Eltrombopag

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

In studies utilising human liver microsomes, eltrombopag (up to 100 M) showed no in vitro inhibition of the CYP450 enzymes 1A2, 2A6, 2C19, 2D6, 2E1, 3A4/5, and 4A9/11 and was an inhibitor of CYP2C8 and CYP2C9 as measured using paclitaxel and diclofenac as the probe substrates. Administration of eltrombopag 75 mg once daily for 7 days to 24 healthy male subjects did not inhibit or induce the metabolism of probe substrates for 1A2 (caffeine), 2C19 (omeprazole), 2C9 (flurbiprofen), or 3A4 (midazolam) in humans. No clinically significant interactions are expected when eltrombopag and CYP450 substrates are co-administered.

Concomitant administration of eltrombopag and OATP1B1 (e.g. methotrexate) and BCRP (e.g. topotecan and methotrexate) substrates should be undertaken with caution.

Eltrombopag is metabolised through multiple pathways including CYP1A2, CYP2C8, UGT1A1, and UGT1A3. Medicinal products that inhibit or induce a single enzyme are unlikely to significantly affect plasma eltrombopag concentrations, whereas medicinal products that inhibit or induce multiple enzymes have the potential to increase (e.g. fluvoxamine) or decrease (e.g. rifampicin) eltrombopag concentrations.

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.

If the use of eltrombopag is deemed necessary for ITP patients with hepatic impairment the starting dose must be 25 mg once daily. After initiating the dose of eltrombopag in patients with hepatic impairment 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 hepatic impairment (Child-Pugh score ≤6). Chronic HCV patients and severe aplastic anaemia patients with hepatic impairment should initiate eltrombopag at a dose of 25 mg once daily. After initiating the dose of eltrombopag in patients with hepatic impairment an interval of 2 weeks should be observed before increasing the dose.

There is an increased risk for adverse events, including hepatic decompensation and thromboembolic events (TEEs), in thrombocytopenic patients with advanced chronic liver disease treated with eltrombopag, either in preparation for invasive procedure or in HCV patients undergoing antiviral therapy.

No dose adjustment is necessary in patients with renal impairment. Patients with impaired renal function should use eltrombopag with caution and close monitoring, for example by testing serum creatinine and/or performing urine analysis.

Eltrombopag chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, selenium and zinc. Administration of a single dose of eltrombopag 75 mg with a polyvalent cation-containing antacid (1524 mg aluminium hydroxide and 1425 mg magnesium carbonate) decreased plasma eltrombopag AUC_0-∞ by 70% (90% CI: 64%, 76%) and C_max by 70% (90% CI: 62%, 76%). Eltrombopag should be taken at least two hours before or four hours after any products such as antacids, dairy products or mineral supplements containing polyvalent cations to avoid significant reduction in eltrombopag absorption due to chelation.

Administration of eltrombopag 75 mg once daily for 5 days with a single 10 mg dose of the OATP1B1 and BCRP substrate rosuvastatin to 39 healthy adult subjects increased plasma rosuvastatin C_max 103% (90% confidence interval [CI]: 82%, 126%) and AUC_0-∞ 55% (90% CI: 42%, 69%). Interactions are also expected with other HMG-CoA reductase inhibitors, including atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin. When co-administered with eltrombopag, a reduced dose of statins should be considered and careful monitoring for statin adverse reactions should be undertaken.

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

Co-administration of a single dose of eltrombopag 200 mg with boceprevir 800 mg every 8 hours did not alter plasma boceprevir AUC_(0-τ), but increased C_max by 20%, and decreased C_min by 32%. The clinical relevance of the decrease in C_min has not been established, increased clinical and laboratory monitoring for HCV suppression is recommended.

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 AUC_0-∞ and C_max. 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 exposure to a clinically significant extent. 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 AUC_0-∞ by 59% and mean C_max 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 AUC_0-∞ by 75% and mean C_max by 79%. This decrease of exposure was attenuated when a single 25 mg dose of eltrombopag powder for oral suspension was administered 2 hours before a high-calcium meal (mean AUC_0-∞ was decreased by 20% and mean C_max by 14%).

