with medicinal products that prolong the QT interval or are associated with atypical ventricular tachycardia. These include in particular certain antiarrhythmics (e.g. quinidine, disopyramide, amiodarone), certain antimicrobial agents (e.g. macrolides, quinolones, triazole antifungals), methadone, certain antihistamines, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) and neuroleptics. Electrolyte imbalances such as hypokalaemia and hypomagnesaemia must be corrected prior to commencing treatment with Revolade.

Malignancies and tumour progression

It cannot be ruled out that TPO receptor agonists may stimulate the progression of haematological malignancies (e.g. MDS or AML).  Revolade is not indicated for the treatment of MDS-induced thrombocytopenia. In a randomised, double-blind, placebo-controlled study in adult patients with MDS, cases of progression of MDS to AML were observed more frequently on eltrombopag than on placebo (12% vs 6%). All-cause mortality was also slightly higher on eltrombopag than on placebo (32% vs 29%). This study was ended early due to these numerical disadvantages for eltrombopag and a lack of efficacy in increasing platelet counts.

Cataracts

Cataracts were observed in toxicology studies with eltrombopag in rodents (see “Preclinical data”).

In controlled studies in thrombocytopenic patients with HCV receiving interferon-based therapy (n = 1439) incident cataracts or progression of pre-existing cataracts were reported in 8% of patients on eltrombopag versus 5% of patients on placebo.

In the two studies (PETIT1 and PETIT2) in paediatric patients with ITP cataracts were observed in 1.2% of all patients on eltrombopag (1 cataract in the double-blind phase and 1 cataract in the open-label phase of the study). Both patients had been previously treated with systemic corticosteroids.

Routine ophthalmological monitoring is recommended to exclude cataracts. Children and adolescents receiving eltrombopag therapy must undergo regular slit-lamp examinations.

Cytogenetic aberrations, MDS and AML in SAA patients

Cytogenetic abnormalities may occur in SAA patients and are associated with a risk of progression to MDS or AML. It cannot reliably be estimated from the data whether eltrombopag additionally increased the risk of cytogenetic abnormalities in SAA patients. In the clinical phase II study with eltrombopag in SAA patients new cytogenetic abnormalities occurred in 8 of 43 patients (5 of these patients exhibited the prognostically unfavourable monosomy 7). The median time to onset of a cytogenetic abnormality was 2.9 months.

In the clinical phase II study with eltrombopag in SAA patients MDS was diagnosed in 3 of 43 patients. The median time from the start of eltrombopag treatment to diagnosis was 3 months.

SAA patients refractory to immunosuppressive therapy or who have undergone considerable prior immunosuppressant treatment are advised to undergo bone marrow aspiration for cytogenetic analysis prior to initiating therapy with Revolade, after 3 months of treatment and 6 months following discontinuation.

Pre-existing MDS and hereditary forms of SAA should be ruled out prior to treatment with Revolade.

Higher exposure in SAA patients

Pharmacokinetic data in 23 SAA patients indicate that the dose-normalised exposure was higher in these patients than in other indications. On the basis of these limited data an increased risk of rare severe adverse effects such as hepatotoxicity, cardiotoxicity, QT prolongation and hypersensitivity reactions cannot be ruled out.

Interactions

Eltrombopag is a substrate of CYP1A2 and CYP2C8 and an inhibitor of CYP2C9 and CYP2C8 in vitro.

In vitro, eltrombopag is an inhibitor of several UGT enzymes. Caution is therefore advised when medicinal products excreted by glucuronidation are combined.

In vitro studies have demonstrated that eltrombopag is not a substrate of the organic anion transporter protein OATP1B1, but is an inhibitor of it.

Furthermore, eltrombopag is a BCRP (Breast Cancer Resistance Protein) substrate and inhibitor, but not a substrate for P‑glycoprotein. However, caution is advised in the case of co-medication with P‑gp substrates.

Influence of other medicinal products on eltrombopag pharmacokinetics

Ciclosporin (BCRP inhibitor):

The administration of a single eltrombopag dose of 50 mg with 200 mg ciclosporin reduced the C_max and AUC_(0-inf) of eltrombopag by 25% (90% CI: 15%, 35%) and 18% (90% CI: 8%, 28%), respectively. When administered with 600 mg ciclosporin, the corresponding reduction was 39% (90% CI: 30%, 47%) and 24% (90% CI: 14%, 32%), respectively.

This decrease in exposure is not considered clinically significant. Eltrombopag dose adjustment is permitted during the course of treatment based on the patient’s platelet count (see “Dosage/Administration”). The platelet count should be monitored at least once weekly for two to three weeks when eltrombopag is co-administered with ciclosporin. The eltrombopag dose may have to be increased based on the platelet count.

Lopinavir/ritonavir:

In healthy volunteers the co-administration of a single dose of 100 mg eltrombopag with repeat-dose LPV/RTV (400/100 mg) twice daily resulted in a reduction in eltrombopag plasma AUC_(0-inf) of 17% (90% CI: 6.6%, 26.6%). Platelet counts should be monitored at least once weekly for 2 to 3 weeks at the start or end of lopinavir/ritonavir therapy.

HCV protease inhibitors:

In healthy subjects co-administration of repeat doses of 800 mg boceprevir every 8 hours or 750 mg telaprevir every 8 hours with a single dose of 200 mg eltrombopag did not alter plasma eltrombopag exposure to a clinically significant extent.

CYP1A2 and CYP2C8 inhibitors and inducers

Eltrombopag is metabolised through multiple pathways, including CYP1A2, CYP2C8, UGT1A1 and UGT1A3. Medicinal products that induce or inhibit only one of these enzymes are unlikely to affect plasma eltrombopag concentrations to a clinically significant extent. However, medicinal products that affect several of these pathways simultaneously may reduce (e.g. rifampicin) or increase (e.g. fluvoxamine) eltrombopag concentrations.

Cotrimoxazole:

As trimethoprim is a CYP2C8 inhibitor, an interaction between eltrombopag and cotrimoxazole cannot be ruled out. Caution is therefore advised when co-administering eltrombopag with cotrimoxazole.

Polyvalent cations (chelation)

Eltrombopag chelates with polyvalent cations such as aluminium, calcium, iron, magnesium, selenium and zinc (see “Pharmacokinetics”). Administration of a single dose of 75 mg eltrombopag with an antacid containing polyvalent cations (1524 mg aluminium hydroxide and 1425 mg magnesium carbonate) reduced eltrombopag C_max and AUC_(0-inf) by 70%. Eltrombopag should be administered at least two hours before or at least four hours after ingesting antacids, dairy products or mineral supplements containing polyvalent cations to avoid a significant reduction in eltrombopag absorption (see “Dosage/Administration”).

Statins:

When eltrombopag and rosuvastatin were co-administered, rosuvastatin exposure was increased. This might also apply to other statins. When statins and eltrombopag are co-administered, it is therefore recommended that the statin dose be reduced by 50% and the patient should be carefully monitored.

HCV protease inhibitors:

Co-administration of a single dose of 200 mg eltrombopag with 750 mg telaprevir every 8 hours did not alter telaprevir exposure in healthy subjects. However, these data can only be extrapolated to the situation in HCV patients to a limited extent. No information on the effect on boceprevir exposure is available.

Lopinavir/ritonavir:

Plasma levels of lopinavir and ritonavir were unaffected by concomitant administration of eltrombopag (100 mg).

