Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Hypersensitivity to eltrombopag or to any of the excipients listed in section 6.1.
There is an increased risk for adverse reactions, including potentially fatal hepatic decompensation and thromboembolic events, in thrombocytopenic HCV patients with advanced chronic liver disease, as defined by low albumin levels ≤35 g/l or model for end stage liver disease (MELD) score ≥10, when treated with eltrombopag in combination with interferon-based therapy. In addition, the benefits of treatment in terms of the proportion achieving sustained virological response (SVR) compared with placebo were modest in these patients (especially for those with baseline albumin ≤35g/l) compared with the group overall. Treatment with eltrombopag in these patients should be initiated only by physicians experienced in the management of advanced HCV, and only when the risks of thrombocytopenia or withholding antiviral therapy necessitate intervention. If treatment is considered clinically indicated, close monitoring of these patients is required.
Safety and efficacy have not been established in combination with direct-acting antiviral agents approved for treatment of chronic hepatitis C infection.
Eltrombopag administration can cause abnormal liver function and severe hepatotoxicity, which might be life-threatening (see section 4.8).
Serum alanine aminotransferase (ALT), aspartate aminotrasferase (AST) and bilirubin should be measured prior to initiation of eltrombopag, every 2 weeks during the dose adjustment phase and monthly following establishment of a stable dose. Eltrombopag inhibits UGT1A1 and OATP1B1, which may lead to indirect hyperbilirubinaemia. If bilirubin is elevated fractionation should be performed. Abnormal serum liver tests should be evaluated with repeat testing within 3 to 5 days. If the abnormalities are confirmed, serum liver tests should be monitored until the abnormalities resolve, stabilise, or return to baseline levels. Eltrombopag should be discontinued if ALT levels increase (≥3 times the upper limit of normal [x ULN] in patients with normal liver function, or ≥3 x baseline or >5 x ULN, whichever is the lower, in patients with pre-treatment elevations in transaminases) and are:
Caution is required when administering eltrombopag to patients with hepatic disease. In ITP and SAA patients a lower starting dose of eltrombopag should be used. Close monitoring is required when administering to patients with hepatic impairment (see section 4.2).
Hepatic decompensation in patients with chronic hepatitis C: Monitoring is required in patients with low albumin levels (≤35 g/l) or with MELD score ≥10 at baseline.
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) occurred more frequently in the eltrombopag arm (11%) than in the placebo arm (6%). In patients with low albumin levels (≤35 g/l) or with a 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. In addition, the benefits of treatment in terms of the proportion achieving SVR compared with placebo were modest in these patients (especially for those with baseline albumin ≤35 g/l) compared with the group overall. 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. The respective interferon summary of product characteristics should be referenced for discontinuation criteria. Eltrombopag should be terminated if antiviral therapy is discontinued for hepatic decompensation.
In controlled studies in thrombocytopenic patients with HCV receiving interferon-based therapy (n=1 439), 38 out of 955 patients (4%) treated with eltrombopag and 6 out of 484 patients (1%) in the placebo group experienced TEEs. Reported thrombotic/thromboembolic complications included both venous and arterial events. The majority of TEEs were non-serious and resolved by the end of the study. Portal vein thrombosis was the most common TEE in both treatment groups (2% in patients treated with eltrombopag versus <1% for placebo). No specific temporal relationship between start of treatment and event of TEE were observed. 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. Eltrombopag should only be administered to such patients after careful consideration of the expected benefits in comparison with the risks. Patients should be closely monitored for signs and symptoms of TEE.
The risk of TEEs has been found to be increased in patients with chronic liver disease (CLD) treated with 75 mg eltrombopag once daily for 2 weeks in preparation for invasive procedures. Six of 143 (4%) adult patients with CLD receiving eltrombopag experienced TEEs (all of the portal venous system) and two of 145 (1%) patients in the placebo group experienced TEEs (one in the portal venous system and one myocardial infarction). Five of the 6 patients treated with eltrombopag experienced the thrombotic complication at a platelet count >200 000/μl and within 30 days of the last dose of eltrombopag. Eltrombopag is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease in preparation for invasive procedures.
