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2013年9月27日，葛兰素史克（GSK），Revolade（eltrombopag，艾曲波帕）新适应症申请获欧盟委员会（EC）批准，用于治疗慢性丙型肝炎（HCV）成人患者的血小板减少症（thrombocytopenia），从而使得这些患者能够启用基于干扰素的疗法，同时也可在干扰素治疗期间应用。
Wait for at least 2 weeks to see the effect of any dose adjustment on the patient's platelet response prior to considering another dose adjustment. The standard eltrombopag dose adjustment, either decrease or increase, would be 25 mg once daily. However, in a few patients a combination of different film-coated tablet strengths on different days may be required. Discontinuation Treatment with eltrombopag should be discontinued if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after four weeks of eltrombopag therapy at 75 mg once daily. Patients should be clinically evaluated periodically and continuation of treatment should be decided on an individual basis by the treating physician. The reoccurrence of thrombocytopenia is possible upon discontinuation of treatment (see section 4.4). Chronic hepatitis C (HCV) associated thrombocytopenia When eltrombopag is given in combination with antivirals reference should be made to the full summary of product characteristics of the respective coadministered medicinal products for comprehensive details of relevant safety information or contraindications. In clinical studies, platelet counts generally began to increase within 1 week of starting eltrombopag. The aim of treatment with eltrombopag should be to achieve the minimum level of platelet counts needed to initiate antiviral therapy, in adherence to clinical practice recommendations. During antiviral therapy, the aim of treatment should be to keep platelet counts at a level that prevents the risk of bleeding complications, normally around 50,000-75,000/µl. Platelet counts > 75,000/µl should be avoided. The lowest dose of eltrombopag needed to achieve the targets should be used. Dose adjustments are based upon the platelet count response. Initial dose regimen Initiate eltrombopag at a dose of 25 mg once daily. No dosage adjustment is necessary for HCV patients of East Asian ancestry or patients with mild hepatic impairment (see section 5.2). Monitoring and dose adjustment The dose of eltrombopag should be adjusted in 25 mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate anti-viral therapy. Platelet counts should be monitored every week prior to starting antiviral therapy. On initiation of antiviral therapy the platelet count may fall, so immediate eltrombopag dose adjustments should be avoided (see Table 2). During antiviral therapy, the dose of eltrombopag should be adjusted as necessary to avoid dose reductions of peginterferon due to decreasing platelet counts that may put patients at risk of bleeding (see Table 2). Platelet counts should be monitored weekly during antiviral therapy until a stable platelet count is achieved, normally around 50,000-75,000/µl. CBCs including platelet counts and peripheral blood smears should be obtained monthly thereafter. Dose reductions on the daily dose by 25 mg should be considered if platelet counts exceed the required target. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. Do not exceed a dose of 100 mg eltrombopag once daily. Table 2 Dose adjustments of eltrombopag in HCV patients during antiviral therapy
- On initiation of antiviral therapy the platelet count may fall, so immediate eltrombopag dose reductions should be avoided. Discontinuation If after 2 weeks of eltrombopag therapy at 100 mg the required platelet level to initiate antiviral therapy is not achieved, eltrombopag should be discontinued. Eltrombopag treatment should be terminated when antiviral therapy is discontinued unless otherwise justified. Excessive platelet count responses or important liver test abnormalities also necessitate discontinuation. Special populations Renal impairment 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 (see section 5.2). Hepatic impairment 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 (see section 4.4). 