Women of childbearing potential/Contraception in males and females:

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

Pregnancy

The effects of eltrombopag on human pregnancy are unknown. Animal studies have shown reproductive toxicity. The potential risk to humans is unknown (see “Preclinical data”). The use of Revolade during pregnancy is not recommended.Breast-feeding

It is not known whether eltrombopag or its metabolites pass into human milk. Studies in rats indicate that eltrombopag is likely to be excreted in breast milk (see “Preclinical data”). It is therefore recommended to stop breast-feeding prior to the start of therapy.

Fertility

Fertility was not affected in male and female rats in the range of human therapeutic exposure. However, a risk to humans cannot be ruled out (see “Preclinical data”).

There have been no studies to investigate the effects of eltrombopag on the ability to drive or to use machines. No detrimental effects on such activities are anticipated based on the pharmacology or adverse effect profile of this medicinal product. The clinical condition of the patient and the safety profile of eltrombopag should be borne in mind when assessing the patient’s ability to perform tasks that require judgement and motor/cognitive skills.

Adverse effects are stated below separately for the different indications. Please note that the occurrence of adverse effects observed in clinical studies in one indication only cannot be ruled out in the other indications. This applies in particular to the SAA indication as only limited study data are available in this case.

The most common severe adverse effects observed in adults in the ITP or HCV studies were hepatotoxicity and thromboembolic events. Adverse drug reactions are listed below by MedDRA classification and using the following frequency categories: very common (1/10), common (1/100 to <1/10), uncommon (1/1,000 to <1/100), rare (1/10,000 to <1/1,000), very rare (<1/10,000).

Adult patients with ITP lasting at least 6 months

The following information is based on pooled data from 3 double-blind, placebo-controlled studies and 3 open-label, uncontrolled studies in the ITP indication in which a total of 763 adult patients were exposed to eltrombopag, with a median duration of exposure of 304 days (max. 898 days).

(For safety in the paediatric population see below)

Infections and infestations

Common:              Influenza, pharyngitis, sinusitis, pneumonia, oropharyngeal herpes, tonsillitis.

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

Uncommon:         Rectosigmoid cancer.

Blood and lymphatic system disorders

Common:              Anaemia, thrombocytopenia, leukocytosis, eosinophilia, leukopenia.

Uncommon:         Increased band neutrophil count, increased platelet count, increased haemoglobin, haemolytic anaemia, anisocytosis, myelocytosis, presence of myelocytes.

Immune system disorders

Uncommon:         Hypersensitivity reactions (e.g. facial swelling).

Metabolism and nutrition disorders

Common:              Hypokalaemia, hyperuricaemia.

Uncommon:         Weight gain, hypocalcaemia, anorexia, gout, increased total protein, increased serum albumin, increased appetite, decreased serum albumin.

Psychiatric disorders

Common:              Insomnia (and other sleep disorders), anxiety, depression. Uncommon:  Altered mood, apathy, feeling sad.

Nervous system disorders

Very common:     Headache (24%).

Common:              Dizziness, paraesthesia, migraine (including cases with aura), hypoaesthesia, somnolence.

Uncommon:         Dysgeusia, tremor, hemiparesis, balance disorder, dysaesthesia, peripheral neuropathy, speech difficulties.

Eye disorders

Common:              Cataract, blurred vision, conjunctival haemorrhage, eye pain, dry eye, reduced visual acuity.

Uncommon:         Increased lacrimation, blepharitis, retinal haemorrhage, cortical cataract, astigmatism, retinal pigment epitheliopathy, keratoconjunctivitis sicca.

Ear and labyrinth disorders

Uncommon:         Earache.

Cardiac disorders

Uncommon:         Tachycardia,        acute      myocardial            infarction,             cardiovascular      disorders, palpitations, sinus tachycardia, QT prolongation.

Vascular disorders

Common:              Hypertension, haematoma, hot flush, thromboembolic events (such as deep vein thrombosis, pulmonary embolism), thrombotic microangiopathy with acute renal failure.

Uncommon:         Superficial thrombophlebitis, cyanosis.

Respiratory, thoracic and mediastinal disorders

Common:              epistaxis

Uncommon:         Sleep apnoea, pulmonary infarction, nasal discomfort, oropharyngeal blistering, sinus disorder.

Gastrointestinal disorders

Very common:     Diarrhoea (13%), nausea (11%).

Common:              Vomiting, upper abdominal discomfort, constipati

on, dyspepsia, abdominal pain, gingival bleeding, mouth haemorrhage, haemorrhoids, abdominal discomfort, flatulence.

Uncommon:       Dry mouth, discoloured faeces, glossodynia, frequent bowel movements, haematemesis, oral discomfort, abdominal rigidity.

Hepatobiliary disorders

Very common:     Increased ALT (11%).

Common:              Increased AST, increased alkaline phosphatase, hyperbilirubinaemia, abnormal hepatic function.

Uncommon:         Drug-induced liver injury, hepatitis, cholestasis, hepatic lesion. A lower frequency             of simultaneous ALT and AST elevation has also been observed.

Skin and subcutaneous tissue disorders

Common:              Rash, pruritus, alopecia, petechiae, hyperhidrosis, urticaria.

Uncommon:         Skin haemorrhage, generalised pruritus, skin discolouration, erythema, skin exfoliation, dermatosis, melanosis, pigmentation disorders.

Musculoskeletal and connective tissue disorders

Very common:     Arthralgia (12%), back pain (11%).

Common:              Pain in extremities, myalgia, musculoskeletal pain (including musculoskeletal chest pain), muscle spasm, bone pain.

Uncommon:         Muscle weakness, sensation of heaviness.

Renal and urinary disorders

Common: Thrombotic microangiopathy with acute renal failure, leukocyturia.

Uncommon:         Proteinuria, increased serum creatinine, renal failure, increased urine protein/creatinine ratio, nocturia, increased blood urea, increased urine pH, lupus nephritis.

General disorders and administration site conditions

Very common:     Fatigue (12%).

Common:              Fever, influenza-like illness, peripheral oedema, asthenia, pain, (non-cardiac) chest pain.

Uncommon:         Malaise, mucosal inflammation, night sweats, feeling jittery, ill-defined disorder, wound inflammation, foreign body sensation.

Paediatric patients with ITP

The safety of eltrombopag was investigated in paediatric patients with previously treated ITP from the age of 1 year in two double-blind studies with a subsequent open-label phase (see “Properties/Actions”). A total of 171 children and adolescents were exposed to eltrombopag. The following data are from the randomised study phase; significant events from the open-label phase of both studies were also taken into consideration.

The most common adverse effects in this population were upper respiratory tract infections, abdominal pain and haematological changes.

Infections and infestations

Very common:     Upper respiratory tract infections (26%), nasopharyngitis (16%)

Common:              Opportunistic infections (e.g. fungal pneumonia), pneumonia, subcutaneous abscesses.

Blood and lymphatic system disorders

Very common:    Anaemia (24%), lymphopenia (22%), neutropenia (16%). Common:       grade 4 neutropenia (i.e. <500/µl).

Metabolism and nutrition disorders

Common:              Decreased appetite, vitamin D deficiency.

Eye disorders

Common:              Cataract (taking into consideration both the double-blind and open-label phase of the studies).

Respiratory, thoracic and mediastinal disorders

Very common:     Cough (14%).

Common:              Oropharyngeal pain, rhinorrhoea.

Gastrointestinal disorders

Very common:                    Abdominal pain (18%).

Common:                           Diarrhoea, toothache.