In eltrombopag clinical studies in ITP thromboembolic events were observed at low and normal platelet counts. Caution should be used when administering eltrombopag to patients with known risk factors for thromboembolism including but not limited to inherited (e.g. Factor V Leiden) or acquired risk factors (e.g. ATIII deficiency, antiphospholipid syndrome), advanced age, patients with prolonged periods of immobilisation, malignancies, contraceptives and hormone replacement therapy, surgery/trauma, obesity and smoking. Platelet counts should be closely monitored and consideration given to reducing the dose or discontinuing eltrombopag treatment if the platelet count exceeds the target levels (see section 4.2). The risk-benefit balance should be considered in patients at risk of TEEs of any aetiology.
No case of TEE was identified from a clinical study in refractory SAA, however the risk of these events cannot be excluded in this patient population due to the limited number of exposed patients. As the highest authorised dose is indicated for patients with SAA (150 mg/day) and due to the nature of the reaction, TEEs might be expected in this patient population.
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. When treatment is considered appropriate, caution is required when administering eltrombopag to patients with hepatic impairment (see sections 4.2 and 4.8).
Thrombocytopenia is likely to reoccur in ITP patients upon discontinuation of treatment with eltrombopag. Following discontinuation of eltrombopag, platelet counts return to baseline levels within 2 weeks in the majority of patients, which increases the bleeding risk and in some cases may lead to bleeding. This risk is increased if eltrombopag treatment is discontinued in the presence of anticoagulants or anti-platelet agents. It is recommended that, if treatment with eltrombopag is discontinued, ITP treatment be restarted according to current treatment guidelines. Additional medical management may include cessation of anticoagulant and/or anti-platelet therapy, reversal of anticoagulation, or platelet support. Platelet counts must be monitored weekly for 4 weeks following discontinuation of eltrombopag.
In HCV clinical studies, a higher incidence of gastrointestinal bleeding, including serious and fatal cases, was reported following discontinuation of peginterferon, ribavirin, and eltrombopag. Following discontinuation of therapy, patients should be monitored for any signs or symptoms of gastrointestinal bleeding.
Eltrombopag may increase the risk for development or progression of reticulin fibres within the bone marrow. The relevance of this finding, as with other thrombopoietin-receptor (TPO-R) agonists, has not been established yet.
Prior to initiation of eltrombopag, the peripheral blood smear should be examined closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable dose of eltrombopag, full blood count (FBC) with white blood cell count (WBC) differential should be performed monthly. If immature or dysplastic cells are observed, peripheral blood smears should be examined for new or worsening morphological abnormalities (e.g. teardrop and nucleated red blood cells, immature white blood cells) or cytopenia(s). If the patient develops new or worsening morphological abnormalities or cytopenia(s), treatment with eltrombopag should be discontinued and a bone marrow biopsy considered, including staining for fibrosis.
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 Revolade have not been established for the treatment of thrombocytopenia due to MDS. Revolade should not be used outside of clinical studies for the treatment of thrombocytopenia due to MDS.
Cytogenetic abnormalities are known to occur in SAA patients. It is not known whether eltrombopag increases the risk of cytogenetic abnormalities in patients with SAA. 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.
In clinical studies with eltrombopag in SAA, 4% of patients (5/133) were diagnosed with MDS. The median time to diagnosis was 3 months from the start of eltrombopag treatment.
For SAA patients refractory to or heavily pretreated with prior immunosuppressive therapy, bone marrow examination with aspirations for cytogenetics is recommended prior to initiation of eltrombopag, at 3 months of treatment and 6 months thereafter. If new cytogenetic abnormalities are detected, it must be evaluated whether continuation of eltrombopag is appropriate.
Cataracts were observed in toxicology studies of eltrombopag in rodents (see section 5.3). In controlled studies in thrombocytopenic patients with HCV receiving interferon therapy (n=1,439), progression of pre-existing baseline cataract(s) or incident cataracts was reported in 8% of the eltrombopag group and 5% of the placebo group. Retinal haemorrhages, mostly Grade 1 or 2, have been reported in HCV patients receiving interferon, ribavirin and eltrombopag (2% of the eltrombopag group and 2% of the placebo group. Haemorrhages occurred on the surface of the retina (preretinal), under the retina (subretinal), or within the retinal tissue. Routine ophthalmologic monitoring of patients is recommended.