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 wait 3 weeks before increasing the dose. No dose adjustment is required for thrombocytopenic patients with chronic HCV and mild hepatic impairment (Child-Pugh score ≤ 6). Thrombocytopenic patients with chronic HCV should initiate eltrombopag at a dose of 25 mg once daily (see section 5.2). After initiating the dose of eltrombopag in patients with hepatic impairment wait 2 weeks before increasing the dose. There is an increased risk for adverse events, including hepatic decompensation and thromboembolic events, in thrombocytopenic patients with advanced chronic liver disease treated with eltrombopag, either in preparation for invasive procedure or in HCV patients undergoing antiviral therapy (see sections 4.4 and 4.8). Older People There are limited data on the use of eltrombopag in ITP patients aged 65 years and older and no clinical experience in ITP patients aged over 85 years. In the clinical studies of eltrombopag, overall no clinically significant differences in safety of eltrombopag were observed between subjects aged at least 65 years and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out (see section 5.2). There are limited data on the use of eltrombopag in HCV patients aged over 75 years. Caution should be exercised in these patients (see section 4.4). East Asian patients Initiation of eltrombopag at a reduced dose of 25 mg once daily may be considered for ITP patients of East Asian ancestry (such as Chinese, Japanese, Taiwanese, Thai or Korean) (see section 5.2). Initiate eltrombopag at a dose of 25 mg once daily in HCV patients of East Asian ancestry. Patient platelet count should continue to be monitored and the standard criteria for further dose modification followed. For ITP or HCV patients of East Asian ancestry with hepatic impairment initiate eltrombopag at a dose of 25 mg once daily. Paediatric population Revolade is not recommended for use in children and adolescents below age 18 due to insufficient data on safety and efficacy. Method of administration The tablets are administered orally. Eltrombopag should be taken at least four hours before or after any products such as antacids, dairy products (or other calcium containing food products), or mineral supplements containing polyvalent cations (e.g. iron, calcium, magnesium, aluminium, selenium and zinc) (see sections 4.5 and 5.2). 4.3 Contraindications Hypersensitivity to eltrombopag or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use 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 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 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. Combination with direct acting antiviral agents Safety and efficacy have not been established in combination with direct acting antiviral agents approved for treatment of chronic hepatitis C infection. Risk of hepatotoxicity Eltrombopag administration can cause abnormal liver function. In the controlled clinical studies in chronic ITP 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 in chronic ITP, 1 patient in the placebo group and 1 patient in the eltrombopag group experienced a Grade 4 liver test abnormality. 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. 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. Eltrombopag inhibits UGT1A1 and OATP1B1, which may lead to indirect hyperbilirubinaemia. If bilirubin is elevated perform fractionation. 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 ULN in patients with normal liver function or ≥ 3X baseline in patients with pre-treatment elevations in transaminases) and are: • progressive, or • persistent for ≥ 4 weeks, or • accompanied by increased direct bilirubin, or • accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation Exercise caution when administering eltrombopag to patients with hepatic disease. In ITP patients use a lower starting dose of eltrombopag and monitor closely when administering to patients with hepatic impairment (see section 4.2). Hepatic decompensation (use with interferon) Hepatic decompensation in patients with chronic hepatitis C: Monitor patients with low albumin levels (≤ 35 g/L) or with Model for End Stage Liver Disease (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) 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 three-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 ≤ 35g/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. Thrombotic/Thromboembolic complications In controlled studies in thrombocytopenic patients with HCV receiving interferon-based therapy (n = 1439), 38 out of 955 subjects (4 %) treated with eltrombopag and 6 out of 484 subjects (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 twofold 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 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 is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease in preparation for invasive procedures. 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. 