Hepatobiliary disorders

Common:              Increased alanine aminotransferase to 3x ULN, increased aspartate aminotransferase, increased alkaline phosphatase, increased bilirubin.

Skin and subcutaneous tissue disorders

Common:              Rash.

General disorders and administration site conditions

Very common:     Pyrexia (18%).

Eltrombopag in combination with peginterferon-/ribavirin-based antiviral treatment in adult patients with HCV infection

The following information is based on pooled data from two double-blind, placebo-controlled studies in which a total of 1,521 patients were exposed to eltrombopag.  The duration of exposure was 1-365 days (median: 182 days).

Infections and infestations

Common:              Urinary tract infection, nasopharyngitis, upper respiratory tract infection, influenza, bronchitis, oral herpes.

Uncommon:         Gastroenteritis, pharyngitis.

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

Common:              Malignant hepatic neoplasm.

Blood and lymphatic system disorders

Very common:     Anaemia (31%).

Common:              Leukopenia, neutropenia, lymphopenia, increased INR, prolonged activated partial thromboplastin time, haemolytic anaemia.

Metabolism and nutrition disorders

Very common:     Decreased appetite (14%).

Common:              Weight loss, hyperglycaemia, decreased serum albumin.

Psychiatric disorders

Common:              Depression, anxiety, sleep disorder.

Uncommon:         Confusion, agitation.

Nervous system disorders

Very common:     Headache (22%).

Common:              Light-headedness, dizziness, impaired concentration, dysgeusia, lethargy, hepatic encephalopathy, amnesia, paraesthesia.

Eye disorders

Common:              Cataract, retinal exudates, dry eye. Uncommon:          Scleral icterus, retinal haemorrhage.

Cardiac disorders

Common:              Palpitations.

Uncommon:         Prolonged QT interval.

Vascular disorders

Common:              Thromboembolic events (including portal vein thrombosis).

Respiratory, thoracic and mediastinal disorders

Very common:     Cough (12%; sometimes productive).

Common:              Dyspnoea (including exertional dyspnoea), oropharyngeal pain.

Gastrointestinal disorders

Very common:     Nausea (18%), diarrhoea (16%).

Common:              Vomiting, abdominal pain, ascites, dyspepsia, dry mouth, constipation, toothache, stomatitis, gastro-oesophageal reflux, haemorrhoids, other abdominal symptoms.

Uncommon:         Gastritis, aphthous stomatitis, oesophageal varices with haemorrhage, flatulence.

Hepatobiliary disorders

Common:              Hyperbilirubinaemia, drug-induced liver injury, jaundice.

Uncommon:         Hepatic failure.

Skin and subcutaneous tissue disorders

Very common:     Pruritus (12%).

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

Uncommon:         Skin lesion.

Musculoskeletal and connective tissue disorders

Very common:     Myalgia (11%).

Common:              Arthralgia, muscle spasms, back pain, pain in extremities, musculoskeletal pain, bone pain.

Renal and urinary disorders

Uncommon:         Dysuria.

General disorders and administration site conditions

Very common:     Pyrexia (26%), fatigue (25%), influenza-like illness (16%), asthenia (13%),

chills (12%).

Common:              Irritability, pain, malaise, non-cardiac chest pain, oedema. Uncommon: Night sweats, chest discomfort.

Definitive immunosuppressive therapy-naive SAA population

The safety of eltrombopag in combination with horse antithymocyte globulin (h-ATG) and ciclosporin in patients with severe aplastic anaemia who had not received prior definitive immunosuppressive therapy (i.e. ATG therapy, alemtuzumab or high-dose cyclophosphamide) was evaluated in a single- arm, sequential-cohort study (see “Properties/Actions”). A total of 154 patients were enrolled and 153 were treated in this study, of whom 92 patients were enrolled in the cohort in which eltrombopag, h-ATG and ciclosporin were initiated concurrently at the recommended dose and schedule (the study’s cohort 3 regimen): eltrombopag up to 150 mg once daily on day 1 to month 6 (D1-M6) in combination with h-ATG on days 1 to 4 and ciclosporin for 6 months followed by low-dose ciclosporin (maintenance dose) for an additional 18 months in patients with a haematologic response at 6 months. The median duration of exposure to eltrombopag in this cohort was 183 days, with 83.7% of patients exposed for >12 weeks. A summary of the safety profile is included under “Warnings and precautions”.

The only adverse drug reaction associated with eltrombopag reported in definitive immunosuppressive therapy-naive SAA patients not previously reported in the refractory SAA study population is skin discolouration, including hyperpigmentation (5.4%). In definitive immunosuppressive therapy-naive SAA patients increased blood bilirubin was reported more frequently (17.4%) than in the refractory SAA study population.

New or worsening liver function laboratory changes (CTCAE grade 3 and grade 4) in the eltrombopag D1-M6 cohort were 15.2% and 2.2% for AST, 26.4% and 4.3% for ALT and 12.1% and 1.1% for bilirubin, respectively.

Paediatric patients

The safety assessment of eltrombopag in paediatric patients aged 2 to 17 years is based on 37 patients enrolled in the single-arm, sequential-cohort study: 2 patients aged 2 to 5 years, 12 patients aged 6 to 11 years and 23 patients aged 12 to 17 years. The safety profile in paediatric patients was consistent with the safety profile observed in the overall population.

Cytogenetic abnormalities

In the single-arm study in patients with definitive immunosuppressive therapy-naive SAA, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. In the entire study across all cohorts clonal cytogenetic evolution occurred in 15 of 153 (10%) patients. 7 patients exhibited loss of chromosome 7, 6 cases of which occurred within 6.1 months. 4 patients had chromosomal aberrations whose significance was unclear and 3 patients had a deletion of chromosome 13 – considered a good prognostic factor in aplastic anaemia – and 1 patient had a follow-up bone marrow examination after 5 years with features of dysplasia with hypercellularity, raising concern for the possible development of MDS. In the Revolade D1-M6 cohort a new cytogenetic change was reported in 7 patients, 4 cases of which were loss of chromosome 7 occurring within 6.1 months. It is unclear whether these findings are due to the underlying disease, the immunosuppressive therapy and/or treatment with eltrombopag.

Refractory SAA study population

The safety of eltrombopag in patients with severe aplastic anaemia was studied in an open-label, uncontrolled study (n = 43) in which 11 and 7 patients were given eltrombopag for more than 6 and more than 12 months, respectively, with a maximum duration of 39 months. The median duration of study treatment was 3.6 months.

 Psychiatric disorders

Very common:     Insomnia (12%).

Nervous system disorders

Very common:     Headache (21%), dizziness (14%).

Eye disorders

Common:              Cataract.

Respiratory, thoracic and mediastinal disorders

Very common:     Cough (23%), oropharyngeal pain (14%), rhinorrhoea (12%).

Gastrointestinal disorders

Very common:     Nausea (33%), diarrhoea (21%), abdominal pain (12%).

Hepatobiliary disorders

Very common:    Increased transaminases (12%). Common:    Hyperbilirubinaemia.

Skin and subcutaneous tissue disorders

Common:              Rash, exfoliative dermatitis, erythema multiforme.

Musculoskeletal and connective tissue disorders

Very common:     Pain in extremities (19%), arthralgia (12%), muscle spasms (12%).

General disorders and administration site conditions

Very common:     Fatigue (30%), pyrexia (14%), chills (12%).

In the SAA study patient bone marrow aspirates were studied for cytogenetic abnormalities. New cytogenetic abnormalities were detected in 7 patients, including 5 patients with changes on chromosome 7.