Food low in calcium (<50 mg calcium), including fruit, lean ham, beef and unfortified (no added calcium, magnesium or iron) fruit juice, unfortified soya milk and unfortified grain, did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content.

A decrease in eltrombopag exposure was observed with co-administration of 200 mg and 600 mg ciclosporin (a BCRP inhibitor). The co-administration of 200 mg ciclosporin decreased the C_max and the AUC_inf of eltrombopag by 25% and 18%, respectively. The co-administration of 600 mg ciclosporin decreased the C_max and the AUC_inf of eltrombopag by 39% and 24%, respectively. Eltrombopag dose adjustment is permitted during the course of the treatment based on the patient’s platelet count. Platelet count should be monitored at least weekly for 2 to 3 weeks when eltrombopag is co-administered with ciclosporin. Eltrombopag dose may need to be increased based on these platelet counts.

There is a theoretical concern that TPO-R agonists may stimulate the progression of existing haematological malignancies such as MDS. TPO-R agonists are growth factors that lead to thrombopoietic progenitor cell expansion, differentiation and platelet production. The TPO-R is predominantly expressed on the surface of cells of the myeloid lineage. For TPO-R agonists there is a concern that they may stimulate the progression of existing haematopoietic malignancies such as MDS.

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

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

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

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

Revolade is not recommended during pregnancy.

It is not known whether eltrombopag/metabolites are excreted in human milk. Studies in animals have shown that eltrombopag is likely secreted into milk; therefore a risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to continue/abstain from eltrombopag therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Women of childbearing potential / Contraception in males and females

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

Fertility

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.

Eltrombopag has negligible influence on the ability to drive and use machines. The clinical status of the 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 require judgement, motor and cognitive skills.

Summary of the safety profile

Immune thrombocytopenia in adult and paediatric patients

The safety of eltrombopag was assessed in adult patients (N=763) using the pooled double-blind, placebo-controlled studies TRA100773A and B, TRA102537 (RAISE) and TRA113765, in which 403 patients were exposed to eltrombopag and 179 to placebo, in addition to data from the completed open-label studies (N=360) TRA108057 (REPEAT), TRA105325 (EXTEND) and TRA112940. Patients received study medication for up to 8 years (in EXTEND). The most important serious adverse reactions were hepatotoxicity and thrombotic/thromboembolic events. The most common adverse reactions occurring in at least 10% of patients included nausea, diarrhoea, increased alanine aminotransferase and back pain.

The safety of eltrombopag in paediatric patients (aged 1 to 17 years) with previously treated ITP has been demonstrated in two studies (N=171). PETIT2 (TRA115450) was a two-part, double-blind and open-label, randomised, placebo-controlled study. Patients were randomised 2:1 and received eltrombopag (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 eltrombopag (n=44) or placebo (n=21), for up to 7 weeks. The profile of adverse reactions was comparable to that seen in adults with some additional adverse reactions, marked ♦ in the table below. The most common adverse reactions in paediatric ITP patients 1 year and older (≥3% and greater than placebo) were upper respiratory tract infection, nasopharyngitis, cough, pyrexia, abdominal pain, oropharyngeal pain, toothache and rhinorrhoea.

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 and safety of eltrombopag in thrombocytopenic patients with HCV infection who were otherwise eligible to initiate antiviral therapy. In the HCV studies the safety population consisted of all randomised patients who received double-blind study medicinal product during Part 2 of ENABLE 1 (eltrombopag treatment n=450, placebo treatment n=232) and ENABLE 2 (eltrombopag treatment n=506, placebo treatment n=252). Patients are analysed according to the treatment received (total safety double-blind population, eltrombopag n=955 and placebo n=484). The most important serious adverse reactions identified were hepatotoxicity and thrombotic/thromboembolic events. The most common adverse reactions occurring in at least 10% of patients included headache, anaemia, decreased appetite, cough, nausea, diarrhoea, hyperbilirubinaemia, alopecia, pruritus, myalgia, pyrexia, fatigue, influenza-like illness, asthenia, chills and oedema.