A QTc study in healthy volunteers dosed 150 mg eltrombopag per day did not show a clinically significant effect on cardiac repolarisation. QTc interval prolongation has been reported in clinical studies of patients with ITP and thrombocytopenic patients with HCV. The clinical significance of these QTc prolongation events is unknown.
A loss of response or failure to maintain a platelet response with eltrombopag treatment within the recommended dosing range should prompt a search for causative factors, including an increased bone marrow reticulin.
The above warnings and precautions for ITP also apply to the paediatric population.
Eltrombopag is highly coloured and so has the potential to interfere with some laboratory tests. Serum discolouration and interference with total bilirubin and creatinine testing have been reported in patients taking Revolade. If the laboratory results and clinical observations are inconsistent, re-testing using another method may help in determining the validity of the result.
This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially ‘sodium-free’.
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 Cmax 103% (90% confidence interval [CI]: 82%, 126%) and AUC0-∞ 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 (see section 5.2).
Concomitant administration of eltrombopag and OATP1B1 (e.g. methotrexate) and BCRP (e.g. topotecan and methotrexate) substrates should be undertaken with caution (see section 5.2).
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 (see section 5.2).
Dose adjustment is not required when eltrombopag is co-administered with either telaprevir or boceprevir. Co-administration of a single dose of eltrombopag 200 mg with telaprevir 750 mg every 8 hours did not alter plasma telaprevir exposure.
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 Cmax by 20%, and decreased Cmin by 32%. The clinical relevance of the decrease in Cmin has not been established, increased clinical and laboratory monitoring for HCV suppression is recommended.
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 Cmax and the AUCinf of eltrombopag by 25% and 18%, respectively. The co-administration of 600 mg ciclosporin decreased the Cmax and the AUCinf 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 (see section 4.2). 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.
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 AUC0-∞ by 70% (90% CI: 64%, 76%) and Cmax by 70% (90% CI: 62%, 76%). Eltrombopag should be taken at least two hours before or four hours after any products such as antacids, dairy products or mineral supplements containing polyvalent cations to avoid significant reduction in eltrombopag absorption due to chelation (see sections 4.2 and 5.2).
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 AUCinf 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.
Eltrombopag is metabolised through multiple pathways including CYP1A2, CYP2C8, UGT1A1, and UGT1A3 (see section 5.2). Medicinal products that inhibit or induce a single enzyme are unlikely 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.
Results of a drug-drug pharmacokinetic (PK) interaction study show that co-administration of repeat doses of boceprevir 800 mg every 8 hours or telaprevir 750 mg every 8 hours with a single dose of eltrombopag 200 mg did not alter plasma eltrombopag exposure to a clinically significant extent.
Medicinal products used in the treatment of ITP in combination with eltrombopag in clinical studies included corticosteroids, danazol, and/or azathioprine, intravenous immunoglobulin (IVIG), and anti-D immunoglobulin. Platelet counts should be monitored when combining eltrombopag with other medicinal products for the treatment of ITP in order to avoid platelet counts outside of the recommended range (see section 4.2).
The administration of eltrombopag tablet or powder for oral suspension formulations with a high-calcium meal (e.g. a meal that included dairy products) significantly reduced plasma eltrombopag AUC0-∞ and Cmax. In contrast, the administration of eltrombopag 2 hours before or 4 hours after a high-calcium meal or with low-calcium food [<50 mg calcium] did not alter plasma eltrombopag exposure to a clinically significant extent (see section 4.2). Administration of a single 50 mg dose of eltrombopag in tablet form with a standard high-calorie, high-fat breakfast that included dairy products reduced plasma eltrombopag mean AUC0-∞ by 59% and mean Cmax by 65%.
Administration of a single 25 mg dose of eltrombopag as powder for oral suspension with a high-calcium, moderate-fat and moderate-calorie meal reduced plasma eltrombopag mean AUC0-∞ by 75% and mean Cmax by 79%. This decrease of exposure was attenuated when a single 25 mg dose of eltrombopag powder for oral suspension was administered 2 hours before a high-calcium meal (mean AUC0-∞ was decreased by 20% and mean Cmax by 14%).