Post-marketing experience

The following adverse effects have been reported during post-approval use of Revolade. They comprise spontaneous case reports and serious adverse events from registries and post-marketing studies (including those in unapproved indications). A precise frequency cannot be given for these adverse effects.

Blood and lymphatic system disorders

Progression to AML in patients with myelodysplastic syndrome.

Skin disorders

In patients taking eltrombopag doses above 100 mg/day reversible skin discolouration such as hyperpigmentation or skin yellowing were observed. These observations primarily relate to indications that require a high dosage of eltrombopag (such as SAA).

--To reports any side effect(s):

Saudi Arabia:

Saudi Food and Drug Authority National Pharmacovigilance Center (NPC):

SFDA call center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

-               Patient Safety Department Novartis Consulting AG - Saudi Arabia: O Toll Free Number: 8001240078

O Phone: +966112658100

O Fax: +966112658107

O Email: adverse.events@novartis.com

Other GCC States:

-- Please contact the relevant competent authority.

To report any complaint(s) : complaints.ksa@novartis.com

In the clinical studies there was one report of overdose where the patient took 5000 mg eltrombopag. Reported adverse events included mild skin rash, transient bradycardia, fatigue and elevated transaminases. Liver enzymes measured between day 2 and day 18 after ingestion peaked at 1.6‑fold the upper limit of normal for AST, 3.9‑fold ULN for ALT and 2.4‑fold ULN for total bilirubin. The maximum platelet count was 929,000/µl. All adverse effects were completely reversible following discontinuation of eltrombopag.

In the event of overdose the platelet count may increase excessively, which may result in thromboembolic complications. Therefore, if overdose occurs, oral administration of a metal cation-containing preparation, for example a calcium, aluminium or magnesium preparation, should be considered to chelate eltrombopag and thus reduce absorption. The platelet count should be closely monitored. Treatment with Revolade should then be reinitiated in accordance with dosage and administration recommendations (see “Dosage/Administration”).

Since eltrombopag is not significantly renally excreted and is highly bound to plasma proteins, haemodialysis would not be expected to be an effective method to accelerate the elimination of eltrombopag.

ATC code

B02BX05

Pharmacodynamic properties

Mechanism of action

Eltrombopag olamine is an oral, small-molecule thrombopoietin receptor (TPO-R) agonist with a molecular weight of 564.65. Eltrombopag is practically insoluble in aqueous buffer solution across a pH range of 1 to 7.4 and is sparingly soluble in water.

Thrombopoietin (TPO) is the main cytokine involved in regulation of megakaryopoiesis and platelet production and is the endogenous ligand for the thrombopoietin receptor (TPO-R).

Eltrombopag interacts with the transmembrane domain of the human TPO-R and initiates signalling cascades similar, but not identical to, those initiated by endogenous thrombopoietin (TPO), inducing proliferation and differentiation of bone marrow progenitor cells.

Pharmacodynamics

Eltrombopag differs from TPO with respect to its effects on platelet aggregation. Unlike TPO, eltrombopag does not lead to adenosine diphosphate (ADP)-induced aggregation in human platelets or induce P-selectin expression. Eltrombopag does not antagonise platelet aggregation induced by ADP or collagen.

Clinical efficacy

Immune (idiopathic) thrombocytopenic purpura (ITP)

Adult patient population

The safety and efficacy of eltrombopag in adult patients previously treated for ITP were investigated in two randomised, double-blind, placebo-controlled studies (TRA102537 RAISE and TRA100773B) and two open-label studies (REPEAT TRA108057 and EXTEND TRA105325). The single-arm phase II study TAPER (CETB115J2411) evaluated the safety and efficacy of eltrombopag and its ability to induce a sustained response after treatment discontinuation in 105 adult ITP patients who relapsed or did not respond to first-line corticosteroid treatment.

Double-blind, placebo-controlled studies

In TRA102537 (RAISE) 197 patients were randomised at a ratio of 2:1 to treatment with eltrombopag (n=135) or with placebo (n=62) and treated for up to 6 months.

With regard to the primary endpoint, “achieving a platelet count between 50,000/µl and 400,000/µl”, eltrombopag was significantly more effective than placebo (odds ratio [OR]: 8.2 [99% CI: 3.59, 18.73], p<0.001). From day 15 a median platelet count above 50,000/μl was maintained in the Revolade group at all visits during therapy; in contrast, the median platelet count in the placebo group

remained at <30,000/μl throughout the study.

At the start of the study clinically significant bleeding (WHO grades 2-4) was reported in 28% and 22% of patients in the placebo and eltrombopag groups, respectively. The proportion of patients with bleeding (grades 1-4) and clinically significant bleeding (grades 2-4) was reduced by approximately 50% in the eltrombopag group during the six-month treatment period.

Concomitant ITP therapies were able to be reduced or discontinued in 59% of patients receiving eltrombopag vs 32% of patients receiving placebo (p<0.016).

Significantly fewer patients on eltrombopag required rescue treatment compared with those on placebo (19% vs 40%; p=0.001).

In study TRA100773B 114 patients with previously treated ITP and a platelet count <30,000/µl were randomised at a ratio of 2:1; 76 patients received eltrombopag and 38 were given placebo. An increase in platelet count to 50,000/μl on day 43 was rated as a response.

59% of patients on eltrombopag responded to the treatment compared with 16% of patients on placebo (OR: 9.6 [95% CI: 3.31, 27.86] p<0.001). At the start of the study 61% of patients in the eltrombopag group and 66% of patients in the placebo group reported bleeding (grade 1-4). By day 43 39% of patients in the eltrombopag group had experienced bleeding compared with 60% in the placebo group (95% CI: 0.26, 0.83, p=0.021).

Open-label, uncontrolled studies

In study TRA108057 (REPEAT) 65 patients with ITP were treated intermittently with eltrombopag in cycles of up to 6 weeks interrupted by 4week off-therapy periods.

The primary endpoint of the study was the proportion of patients who achieved a platelet count of

50,000/μl and at least 2x baseline in cycle 2 or 3, provided there had been a response in cycle 1.

Of the 65 patients in total, 52 responded to eltrombopag in cycle 1 and 45 of these also responded in the second or third treatment cycle.

Both overall bleeding (WHO grades 1-4) and clinically significant bleeding (WHO grades 2-4) decreased during the treatment phases in each cycle.

In study TRA105325 (EXTEND) eltrombopag was administered to 302 patients who had previously taken part in an eltrombopag study. The duration of treatment ranged from 2 days to 8.76 years (median: 2.37 years). The mean daily dose was 50.2 mg (SD 21.56). The median baseline platelet count prior to eltrombopag administration was 19,000/ml. The eltrombopag dose was able to be adjusted individually.

The median platelet counts after 1, 2, 3, 4, 5, 6 and 7 years of the study were 85,000//l, 85,000/l, 105,000/ml, 64,000/ml, 75,000/l, 119,000/l and 76,000/ml.

Study CETB115J2411 (TAPER) was a single-arm phase II study in ITP patients treated with eltrombopag after failure of first-line corticosteroid treatment irrespective of time since diagnosis. A total of 105 patients were enrolled in the study and started treatment with 50 mg eltrombopag once daily (25 mg once daily for patients of East-/Southeast Asian ancestry except for Japanese patients in Japan, who received 12.5 mg once daily). The dose of eltrombopag was adjusted during the treatment period based on individual platelet counts with the goal to achieve a platelet count ≥100,000/µl.