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, exercise caution when administering eltrombopag to patients with hepatic impairment (see sections 4.2 and 4.8). Bleeding following discontinuation of eltrombopag 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 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. In HCV clinical trials, 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. Bone marrow reticulin formation and risk of bone marrow fibrosis 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, 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. Progression of existing Myelodysplastic Syndrome (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 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 outside of clinical trials for the treatment of thrombocytopenia due to MDS or any other cause of thrombocytopenia other than the approved indications. Ocular changes 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 = 1439), 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. QT/QTc prolongation 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 trials of patients with ITP and thrombocytopenic patients with HCV. The clinical significance of these QTc prolongation events is unknown. Loss of response to eltrombopag A loss of response or failure to maintain a platelet response with eltrombopag treatment within the recommended dosing range should prompt a search for causative factors, including an increased bone marrow reticulin. This medicinal product contains less than 1 mmol sodium (23 mg) per 100 mg, i.e. essentially 'sodium- free'. 4.5 Interaction with other medicinal products and other forms of interaction Efects of eltrombopag on other medicinal products HCV Protease Inhibitors 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 Q8h did not alter plasma telaprevir exposure. Co-administration of a single dose of eltrombopag 200 mg with boceprevir 800 mg Q8h did not alter plasma boceprevir AUC(0-), 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. HMG CoA reductase inhibitors 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 % 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). OATP1B1 and BCRP substrates Concomitant administration of eltrombopag and OATP1B1 (e.g. methotrexate) and BCRP (e.g. topotecan and methotrexate) substrates should be undertaken with caution (see section 5.2). Cytochrome P450 substrates In studies 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 (see section 5.2). Effects of other medicinal products on eltrombopag CYP1A2 and CYP2C8 inhibitors and inducers Eltrombopag is metabolized 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. HCV Protease Inhibitors Results of a drug-drug pharmacokinetic (PK) interaction study show that co-administration of repeat doses of boceprevir 800 mg Q8h or telaprevir 750 mg Q8h with a single dose of eltrombopag 200 mg did not alter plasma eltrombopag exposure to a clinically significant extent. Polyvalent cations (chelation) 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 sections 4.2 and 5.2). Food interaction 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 sections 4.2 and 5.2). Lopinavir/ritonavir 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(0-∞) 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 for treatment of ITP 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). 4.6 Fertility, pregnancy and lactation Pregnancy 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. Women of childbearing potential / Contraception in males and females Revolade is not recommended in women of childbearing potential not using contraception. Breast-feeding 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 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). 4.7 Effects on ability to drive and use machines 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 judgment, motor and cognitive skills. 4.8 Undesirable effects Based on an analysis of all chronic ITP patients receiving eltrombopag in 3 controlled and 2 uncontrolled clinical studies, the overall incidence of adverse reactions 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. ENABLE 1 (TPL103922 N=716) and ENABLE 2 (TPL108390 N=805) were randomized, double-blind, placebo-controlled, multicentre studies to assess the efficacy and safety of eltrombopag in thrombocytopenic subjects with HCV infection who were otherwise eligible to initiate antiviral therapy with interferon and ribavirin therapy(see section 5.1). In the HCV studies the safety population consisted of all randomized subjects who received double-blind study drug during Part 2 of ENABLE 1 (eltrombopag treatment N=449, placebo N=232) and ENABLE 2 (eltrombopag treatment N=506, placebo N=252). Subjects 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 in the ITP or HCV trials were hepatotoxicity and thrombotic/thromboembolic events. The most common adverse reactions (experienced by at least 10 % of patients) of any grade in the ITP or HCV trials included; headache, anaemia, decreased appetite, insomnia, cough, nausea, diarrhoea, alopecia, pruritus, myalgia, pyrexia, fatigue, influenza like illness, asthenia, chills and peripheral oedema. The