Food low in calcium (<50 mg calcium), including fruit, lean ham, beef and unfortified (no 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 (see sections 4.2 and 4.5).
There are no or limited amount of data from the use of eltrombopag in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Revolade is not recommended during pregnancy.
Revolade is not recommended in women of childbearing potential not using contraception.
It is not known whether eltrombopag/metabolites are excreted in human milk. Studies in animals have shown that eltrombopag is likely secreted into milk (see section 5.3); therefore a risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to continue/abstain from Revolade therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility was not affected in male or female rats at exposures that were comparable to those in humans. However a risk for humans cannot be ruled out (see section 5.3).
Eltrombopag has negligible influence on the ability to drive and use machines. The clinical status 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.
The safety of Revolade was assessed in adult patients (N=763) using the pooled double-blind, placebo-controlled studies TRA100773A and B, TRA102537 (RAISE) and TRA113765, in which 403 patients were exposed to Revolade and 179 to placebo, in addition to data from the completed open-label studies (N=360) TRA108057 (REPEAT), TRA105325 (EXTEND) and TRA112940 (see section 5.1). 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 Revolade in paediatric patients (aged 1 to 17 years) with previously treated ITP has been demonstrated in two studies (N=171) (see section 5.1). PETIT2 (TRA115450) was a two-part, double-blind and open-label, randomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=63) or placebo (n=29) for up to 13 weeks in the randomised period of the study. PETIT (TRA108062) was a three-part, staggered-cohort, open-label and double-blind, randomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=44) or placebo (n=21), for up to 7 weeks. The profile of adverse reactions was comparable to that seen in adults 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.
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 Revolade 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 (Revolade treatment n=450, placebo treatment n=232) and ENABLE 2 (Revolade treatment n=506, placebo treatment n=252). Patients are analysed according to the treatment received (total safety double-blind population, Revolade 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.
The safety of Revolade 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 (see section 5.1). 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.
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:
| System organ class | Frequency | Adverse reaction |
|---|---|---|
| Infections and infestations | Very common | Nasopharyngitis♦, upper respiratory tract infection♦ |
| Common | Pharyngitis, influenza, oral herpes, pneumonia, sinusitis, tonsillitis, respiratory tract infection, gingivitis | |
| Uncommon | Skin infection | |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Uncommon | Rectosigmoid cancer |
| Blood and lymphatic system disorders | Common | Anaemia, eosinophilia, leukocytosis, thrombocytopenia, haemoglobin decreased, white blood cell count decreased |
| Uncommon | Anisocytosis, haemolytic anaemia, myelocytosis, band neutrophil count increased, myelocyte present, platelet count increased, haemoglobin increased | |
| Immune system disorders | Uncommon | Hypersensitivity |
| Metabolism and nutrition disorders | Common | Hypokalaemia, decreased appetite, blood uric acid increased |
| Uncommon | Anorexia, gout, hypocalcaemia | |
| Psychiatric disorders | Common | Sleep disorder, depression |
| Uncommon | Apathy, mood altered, tearfulness | |
| Nervous system disorders | Common | Paraesthesia, hypoaesthesia, somnolence, migraine |
| Uncommon | Tremor, balance disorder, dysaesthesia, hemiparesis, migraine with aura, neuropathy peripheral, peripheral sensory neuropathy, speech disorder, toxic neuropathy, vascular headache | |
| Eye disorders | Common | Dry eye, vision blurred, eye pain, visual acuity reduced |
| Uncommon | Lenticular opacities, astigmatism, cataract cortical, lacrimation increased, retinal haemorrhage, retinal pigment epitheliopathy, visual impairment, visual acuity tests abnormal, blepharitis, keratoconjunctivitis sicca | |