Results of primary analysis of sustained response to treatment

In patients who reached a platelet count of ≥100,000/μl and maintained a platelet count of ≥70,000/μl for 2 months eltrombopag was able to be discontinued and treatment ended. To be considered as having achieved a sustained response to treatment, a patient had to maintain a platelet count of ≥30,000/μl, without bleeding adverse events occurring or rescue therapy being required, both during treatment tapering and following discontinuation of treatment until month 12.

In terms of tapering, the dose was reduced by 25 mg every 2 weeks if platelet counts were stable, followed by a dose of 25 mg on alternate days for 2 weeks until treatment discontinuation.

The duration of tapering was individualised depending on the starting dose and patient response. The dose was reduced in smaller decrements of 12.5 mg every second week for patients of East-/Southeast Asian ancestry. If a relapse (defined as platelet count of <30,000/μl) occurred during the 12 month treatment period, patients were offered a new course of Revolade/Promacta at the appropriate starting dose.

The study met the primary endpoint by demonstrating that eltrombopag was able to induce a sustained response to treatment, without bleeding events occurring or rescue therapy being required, by month 12 in 32 of the 105 enrolled patients (30.5%; p<0.0001; 95% CI: 21.9, 40.2).

89 patients (84.8%) achieved a complete response (platelet count ≥100,000/μl) and 65 patients (61.9%) maintained the complete response for at least 2 months with no platelet counts decreasing to <70,000/μl. 44 patients (41.9%) were able to be tapered off eltrombopag through treatment discontinuation while maintaining a platelet count of ≥30,000/μl without bleeding adverse events occurring or rescue therapy being required (Table 8).

The median duration of sustained response after treatment discontinuation to month 12 was 33.3 weeks (range: 4 51).

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

Table 8  Proportion of patients with sustained response to treatment at month 12 (full analysis set) during taper

Results of an analysis of early response to treatment by time since ITP diagnosis

An ad-hoc analysis was conducted on the n=105 patients by time since ITP diagnosis to assess the early response to eltrombopag treatment across four different ITP duration categories (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 duration 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 October 2021) patients were treated with eltrombopag for a median (25th to 75th percentile) duration of 6.2 months (2.3 to 12.0). The median (25th to 75th percentile) platelet count at baseline was 16,000/μl (7,800 to 28,000/μl).

A platelet count response, defined as a platelet count of ≥50,000/μl at least once by week 9 without rescue therapy, was achieved in 84% (95% CI: 71%, 93%) of newly diagnosed patients (ITP duration <3 months), 91% (95% CI: 70%, 99%) and 94% (95% CI: 73%, 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%, 98%) of chronic ITP patients.

The proportion of patients with a complete response, defined as a platelet count of ≥100,000/μl at least once by week 9 without rescue therapy, was 75% (95% CI: 60%, 86%) in newly diagnosed patients (ITP duration <3 months), 76% (95% CI: 53%, 92%) and 72% (95% CI: 47%, 90%) in persistent ITP patients (ITP duration 3 to <6 months and 6 to ≤12 months, respectively) and 87% (95% CI: 60%, 98%) in chronic ITP patients.

The proportion of patients with a durable response, defined as a platelet count of ≥50,000/μl for at least 6 out of 8 consecutive assessments without rescue therapy during the first 6 months on study, was 71% (95% CI: 56%, 83%) in newly diagnosed ITP patients, 81% (95% CI: 58%, 95%) and 72% (95% CI: 47%, 90%) in persistent ITP patients (ITP duration 3 to <6 months and 6 to ≤12 months, respectively) and 80% (95% CI: 52%, 96%) in chronic ITP patients.

 When assessed with the WHO Bleeding Scale, the proportion of newly diagnosed and persistent ITP patients 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 safety profile.

Paediatric ITP patient population

The safety and efficacy of eltrombopag in paediatric patients aged from 1 year with previously treated ITP were investigated in two double-blind studies.

TRA115450 (PETIT2): The study comprised a 13-week double-blind, placebo-controlled phase (part 1) followed by a 24-week open-label phase (part 2). The patients had been refractory to two or three previous ITP therapies (IVIG, corticosteroids, anti-D immunoglobulin, rituximab) or had subsequently suffered a relapse or could not continue other ITP treatments for medical reasons and had a platelet count of <30,000/µl. 92 patients were randomised (2:1) to eltrombopag (n = 63) or placebo (n = 29) in three age cohorts. The eltrombopag dose was adjusted and titrated based on individual platelet counts, age, body weight and ethnicity (non-Asian vs Asian descent). The primary endpoint was a sustained response, defined as the proportion of patients on eltrombopag that achieved platelet counts of

≥50‘000/µl between week 5 and week 12 of the double-blind, randomised phase for at least 6 of the 8 weeks (without use of rescue medication).

Overall, a significantly greater proportion of eltrombopag patients (39.7%) achieved the primary endpoint compared with placebo patients (3.4%) (OR: 18.0 [95% CI: 2.3, 140.9] p < 0.001). The result was similar across all three age cohorts (Table 9).

Table 9: PETIT2: Sustained platelet count response rates in paediatric patients with ITP lasting at least 12 months by age cohort

Significantly fewer eltrombopag patients required rescue treatment during the randomised phase compared to placebo patients (12/63 vs 7/29, p = 0.032).

After 12 weeks eltrombopag had no significant effect on WHO grade 2-4 bleeding (4.8% for eltrombopag vs 6.9%), but did reduce WHO grade 1-4 bleeding to 36.5% versus 55.2% on placebo. WHO grade 4 bleeding did not occur in PETIT2.

TRA108062 (PETIT): 67 paediatric patients who had had ITP for 6 months were included. This criterion does not correspond to chronic ITP lasting for at least 12 months. PETIT was planned as a phase II dose-finding study. The primary endpoint was the proportion of patients who achieved platelet counts of ≥50‘000/µl between week 1 and week 6 of the randomised phase at least once.

Patients had been refractory to at least one prior ITP therapy or had subsequently suffered a relapse and had a platelet count of <30,000/µl. Approximately 85% of the patients had had at least 2 previous treatments (IVIG, corticosteroids, etc.). During the randomised study phase patients were randomised (2:1) to eltrombopag (n = 45) or placebo (n = 22) in three age cohorts. The eltrombopag dose could be adjusted based on individual platelet counts.

Overall, a significantly greater proportion of eltrombopag patients (62.2%) achieved the primary endpoint compared with placebo patients (31.8%) (OR: 4.3 [95% CI: 1.4, 13.3] p < 0.011). The results are summarised for all three age cohorts in Table 10. In the 1-5 years age group no effective dose could be determined as the spontaneous remission rate in the placebo group was very high due to the 6-month inclusion criterion.

Table 10: PETIT: Platelet count response rates in paediatric patients with ITP lasting at least 12 months

Significantly fewer eltrombopag patients required rescue medication during the randomised phase compared to placebo patients (6/45 vs 11/22, p = 0.002).

During PETIT’s double-blind phase 73.3% of patients on eltrombopag experienced WHO grade 1-4 bleeding and 26.7% experienced grade 2-4 bleeding. On placebo the corresponding incidences were 90.9% and 59.1%, respectively.

In the global health score questionnaire eltrombopag did not demonstrate any significant benefit or positive trend compared to placebo over a total of 6 weeks during PETIT.