adverse reactions in the ITP studies (N = 446) and in the HCV studies (N = 955) are listed below by MedDRA system organ class and by frequency: 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) Summary of the safety profile Tabulated list of adverse reactions ITP study population Infections and infestations Uncommon Pharyngitis, Urinary tract infection, Influenza, Nasopharyngitis, Oral herpes, Pneumonia, Sinusitis, Tonsillitis, Upper respiratory tract infection Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uncommon Rectosigmoid cancer Blood and lymphatic system disorders 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 Immune system disorders Uncommon Hypersensitivity Metabolism and nutrition disorders Uncommon Anorexia, Hypokalaemia, Decreased appetite, Increased appetite, Gout, Hypocalcaemia, Blood uric acid increased Psychiatric disorders Common Insomnia Uncommon Sleep disorder, Anxiety, Depression, Apathy, Mood altered, Tearfulness Nervous systems disorders 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 Eye disorders 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 Ear and labyrinth disorders Uncommon Ear pain, Vertigo Cardiac disorders Uncommon Tachycardia, Acute myocardial infarction, Cardiovascular disorder, Cyanosis, Palpitations, Sinus tachycardia, Electrocardiogram QT prolonged Vascular disorders Uncommon Deep vein thrombosis, Hypertension, Embolism, Hot flush, Thrombophlebitis superficial, Flushing, Haematoma Respiratory, thoracic and mediastinal disorders Uncommon Epistaxis, Pulmonary embolism, Pulmonary infarction, Cough, Nasal discomfort, Oropharyngeal blistering, Oropharyngeal pain, Sinus disorder, Sleep apnoea syndrome Gastrointestinal disorders 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 Hepatobiliary disorders 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. Skin and subcutaneous tissue disorders 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 Musculoskeletal and connective tissue disorders Common Arthralgia, Myalgia, Muscle spasm, Bone pain Uncommon Muscular weakness, Pain in extremity, Sensation of heaviness Renal and urinary disorders Uncommon Renal failure, Leukocyturia, Lupus nephritis, Nocturia, Proteinuria, Blood urea increased, Blood creatinine increased, Urine protein/creatinine ratio increased General disorders and administration site conditions 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 Investigations Uncommon Blood albumin increased, Blood alkaline phosphatase increased, Protein total increased, Weight increased, Blood albumin decreased, pH urine increased Injury, poisoning and procedural complications Uncommon Contusion, Sunburn HCV study population (in combination with anti-viral interferon and ribavirin therapy) Infections and infestations Common Urinary tract infection, Upper respiratory tract infection, Bronchitis, Nasopharyngitis, Influenza, Oral herpes, 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, Haemolytic anaemia Metabolism and nutrition disorders Very common Decreased appetite Common Hyperglycaemia, Abnormal loss of weight Psychiatric disorders Very common Insomnia Common Depression, Anxiety, Sleep disorder, Confusional state, Agitation Nervous systems disorders Very common Headache Common
b 21 out of 63 (33 %) patients treated with eltrombopag who were taking an ITP medication at baseline permanently discontinued all baseline ITP medications. At baseline, more than 70 % of ITP patients in each treatment group reported any bleeding (WHO Grades 1-4) and more than 20 % reported clinically significant bleeding (WHO Grades 2-4), respectively. The proportion of eltrombopag-treated patients with any bleeding (Grades 1-4) and clinically significant bleeding (Grades 2-4) was reduced from baseline by approximately 50 % from Day 15 to the end of treatment throughout the 6 month treatment period. TRA100773B: The primary efficacy endpoint was the proportion of responders, defined as ITP patients who had an increase in platelet counts to ≥ 50,000/μl at Day 43 from a baseline of < 30,000/μl; patients who withdrew prematurely due to a platelet count > 200,000/μl were considered responders, those that discontinued for any other reason were considered non-responders irrespective of platelet count. A total of 114 patients with previously treated chronic ITP were randomised 2:1 eltrombopag (n = 76) to placebo (n = 38). Table 4: Efficacy results from TRA100773B