| Ear and labyrinth disorders | Common | Ear pain, vertigo |
| Cardiac disorders | Uncommon | Tachycardia, acute myocardial infarction, cardiovascular disorder, cyanosis, sinus tachycardia, electrocardiogram QT prolonged |
| Vascular disorders | Common | Deep vein thrombosis, haematoma, hot flush |
| Uncommon | Embolism, thrombophlebitis superficial, flushing | |
| Respiratory, thoracic and mediastinal disorders | Very common | Cough♦ |
| Common | Oropharyngeal pain♦, rhinorrhoea♦ | |
| Uncommon | Pulmonary embolism, pulmonary infarction, nasal discomfort, oropharyngeal blistering, sinus disorder, sleep apnoea syndrome | |
| Gastrointestinal disorders | Very common | Nausea, diarrhoea |
| Common | Mouth ulceration, toothache♦, vomiting, abdominal pain*, mouth haemorrhage, flatulence *Very common in paediatric ITP | |
| Uncommon | Dry mouth, glossodynia, abdominal tenderness, faeces discoloured, food poisoning, frequent bowel movements, haematemesis, oral discomfort | |
| Hepatobiliary disorders | Very common | Alanine aminotransferase increased† |
| Common | Aspartate aminotransferase increased†, hyperbilirubinaemia, hepatic function abnormal | |
| Uncommon | Cholestasis, hepatic lesion, hepatitis, drug-induced liver injury | |
| Skin and subcutaneous tissue disorders | Common | Rash, alopecia, hyperhidrosis, pruritus generalised, petechiae |
| Uncommon | Urticaria, dermatosis, cold sweat, erythema, melanosis, pigmentation disorder, skin discolouration, skin exfoliation | |
| Musculoskeletal and connective tissue disorders | Very common | Back pain |
| Common | Myalgia, muscle spasm, musculoskeletal pain, bone pain | |
| Uncommon | Muscular weakness | |
| Renal and urinary disorders | Common | Proteinuria, blood creatinine increased, thrombotic microangiopathy with renal failure‡ |
| Uncommon | Renal failure, leukocyturia, lupus nephritis, nocturia, blood urea increased, urine protein/creatinine ratio increased | |
| Reproductive system and breast disorders | Common | Menorrhagia |
| General disorders and administration site conditions | Common | Pyrexia*, chest pain, asthenia *Very common in paediatric ITP |
| Uncommon | Feeling hot, vessel puncture site haemorrhage, feeling jittery, inflammation of wound, malaise, sensation of foreign body | |
| Investigations | Common | Blood alkaline phosphatase increased |
| Uncommon | Blood albumin increased, protein total increased, blood albumin decreased, pH urine increased | |
| Injury, poisoning and procedural complications | Uncommon | Sunburn |
♦ 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):
| System organ class | Frequency | Adverse reaction |
|---|---|---|
| Infections and infestations | Common | Urinary tract infection, upper respiratory tract infection, bronchitis, nasopharyngitis, influenza, oral herpes |
| Uncommon | Gastroenteritis, pharyngitis | |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Common | Hepatic neoplasm malignant |
| Blood and lymphatic system disorders | Very common | Anaemia |
| Common | Lymphopenia | |
| Uncommon | Haemolytic anaemia | |
| Metabolism and nutrition disorders | Very common | Decreased appetite |
| Common | Hyperglycaemia, abnormal loss of weight | |
| Psychiatric disorders | Common | Depression, anxiety, sleep disorder |
| Uncommon | Confusional state, agitation | |
| Nervous system disorders | Very common | Headache |
| Common | Dizziness, disturbance in attention, dysgeusia, hepatic encephalopathy, lethargy, memory impairment, paraesthesia | |
| Eye disorders | Common | Cataract, retinal exudates, dry eye, ocular icterus, retinal haemorrhage |
| Ear and labyrinth disorders | Common | Vertigo |
| Cardiac disorders | Common | Palpitations |
| Respiratory, thoracic and mediastinal disorders | Very common | Cough |
| Common | Dyspnoea, oropharyngeal pain, dyspnoea exertional, productive cough | |
| Gastrointestinal disorders | Very common | Nausea, diarrhoea |
| Common | Vomiting, ascites, abdominal pain, abdominal pain upper, dyspepsia, dry mouth, constipation, abdominal distension, toothache, stomatitis, gastrooesophagal reflux disease, haemorrhoids, abdominal discomfort, varices oesophageal | |
| Uncommon | Oesophageal varices haemorrhage, gastritis, aphthous stomatitis | |
| Hepatobiliary disorders | Common | Hyperbilirubinaemia, jaundice, drug-induced liver injury |