Chronic hepatitis C-associated thrombocytopenia

The efficacy and safety of eltrombopag for the treatment of thrombocytopenia in patients with HCV infection were evaluated in two randomised, double-blind, placebo-controlled studies. ENABLE 1 utilised peginterferon alfa-2a plus ribavirin for antiviral treatment and ENABLE 2 utilised peginterferon alfa-2b plus ribavirin. In both studies patients with a platelet count of <75,000/μl were enrolled. The patients were stratified by platelet count (<50,000/µl vs ≥50,000/µl to <75,000/µl), screening HCV RNA (<800,000 IU/ml vs ≥800,000 IU/ml) and HCV genotype (genotype 2/3 vs genotype 1/4/6).

During the induction phase (prior to antiviral treatment) patients received open-label eltrombopag to increase the platelet count to ≥90,000/µl (ENABLE 1) and ≥100,000/µl (ENABLE 2). Eltrombopag was administered at a starting dose of 25 mg once daily for two weeks, then increased in 25 mg increments at two to three week intervals to achieve the required platelet count for phase 2 of the study. The maximum induction phase duration allowed was 9 weeks. Once the desired platelet count was achieved, the patients were transferred to the controlled antiviral therapy phase and randomised to eltrombopag or placebo at a ratio of 2:1. Eltrombopag was administered in combination with antiviral treatment for up to 48 weeks.

The primary efficacy endpoint for both studies was sustained virological response (SVR = HCV RNA not detectable after 24 weeks of antiviral therapy). Approximately 70% of patients were genotype 1/4/6 and 30% were genotype 2/3. Approximately 30% of patients had been treated with prior HCV therapies, primarily pegylated interferon plus ribavirin. The median platelet count at the start of the study (approximately 60,000/µl) was similar in all treatment groups. The median time to achieve the target platelet count of ≥90,000/µl (ENABLE 1) or ≥100,000/µl (ENABLE 2) was two weeks.

In both HCV studies a significantly greater proportion of patients treated with eltrombopag achieved SVR compared to those treated with placebo (see Table 11). In patients with prior interferon treatment 12% of patients on eltrombopag demonstrated SVR compared to 5% in on placebo. No advantage of eltrombopag over placebo was discernible in the subgroup of patients ≥65 years of age.

Table 11: ENABLE 1 and ENABLE 2 virological response

a Eltrombopag in combination with peginterferon alfa-2a (180 µg once weekly for 48 weeks for genotypes 1 or 4; 24 weeks for genotypes 2 or 3) plus ribavirin (800-1200 mg/day in 2 divided oral doses)

b Eltrombopag in combination with peginterferon alfa-2b (1.5µg/kg once weekly for 48 weeks for genotype 1 or 4; 24 weeks for genotype 2 or 3) plus ribavirin (800-1400 mg orally)

c Target was a platelet count ≥90,000/µl (ENABLE 1) or ≥100,000/µl (ENABLE 2).

Significantly fewer patients on eltrombopag required an antiviral dose reduction compared with those on placebo (55% vs 73%). The incidence of premature withdrawal from antiviral therapy was significantly lower in patients on eltrombopag than in those on placebo (45% vs 60%, p≤0.0001). 76% of patients on eltrombopag had minimum platelet counts of ≥50,000/µl compared to 19% on placebo. The proportion of patients who had minimum platelet counts fall to <25,000/µl during treatment was 3% on eltrombopag compared 20% on placebo. In the eltrombopag group the SVR rate in patients with high viral loads (>800,000) was 18% compared to 8% in the placebo group.

Revolade has not been tested in combination with HCV protease inhibitors (e.g. boceprevir, telaprevir).

Definitive immunosuppressive therapy-naive severe aplastic anaemia study

Eltrombopag in combination with horse antithymocyte globulin (h-ATG) and ciclosporin was investigated in a single-arm, single-centre, open-label, sequential-cohort study in patients with severe aplastic anaemia who had not received prior definitive immunosuppressive therapy (i.e. ATG therapy, alemtuzumab or high-dose cyclophosphamide). The various cohorts differed in the start day and duration of eltrombopag treatment and the initiation of low-dose ciclosporin (maintenance dose) in patients who achieved a haematologic response at 6 months. A total of 153 patients received eltrombopag in sequential cohorts:

Eltrombopag on day 14 to month 6 (D14-M6) plus h-ATG and ciclosporin (the study’s cohort 1 regimen, n=30).

Eltrombopag on day 14 to month 3 (D14-M3) plus h-ATG and ciclosporin (the study’s cohort 2 regimen, n=31), with half of the patients eligible to receive low-dose ciclosporin (maintenance dose) if they had achieved a haematologic response at 6 months.

Eltrombopag on day 1 to month 6 (D1-M6) plus h-ATG and ciclosporin (the study’s cohort 3 regimen, n=92), with all patients eligible to receive low-dose ciclosporin (maintenance dose) if they had achieved a haematologic response at 6 months.

The starting dose of eltrombopag for adults and paediatric patients aged 12 to 17 years was 150 mg once daily (a reduced dose of 75 mg was administered to East and Southeast Asians), 75 mg once daily for patients aged 6 to 11 years (a reduced dose of 37.5 mg was administered to East and Southeast Asians) and 2.5 mg/kg once daily for patients aged 2 to 5 years (a reduced dose of 1.25 mg/kg was administered to East and Southeast Asians). The dose of eltrombopag was reduced if the platelet count exceeded 200,000/μl and interrupted and reduced if it exceeded 400,000/μl.

All patients received 40 mg/kg/day h-ATG on days 1 to 4 of the six-month treatment period and a total daily dose of 6 mg/kg/day ciclosporin for 6 months in patients aged 12 years and over or a total daily dose of 12 mg/kg/day for 6 months in patients aged 2 to 11 years. A maintenance dose of 2 mg/kg/day ciclosporin was administered for an additional 18 months to 15 patients who achieved a haematologic response at 6 months in the eltrombopag D14-M3 cohort and all patients who achieved a haematologic response at 6 months in the eltrombopag D1-M6 cohort.

Data from the recommended schedule of eltrombopag on day 1 to month 6 in combination with h-ATG and ciclosporin (the study’s cohort 3 regimen) are presented below. This cohort had the highest complete response rates.

In the eltrombopag D1-M6 cohort the median age was 28.0 years (range 5 to 82 years), with 16.3% and 28.3% of patients ≥65 years of age and <18 years of age, respectively. 45.7% of patients were male and the majority of patients were Caucasian (62.0%).

The efficacy of eltrombopag in combination with h-ATG and ciclosporin was established on the basis of complete haematological response at 6 months. A complete response was defined as haematological parameters meeting all three of the following values on two consecutive serial blood count measurements at least one week apart: absolute neutrophil count (ANC) >1,000/μl, platelet count

>100,000/μl and haemoglobin >10 g/dl. A partial response was defined as blood counts no longer meeting the standard criteria for severe pancytopenia in severe aplastic anaemia equivalent to two of the following values on two consecutive serial blood count measurements at least one week apart: ANC >500/μl, platelet count >20,000/μl or reticulocyte count >60,000/μl.

Table 12   Efficacy results in definitive immunosuppressive therapy-naive SAA patients

The overall and complete haematologic response rates were 56.4% and 38.5%, respectively, in year 1 (n=78) and 38.7% and 30.6%, respectively, in year 2 (n=62).