Severe aplastic anaemia in adult patients

The safety of eltrombopag in severe aplastic anaemia 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. The most common adverse reactions occurring in at least 10% of patients included headache, dizziness, cough, oropharyngeal pain, rhinorrhoea, nausea, diarrhoea, abdominal pain, transaminases increased, arthralgia, pain in extremity, muscle spasms, fatigue and pyrexia.

List of adverse reactions

The adverse reactions in the adult ITP studies (N=763), paediatric ITP studies (N=171), the HCV studies (N=1 520), the SAA studies (N=43) and post-marketing reports are listed below by MedDRA system organ class and by frequency. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. The corresponding frequency category for each adverse drug reaction is based on the following 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 available data).

ITP study population:

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

HCV study population (in combination with anti-viral interferon and ribavirin therapy):

^† Grouped term with preferred terms oliguria, renal failure and renal impairment

SAA study population:

Description of selected adverse reactions

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 of occurrence) deep vein thrombosis (n=6), pulmonary embolism (n=6), acute myocardial infarction (n=2), cerebral infarction (n=2), embolism (n=1).

In a placebo-controlled study (n=288, Safety population), following 2 weeks' treatment in preparation for invasive procedures, 6 of 143 (4%) adult patients with chronic liver disease receiving eltrombopag experienced 7 TEEs of the portal venous system and 2 of 145 (1%) patients in the placebo group experienced 3 TEEs. Five of the 6 patients treated with eltrombopag experienced the TEE at a platelet count >200 000/μl

No specific risk factors were identified in those patients who experienced a TEE with the exception of platelet counts ≥200 000/μl.

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 group experienced TEEs. Portal vein thrombosis was the most common TEE in both treatment groups (2% in patients treated with eltrombopag versus <1% for placebo). Patients with low albumin levels (≤35 g/l) or MELD ≥10 had 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.

Hepatic decompensation (use with interferon)

Chronic HCV patients with cirrhosis may be at risk of hepatic decompensation when receiving alfa interferon therapy. In 2 controlled clinical studies in thrombocytopenic patients with HCV, hepatic decompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterial peritonitis) 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-fold greater risk of hepatic decompensation and an increase in the risk of a fatal adverse event compared to those with less advanced liver disease. Eltrombopag should only be administered to 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 hepatic decompensation.

Hepatotoxicity

In the controlled clinical studies in chronic ITP with eltrombopag, increases in serum ALT, AST and bilirubin were observed.

These findings were mostly mild (Grade 1-2), reversible and not accompanied by clinically significant symptoms that would indicate an impaired liver function. Across the 3 placebo-controlled studies in adults with chronic ITP, 1 patient in the placebo group and 1 patient in the eltrombopag group experienced 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 the eltrombopag and placebo groups, respectively.

In 2 controlled clinical studies in patients with HCV, ALT or AST ≥3 x ULN was reported in 34% and 38% of the eltrombopag and placebo groups, respectively. Most patients receiving eltrombopag in combination 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 placebo groups, respectively.

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

Thrombocytopenia following discontinuation of treatment

In the 3 controlled clinical ITP studies, transient decreases in platelet counts to levels lower than baseline were observed following discontinuation of treatment in 8% and 8% of the eltrombopag and placebo groups, respectively.

Increased bone marrow reticulin

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

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 new cytogenetic abnormalities was observed in 17.1% of adult patients [7/41 (where 4 of them had changes in 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 or age related modifications as indicated) (ELT116826), the incidence of new cytogenetic abnormalities was observed in 22.6% of adult patients [7/31 (where 3 of them had changes in chromosome 7)]. All 7 patients had normal cytogenetics at baseline. Six patients had cytogenetic abnormality at Month 3 of eltrombopag 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 following treatment with eltrombopag, in the two ongoing studies (ELT116826 and ELT116643), 1/28 (4%) and 1/62 (2%) patient has been diagnosed with MDS or AML in each study.