| Uncommon | Portal vein thrombosis, hepatic failure | |
| Skin and subcutaneous tissue disorders | Very common | Pruritus |
| Common | Rash, dry skin, eczema, rash pruritic, erythema, hyperhidrosis, pruritus generalised, alopecia | |
| Uncommon | Skin lesion, skin discolouration, skin hyperpigmentation, night sweats | |
| Musculoskeletal and connective tissue disorder | Very common | Myalgia |
| Common | Arthralgia, muscle spasms, back pain, pain in extremity, musculoskeletal pain, bone pain | |
| Renal and urinary disorders | Uncommon | Thrombotic microangiopathy with acute renal failure†, dysuria |
| General disorders and administration site conditions | Very common | Pyrexia, fatigue, influenza-like illness, asthenia, chills |
| Common | Irritability, pain, malaise, injection site reaction, non- cardiac chest pain, oedema, oedema peripheral | |
| Uncommon | Injection site pruritus, injection site rash, chest discomfort | |
| Investigations | Common | Blood bilirubin increased, weight decreased, white blood cell count decreased, haemoglobin decreased, neutrophil count decreased, international normalised ratio increased, activated partial thromboplastin time prolonged, blood glucose increased, blood albumin decreased |
| Uncommon | Electrocardiogram QT prolonged |
† Grouped term with preferred terms oliguria, renal failure and renal impairment
SAA study population:
| System organ class | Frequency | Adverse reaction |
|---|---|---|
| Blood and lymphatic system disorders | Common | Neutropenia, splenic infarction |
| Metabolism and nutrition disorders | Common | Iron overload, decreased appetite, hypoglycaemia, increased appetite |
| Psychiatric disorders | Common | Anxiety, depression |
| Nervous system disorders | Very common | Headache, dizziness |
| Common | Syncope | |
| Eye disorders | Common | Dry eye, cataract, ocular icterus, vision blurred, visual impairment, vitreous floaters |
| Respiratory, thoracic and mediastinal disorders | Very common | Cough, oropharyngeal pain, rhinorrhoea |
| Common | Epistaxis | |
| Gastrointestinal disorders | Very common | Diarrhoea, nausea, gingival bleeding, abdominal pain |
| Common | Oral mucosal blistering, oral pain, vomiting, abdominal discomfort, constipation, abdominal distension, dysphagia, faeces discoloured, swollen tongue, gastrointestinal motility disorder, flatulence | |
| Hepatobiliary disorders | Very common | Transaminases increased |
| Common | Blood bilirubin increased (hyperbilirubinemia), jaundice | |
| Not known | Drug-induced liver injury* * Cases of drug-induced liver injury have been reported in patients with ITP and HCV | |
| Skin and subcutaneous tissue disorders | Common | Petechiae, rash, pruritus, urticaria, skin lesion, rash macular |
| Not known | Skin discolouration, skin hyperpigmentation | |
| Musculosketal and connective tissue disorders | Very common | Arthralgia, pain in extremity, muscle spasms |
| Common | Back pain, myalgia, bone pain | |
| Renal and urinary disorders | Common | Chromaturia |
| General disorders and administration site conditions | Very common | Fatigue, pyrexia, chills |
| Common | Asthenia, oedema peripheral, malaise | |
| Investigations | Common | Blood creatine phosphokinase increased |
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) (see section 4.4).
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 (see section 4.4).
In controlled studies in thrombocytopenic patients with HCV (n=1 439), 38 out of 955 patients (4%) treated with eltrombopag experienced a TEE and 6 out of 484 patients (1%) in the placebo 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) (see section 4.4). 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.
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 (see section 4.4).
In the controlled clinical studies in chronic ITP with eltrombopag, increases in serum ALT, AST and bilirubin were observed (see section 4.4).
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.
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 (see section 4.4).
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 (see section 4.4).
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.
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.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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