Paediatric patients

37 patients aged 2 to 17 years were enrolled in the single-arm, sequential-cohort study. Of the

36 patients who reached the 6-month assessment point or withdrew earlier, the complete response rate at 6 months was 30.6% (0/2 in patients aged 2 to 5 years, 1/12 in patients aged 6 to 11 years and 10/22 in patients aged 12 to 17 years) and the overall response rate at 6 months was 72.2% (2/2 in patients aged 2 to 5 years, 7/12 in patients aged 6 to 11 years and 17/22 in patients aged 12 to 17 years). Of 25 evaluable patients in the eltrombopag D1-M6 cohort the complete response rate at 6 months was 28% and the overall response rate at 6 months was 68.0%.

Refractory severe aplastic anaemia

Eltrombopag was studied in a single-arm, single-centre, open-label study in 43 patients with severe aplastic anaemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count ≤30,000/µl.

Eltrombopag was administered at a starting dose of 50 mg once daily for two weeks and then increased at weekly intervals in 25 mg increments up to a maximum dose of 150 mg once daily.

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

Haematological response was defined as meeting one or more of the following criteria: 1) platelet count increase to 20,000/μl above baseline or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) haemoglobin concentration increase by >1.5 g/dl or a reduction of RBC transfusions by ≥4 units for 8 consecutive weeks; 3) absolute neutrophil count (ANC) increase of 100% or an ANC increase >0.5 x 10⁹/l.

The treated population had a median age of 45 years (age range 17 to 77 years) and 56% of patients were male. At the start of the study the median platelet count was 20,000/μl, haemoglobin concentration was 8.4 g/dl and ANC was 0.58 x 10⁹/l. 68% of patients were RBC transfusion- dependent and 91% were platelet transfusion-dependent.

The majority of patients (84%) had received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at the start of the study.

Eltrombopag treatment was discontinued after 16 weeks if no haematological response or transfusion independence was observed. Patients who responded to treatment continued therapy in an extension phase of the study.

After 12-16 weeks the haematological response rate was 40% (95% CI: 25, 56).

During the extension phase bi- or trilineage blood cell responses were observed in 9/17 patients in total: in 4/17 patients after 12-16 weeks, in 1 further patient after 6 months and in two further patients after 9 and 12 months, respectively.

The longest platelet transfusion-free interval in responders ranged from 8 to 1,096 days with a median of approximately 200 days. The longest RBC transfusion-free period in responders ranged from 15 to 1,082 days with a median of approximately 208 days.

4 patients who tapered off treatment with eltrombopag following a trilineage response maintained a response for a median follow-up period of 8 months (7.2, 10.6 months).

Pharmacokinetics

Absorption

The peak concentration of eltrombopag is achieved 2 to 6 hours after oral administration. The absolute bioavailability of eltrombopag in humans has not been established.

Food effect

Administration of a single 50 mg eltrombopag dose as a film-coated tablet with a standard breakfast (high calorie and high fat) that also included dairy products reduced plasma eltrombopag AUC0-inf by 59% and Cmax by 65%.

Upon administration of a single dose of 25 mg eltrombopag powder for oral suspension with a calcium-rich meal with a moderate fat and calorie content eltrombopag plasma AUC(0-inf) decreased by 75% (90% CI: 71%, 88%) and Cmax by 79% (90% CI: 76%, 82%). Upon administration of a single dose of 25 mg eltrombopag powder for oral suspension 2 hours before a calcium-rich meal the effect was weaker, with eltrombopag plasma AUC(0-inf) decreasing by 20% (90% CI: 9%, 29%) and Cmax by 14% (90% CI: 2%, 25%).

Food low in calcium (<50 mg calcium) such as fruit, lean ham, beef, unfortified fruit juice, soya milk and cereals (no added calcium, magnesium or iron) had no significant effect on eltrombopag exposure, regardless of calorie and fat content.

Distribution

Eltrombopag is >99.9% bound to human plasma proteins.

Metabolism

Eltrombopag is primarily metabolised by cleavage, oxidation and conjugation with glucuronic acid (UGT1A1 and UGT1A3), glutathione or cysteine. In a human radiolabel study eltrombopag accounted for approximately 64% of plasma radiocarbon AUC(0-inf). Minor metabolites, each accounting for

<10% of plasma radioactivity and arising from glucuronidation and oxidation, were also detected. Around 20% of the dose was metabolised by oxidation. In vitro studies identified CYP1A2 and CYP2C8 as the isoenzymes responsible for oxidative metabolism.

Elimination

Eltrombopag is extensively metabolised. 59% of eltrombopag is excreted via the faeces (with 20% of the dose as unchanged eltrombopag). 31% of the dose is found in the urine as metabolites. The unchanged parent compound is not detectable in the urine.

The plasma elimination half-life of eltrombopag is 21-32 hours.

Pharmacokinetics in special populations

Gender:

Based on two population pharmacokinetic analyses of eltrombopag in ITP and HCV patients plasma AUC(0-) was approx. 24-41% higher in female than in male patients.

Ethnicity:

Based on two population pharmacokinetic analyses of eltrombopag in ITP and HCV patients those of Asian descent (i.e. Japanese, Chinese, Taiwanese and Korean patients) had approximately 50-55% higher plasma AUC0-∞ than non-Asian patients of mainly Caucasian descent.

Paediatric ITP population

The pharmacokinetics of eltrombopag dosed once daily were evaluated in two studies (TRA108062/PETIT and TRA115450/PETIT-2) in 168 paediatric ITP patients aged 1-17 years. Apparent eltrombopag plasma clearance following oral administration (CL/F) increased with increasing body weight. The influence of ethnicity and gender on estimated eltrombopag plasma CL/F was consistent in paediatric and adult patients. Paediatric ITP patients of Asian descent exhibited approximately 43% higher eltrombopag plasma AUC(0-) than patients of non-Asian descent. Female paediatric ITP patients exhibited approximately 25% higher eltrombopag plasma AUC(0-) than male patients.

The estimated pharmacokinetic parameters of eltrombopag in paediatric ITP patients are presented in Table 13.

Table 13: Mean (95% CI) steady-state plasma eltrombopag pharmacokinetic parameters (50 mg once daily) in paediatric ITP patients

aData from adult patients with ITP from studies TRA100773A, TRA100773B and TRA108109.

^bData in the paediatric population presented as the geometric mean (95% CI). AUC(0-) and Cmax are based on population pharmacokinetic post hoc estimates.

The median daily doses administered in the paediatric studies in the individual age groups were as follows:

1 to 5 years (n = 40): 37.0 mg (range 8.8 mg-68.0 mg)

6 to 11 years (n = 70): 57.6 mg (range 4.7 mg-68.0 mg)

12 to 17 years (n = 61): 64.0 mg (range 18.6 mg-74.41 mg)

Approximately 50% of patients aged 6-17 years in the TRA115450/PETIT2 study had their dose increased to the maximum dose of 75 mg.

Elderly patients

Age-specific differences in the pharmacokinetics of eltrombopag were evaluated using a population pharmacokinetic analysis of data from 28 healthy subjects and 635 patients with HCV aged 19 to 74 years. Based on model estimates elderly patients (>60 years) had an approx. 36% higher plasma AUC(0-inf) than younger patients (see “Dosage/Administration”).

Renal impairment:

Eltrombopag is not excreted via the kidneys. In cases of severe renal impairment the AUC(0-inf) is reduced by 60%. This may be a consequence of dysproteinaemia.

Hepatic impairment:

The administration of a single 50 mg dose resulted in an increase in eltrombopag AUC(0-inf) of 41% in subjects with mild hepatic impairment, 93% in subjects with moderate hepatic impairment and 80% in subjects with severe hepatic impairment compared with healthy subjects.

