Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: GlaxoSmithKline Trading Services Limited 6900 Cork Airport Business Park Kinsale Road Cork Ireland
Hypersensitivity to eltrombopag or to any of the excipients listed in section 6.1.
Eltrombopag administration can cause abnormal liver function. In clinical studies with eltrombopag, increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin were observed (see section 4.8).
These findings were mostly mild (Grade 1-2), reversible and not accompanied by clinically significant symptoms that would indicate an impaired liver function. Across the 3 placebo-controlled studies, 1 patient in the placebo group and 1 patient in the eltrombopag group experienced a Grade 4 liver test abnormality.
Serum ALT, AST and bilirubin should be measured prior to initiation of eltrombopag, every 2 weeks during the dose adjustment phase and monthly following establishment of a stable dose. Abnormal serum liver tests should be evaluated with repeat testing within 3 to 5 days. If the abnormalities are confirmed, serum liver tests should be monitored until the abnormalities resolve, stabilise, or return to baseline levels. Eltrombopag should be discontinued if ALT levels increase (≥ 3X the upper limit of normal [ULN]) and are:
Exercise caution when administering eltrombopag to patients with hepatic disease. Use a lower starting dose of eltrombopag and monitor closely when administering eltrombopag to patients with hepatic impairment (see section 4.2).
Thrombotic/Thromboembolic complications may occur in patients with ITP. Platelet counts above the normal range present a theoretical risk of thrombotic/thromboembolic complications. In eltrombopag clinical trials 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 thromboembolic events (TEEs) of any aetiology.
The risk TEEs has been found to be increased in patients with chronic liver disease (CLD) treated with 75 mg eltrombopag once daily for two 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 %) subjects 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 should not be used in 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 exercise caution when administering eltrombopag to ITP patients with hepatic impairment (see sections 4.2 and 4.8).
Thrombocytopenia is likely to reoccur upon discontinuation of treatment with eltrombopag. Following discontinuation of eltrombopag, platelet counts return to baseline levels within 2 weeks in the majority of patients, which increase the bleeding risk and in some cases may lead to bleeding. This risk is increased if eltrombopag treatment is discontinued in the presence of anticoagulants or anti-platelet agents. It is recommended that, if treatment with eltrombopag is discontinued, ITP treatment be restarted according to current treatment guidelines. Additional medical management may include cessation of anticoagulant and/or anti-platelet therapy, reversal of anticoagulation, or platelet support. Platelet counts must be monitored weekly for 4 weeks following discontinuation of eltrombopag.
Eltrombopag may increase the risk for development or progression of reticulin fibers within the bone marrow. The relevance of this finding, as with other thrombopoietin receptor (TPO-R) agonists, has not been established yet.
Prior to initiation of eltrombopag, the peripheral blood smear should be examined closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable dose of eltrombopag, complete blood count (CBC) with white blood cell count (WBC) differential should be performed monthly. If immature or dysplastic cells are observed, peripheral blood smears should be examined for new or worsening morphological abnormalities (e.g., teardrop and nucleated red blood cells, immature white blood cells) or cytopenia(s). If the patient develops new or worsening morphological abnormalities or cytopenia(s), treatment with eltrombopag should be discontinued and a bone marrow biopsy considered, including staining for fibrosis.
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 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 use in other thrombocytopenic conditions including chemotherapy-induced thrombocytopenia or MDS. Eltrombopag should not be used for the treatment of thrombocytopenia due to MDS or any other cause of thrombocytopenia other than ITP outside of clinical trials.
Cataracts were observed in toxicology studies of eltrombopag in rodents (see section 5.3). The clinical relevance of this finding is unknown. Routine monitoring of patients for cataracts is recommended.
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.