The influence of hepatic impairment on the pharmacokinetics of eltrombopag following repeat administration was evaluated using a population pharmacokinetic analysis in 28 healthy adults and 714 patients with hepatic impairment (673 patients with HCV and 41 patients with chronic liver disease of other aetiology). Of the 714 patients 642 had mild hepatic impairment, 67 had moderate hepatic impairment and 2 had severe hepatic impairment. Compared to healthy subjects patients with mild hepatic impairment (Child-Pugh score 5 and 6) and patients with moderate hepatic impairment (Child-Pugh score 7-9) had approximately 111% (95% CI: 45% to 283%) and 183% (95% CI: 90% to 450%) higher AUC(0-τ), respectively. In patients with hepatic impairment the exposure in HCV patients was more markedly elevated (see “Dosage/Administration” and “Warnings/precautions”).

SAA patients

Pharmacokinetic data for SAA patients are limited to preliminary results in 23 SAA patients (including 3 adolescents). The dose-normalised exposure (AUC(0-τ), Cmax) in these patients was 2 to 3 times higher than the exposure observed in healthy subjects or ITP patients and corresponded approximately to that in HCV patients.

Safety pharmacology and repeated-dose toxicity

Treatment-related, dose-dependent and time-dependent cataracts were detected in rodents. These occurred in mice after 6 weeks and in rats after 28 weeks of administering doses equivalent to 3 times the systemic exposure (AUC) in adult HCV patients (100 mg/day) and ≥6 times the systemic exposure (AUC) in adult ITP patients (75 mg/day). Longer treatment durations (13 weeks and 39 weeks, respectively) resulted in even smaller safety margins for ITP and HCV patients.

A toxic effect on renal tubules was observed in rats and mice in studies lasting up to 14 days at exposures generally associated with morbidity and mortality. This renal toxicity was also observed in a two-year carcinogenicity study in mice at oral doses of 25, 75 and 150 mg/kg/day. These effects were less severe at lower doses and were characterised by a number of regenerative changes. Exposure at the lowest effective dose was equivalent to 0.6 times the systemic exposure (AUC) in HCV patients (100 mg/day) and 1.2 or 0.8 times the systemic exposure (AUC) in adult or paediatric ITP patients (75 mg/day). After prolonged administration of eltrombopag resulting in systemic exposure (AUC) comparable to that in HCV patients (100 mg/day) or equivalent to 4 to 2 times that in adult or paediatric ITP patients (75 mg/day) no renal toxicity was observed in rats after 28 weeks or in dogs after 52 weeks.

Due to small safety margins secondary pharmacological effects (e.g. in the cardiovascular system) cannot be ruled out at higher systemic exposure.

Carcinogenicity and mutagenicity

Eltrombopag did not prove to be carcinogenic in mice at doses of up to 75 mg/kg/day or in rats at doses of up to 40 mg/kg/day. This is equivalent to 2 times the systemic exposure (AUC) in HCV patients (100 mg/day) and 4 or 2 times the systemic exposure (AUC) in adult or paediatric ITP patients at 75 mg/day. In a bacterial mutation assay and in two in vivo assays in rats eltrombopag was neither mutagenic nor clastogenic at 7 times the systemic exposure (Cmax) in HCV patients (100 mg/day) and 12 to 8 times the systemic exposure (Cmax) in adult or paediatric ITP patients (75 mg/day). In the in vitro mouse lymphoma assay eltrombopag exhibited a slightly positive result (<3-fold increase in mutation frequency). All the in vitro and in vivo findings indicate that eltrombopag does not pose a genotoxic risk to humans.

Newer in vitro studies show a bell-shaped dose-response relationship. Merely doubling the concentration from 6.8 to 13.6 µM eltrombopag resulted in inhibited cell proliferation (cytotoxicity) rather than the expansion of haematopoietic stem cells.

Reproductive toxicity

Eltrombopag did not prove to be teratogenic in rats or rabbits. Eltrombopag had no effect on female fertility, early embryonic development or embryofetal development in rats at doses up to 20 mg/kg/day (equivalent to the systemic exposure (AUC) in HCV patients at 100 mg/day and 2 times the systemic exposure (AUC) in adult or adolescent (12 17 years of age) ITP patients at 75 mg/day). There was no effect on fertility in male rats at doses up to 40 mg/kg/day (equivalent to 2 times the systemic exposure in HCV patients at 100 mg/day). There was also no effect on embryofetal development in rabbits at doses up to 150 mg/kg/day (equivalent to 0.3 times the systemic exposure (AUC) in HCV patients or 0.4 to 0.6 times the systemic exposure (AUC) in adult or paediatric ITP patients at 75 mg/day). However, at maternally toxic doses of 60 mg/kg/day (3 times the systemic exposure (AUC) in HCV patients at 100 mg/day and up to 7 times the systemic exposure (AUC) in adult or adolescent (12 to 17 years of age) ITP patients at 75 mg/day) in rats eltrombopag treatment resulted in embryolethality (increased pre- and post-implantation loss), a lower number of cervical ribs and reduced fetal body weight. In the pre- and postnatal development study in rats (in which the neonates were probably exposed to eltrombopag through their mother’s milk) there were no adverse effects on pregnancy, parturition or lactation of F0-generation female rats at maternally non-toxic doses (10 and 30 mg/kg/day) and no effects on the growth, development and neurobehavioural or reproductive function of the offspring.

Toxicity studies in juvenile animals

To support the administration of eltrombopag to paediatric patients, studies on juvenile toxicity were performed. The observed higher sensitivity of very young animals was likely due to the higher systemic exposure compared to older juvenile animals. After administration of non-toxic doses to unweaned juvenile rats from day 4 to day 32 (at the end of the administration period approximately equivalent to a 2-year-old child) ocular opacities were observed (pathohistological investigations were not carried out). The administered doses were equivalent to 9 times the maximum systemic exposure in paediatric ITP patients (75 mg/day). However, no cataracts were observed in juvenile rats at doses equivalent to 5 times the systemic exposure (AUC) in paediatric ITP patients. Cataracts were not observed in adult dogs after 52 weeks of treatment with doses equivalent to the systemic exposure (AUC) in HCV patients (100 mg/day) or 2 times the systemic exposure (AUC) in adult or paediatric ITP patients (75 mg/day).

Other information

Effect on diagnostic methods

Eltrombopag is highly coloured and so has the potential to interfere with some laboratory tests. Serum discolouration and interference with total bilirubin and creatinine laboratory tests have been reported. If laboratory test results and clinical findings are inconsistent, evaluation of aminotransferases in the presence of clinical jaundice may help in determining the validity of low total bilirubin levels.

Blood urea should be determined in the event of unexpectedly high serum creatinine levels. The result should be re-tested using another method as necessary.

Revolade 25 mg film-coated tablets

Tablet core

Magnesium stearate

Mannitol (E421)

Microcrystalline cellulose

Povidone

Sodium starch glycolate

Tablet coating

Hypromellose (E464)

Macrogol 400 (E1521)

Polysorbate 80 (E433)

Titanium dioxide (E171)

Revolade 50 mg film-coated tablets

Tablet core

Magnesium stearate

Mannitol (E421)

Microcrystalline cellulose

Povidone

Sodium starch glycolate

Tablet coating

Hypromellose (E464)

Iron oxide red (E172)

Iron oxide yellow (E172)

Macrogol 400 (E1521)

Titanium dioxide (E171)

Not applicable.

Do not store above 30°C/Store below 30°C

Film-coated tablets

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

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.