In vitro studies demonstrated that eltrombopag is not a substrate for the organic anion transporter polypeptide, OATP1B1, but is an inhibitor of this transporter. In vitro studies also demonstrated that eltrombopag is a breast cancer resistance protein (BCRP) substrate and inhibitor. Administration of eltrombopag 75 mg once daily for 5 days with a single 10 mg dose of the OATP1B1 and BCRP substrate rosuvastatin to 39 healthy adult subjects increased plasma rosuvastatin Cmax 103 % (90 % CI: 82 %, 126 %) and AUC0-∞ 55 % (90 % CI: 42 %, 69 %). Interactions are also expected with other HMG-CoA reductase inhibitors, including pravastatin, simvastatin and lovastatin, however, clinically significant interactions are not expected between eltrombopag and atorvastatin or fluvastatin. When co-administered with eltrombopag, a reduced dose of statins should be considered and careful monitoring for statin side effects should be undertaken.
Concomitant administration of eltrombopag and OATP1B1 (e.g. methotrexate) and BCRP (e.g. topotecan and methotrexate) substrates should be undertaken with caution.
In studies utilizing human liver microsomes, eltrombopag (up to 100 μM) 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.
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 %). Antacids, dairy products and other products containing polyvalent cations, such as mineral supplements, must be administered at least four hours apart from eltrombopag dosing to avoid significant reduction in eltrombopag absorption due to chelation (see section 4.2).
Administration of a single 50 mg-dose of eltrombopag with a standard high-calorie, high-fat breakfast that included dairy products reduced plasma eltrombopag AUC0-∞ by 59 % (90 % CI: 54 %, 64 %) and Cmax by 65 % (90 % CI: 59 %, 70 %). Food low in calcium [< 50 mg calcium] including fruit, lean ham, beef and unfortified (no added calcium, magnesium, iron) fruit juice, unfortified soy milk, and unfortified grain did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content (see section 4.2).
Co-administration of eltrombopag with lopinavir/ritonavir (LPV/RTV) may cause a decrease in the concentration of eltrombopag. A study in 40 healthy volunteers showed that the co-administration of single dose eltrombopag 100 mg with repeat dose LPV/RTV 400 /100 mg twice daily resulted in a reduction in eltrombopag plasma AUC by 17 % (90 % CI: 6.6 %, 26.6 %). Therefore, caution should be used when co-administration of eltrombopag with LPV/RTV takes place. Platelet count should be closely monitored in order to ensure appropriate medical management of the dose of eltrombopag when lopinavir/ritonavir therapy is initiated or discontinued.
Medicinal products 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).
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 and 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.
No studies on the effects on the ability to drive and use machines have been performed.
Based on an analysis of all chronic ITP patients receiving eltrombopag in 3 controlled and 2 uncontrolled clinical studies, the overall incidence of adverse events in subjects treated with eltrombopag was 82 % (367/446). The median duration of exposure to eltrombopag was 304 days and patient year’s exposure was 377 in this study population.
The adverse events listed below by MedDRA system organ class and by frequency are those that the investigator considered treatment related (N = 446). The frequency categories are defined as:
Very common (≥ 1/10)
Common (≥ 1/100 to < 1/10)
Uncommon (≥ 1/1,000 to < 1/100)
Rare (≥ 1/10,000 to < 1/1,000)
Very rare (< 1/10,000)
Not known (cannot be estimated from the available data)
Uncommon: Pharyngitis, Urinary tract infection, Influenza, Nasopharyngitis, Oral herpes, Pneumonia, Sinusitis, Tonsillitis, Upper respiratory tract infection
Uncommon: Rectosigmoid cancer
Uncommon: Anaemia, Anisocytosis, Eosinophilia, Haemolytic anaemia, Leukocytosis, Myelocytosis, Thrombocytopenia, Haemoglobin increased, Band neutrophil count increased, Haemoglobin decreased, Myelocyte present, Platelet count increased, White blood cell count decreased
Uncommon: Hypersensitivity
Uncommon: Anorexia, Hypokalaemia, Decreased appetite, Increased appetite, Gout, Hypocalcaemia, Blood uric acid increased
Common: Insomnia
Uncommon: Sleep disorder, Anxiety, Depression, Apathy, Mood altered, Tearfulness
Very Common: Headache
Common: Paraesthesia
Uncommon: Dizziness, Dysgeusia, Hypoaesthesia, Somnolence, Migraine, Tremor, Balance disorder, Dysaesthesia, Hemiparesis, Migraine with aura, Neuropathy peripheral, Peripheral sensory neuropathy, Speech disorder, Toxic neuropathy, Vascular headache
Common: Cataract, Dry eye
Uncommon: Vision blurred, Lenticular opacities, Astigmatism, Cataract cortical, Conjunctival haemorrhage, Eye pain, Lacrimation increased, Retinal haemorrhage, Retinal pigment epitheliopathy, Visual acuity reduced, Visual impairment, Visual acuity tests abnormal, Blepharitis and Keratoconjunctivitis sicca
Uncommon: Ear pain, Vertigo
Uncommon: Tachycardia, Acute myocardial infarction, Cardiovascular disorder, Cyanosis, Palpitations, Sinus tachycardia, Electrocardiogram QT prolonged
Uncommon: Deep vein thrombosis, Hypertension, Embolism, Hot flush, Thrombophlebitis superficial, Flushing, Haematoma
Uncommon: Epistaxis, Pulmonary embolism, Pulmonary infarction, Cough, Nasal discomfort, Oropharyngeal blistering, Oropharyngeal pain, Sinus disorder, Sleep apnoea syndrome
Common: Nausea, Diarrhoea, Constipation, Abdominal pain upper
Uncommon: Abdominal discomfort, Abdominal distension, Dry mouth, Dyspepsia, Vomiting, Abdominal pain, Gingival bleeding, Glossodynia, Haemorrhoids, Mouth haemorrhage, Abdominal tenderness, Faeces discoloured, Flatulence, Food poisoning, Frequent bowel movements, Haematemesis, Oral discomfort
Common: Alanine aminotransferase increased*, Aspartate aminotransferase increased*, Blood bilirubin increased, Hyperbilirubinaemia, Hepatic function abnormal
Uncommon: Cholestasis, Hepatic lesion, Hepatitis
* Increase of alanine aminotransferase and aspartate aminotransferase may occur simultaneously, although at a lower frequency.
Common: Rash, Pruritus, Alopecia
Uncommon: Ecchymosis, Hyperhidrosis, Pruritus generalised, Urticaria, Dermatosis, Petechiae, Cold sweat, Erythema, Melanosis, Night sweats, Pigmentation disorder, Skin discolouration, Skin exfoliation, Swelling face
Common: Arthralgia, Myalgia, Muscle spasm, Bone pain
Uncommon: Muscular weakness, Pain in extremity, Sensation of heaviness
Uncommon: Renal failure, Leukocyturia, Lupus nephritis, Nocturia, Proteinuria, Blood urea increased, Blood creatinine increased, Urine protein/creatinine ratio increased
Common: Fatigue, Oedema peripheral
Uncommon: Chest pain, Feeling hot, Pain, Vessel puncture site haemorrhage, Asthenia, Feeling jittery, Ill-defined disorder, Inflammation of wound, Influenza like illness, Malaise, Mucosal inflammation, Non-cardiac chest pain, Pyrexia, Sensation of foreign body
Uncommon: Blood albumin increased, Blood alkaline phosphatase increased, Protein total increased, Weight increased, Blood albumin decreased, pH urine increased
Uncommon: Contusion, Sunburn
In 3 controlled and 2 uncontrolled clinical studies, among adult chronic ITP patients receiving eltrombopag (n = 446), 17 subjects experienced a total of 19 TEEs, which included (in descending order of occurrence) deep vein thrombosis (n = 6), pulmonary embolism (n = 6), acute myocardial infarction (n = 2), cerebral infarction (n = 2), embolism (n = 1) (see section 4.4).
In a placebo-controlled study (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 %) subjects 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 subjects who experienced a TEE with the exception of platelet counts ≥ 200,000/µl (see section 4.4).
In the 3 controlled clinical studies, transient decreases in platelet counts to levels lower than baseline were observed following discontinuation of treatment in 8 % and 8 % of the eltrombopag and placebo groups, respectively (see section 4.4).
Across the programme, no subjects had evidence of clinically relevant bone marrow abnormalities or clinical findings that would indicate bone marrow dysfunction. In one patient, eltrombopag treatment was discontinued due to bone marrow reticulin (see section 4.4).
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