In both RAISE and TRA100773B the response to eltrombopag relative to placebo was similar irrespective of ITP medication use, splenectomy status and baseline platelet count (≤ 15,000/µl, > 15,000/µl) at randomisation. In RAISE and TRA100773B studies, in the subgroup of ITP patients with baseline platelet count ≤ 15,000/μl the median platelet counts did not reach the target level (> 50,000/μl), although in both studies 43 % of these patients treated with eltrombopag responded after 6 weeks of treatment. In addition, in the RAISE study, 42 % of patients with baseline platelet count ≤ 15,000/μl treated with eltrombopag responded at the end of the 6 month treatment period. Forty-two to 60 % of the eltrombopag-treated patients in the RAISE study were receiving 75 mg from Day 29 to the end of treatment. An open label, repeat dose study (3 cycles of 6 weeks of treatment, followed by 4 weeks off treatment) showed that episodic use with multiple courses of eltrombopag has demonstrated no loss of response. Eltrombopag was administered to 299 ITP patients in an open-label extension study, 126 patients completed 1 year, 48 completed 18 months and 17 completed 2 years. The median baseline platelet count was 19,500/μl prior to eltrombopag administration. Median platelet counts at 12, 18 and 24 months on study were 68,000/μl, 75,000/μl and 119,000/μl, respectively. Chronic hepatitis C associated thrombocytopenia studies The efficacy and safety of eltrombopag for the treatment of thrombocytopenia in patients with HCV infection were evaluated in two randomized, double-blind, placebo-controlled studies. ENABLE 1 utilized peginterferon alfa-2a plus ribavirin for antiviral treatment and ENABLE 2 utilized peginterferon alfa-2b plus ribavirin. Patients did not receive direct acting antiviral agents. In both studies, patients with a platelet count of < 75,000/µl were enrolled and stratified by platelet count (< 50,000/µl and ≥ 50,000/µl to < 75,000/µl), screening HCV RNA (< 800,000 IU/ml and ≥ 800,000 IU/ml), and HCV genotype (genotype 2/3, and genotype 1/4/6). Baseline disease characteristics were similar in both studies and were consistent with compensated cirrhotic HCV patient population. The majority of patients were HCV genotype 1 (64 %) and had bridging fibrosis/cirrhosis. Thirty-one percent of patients had been treated with prior HCV therapies, primarily pegylated interferon plus ribavirin. The median baseline platelet count was 59,500/µl in both treatment groups: 0.8 %, 28 % and 72 % of the patients recruited had platelet counts < 20,000/µl, < 50.000/µl and ≥ 50,000/µl respectively. The studies consisted of two phases – a pre-antiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, subjects received open-label eltrombopag to increase the platelet count to ≥ 90,000/µl for ENABLE 1 and ≥ 100,000/µl for ENABLE 2. The median time to achieve the target platelet count ≥ 90,000/µl (ENABLE 1) or ≥ 100,000/µl (ENABLE 2) was 2 weeks. The primary efficacy endpoint for both studies was sustained virologic response (SVR), defined as the percentage of patients with no detectable HCV-RNA at 24 weeks after completion of the planned treatment period. In both HCV studies, a significantly greater proportion of patients treated with eltrombopag (n = 201, 21 %) achieved SVR compared to those treated with placebo (n=65, 13 %) (see Table 5). The improvement in the proportion of patients who achieved SVR was consistent across all subgroups in the randomisation strata (baseline platelet counts (< 50,000 vs. > 50,000), viral load (< 800,000 IU/ml vs. ≥ 800,000 IU/ml) and genotype (2/3 vs. 1/4/6)). Table 5: Virologic response in HCV patients in ENABLE 1 and ENABLE 2
b Eltrombopag given in combination with peginterferon alfa-2b (1.5 mcg/kg once weekly for 48 weeks for genotype 1/4/6; 24 weeks for genotype 2/3) plus ribavirin (800 to 1400 mg orally in 2 divided doses) c Target platelet count was ≥ 90,000/µl for ENABLE 1 and ≥ 100,000/µl for ENABLE 2. For ENABLE 1, 682 patients were randomised to the antiviral treatment phase; however 2 subjects then withdrew consent prior to receiving antiviral therapy. d P value < 0.05 for eltrombopag versus placebo e 64 % subjects participating in ENABLE 1 and ENABLE 2 were genotype 1 f Post-hoc analyses Other secondary findings of the studies included the following; significantly fewer patients treated with eltrombopag prematurely discontinued antiviral therapy compared to placebo (45 % vs. 60 %, p = < 0.0001). A greater proportion of patients on eltrombopag did not require any antiviral dose reduction as compared to placebo (45 % versus 27 %). Eltrombopag treatment delayed and reduced the number of peginterferon dose reductions. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Revolade in one or more subsets of the paediatric population in chronic idiopathic thrombocytopenic purpura (ITP) and Secondary Thrombocytopenia (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Pharmacokinetics The plasma eltrombopag concentration-time data collected in 88 patients with ITP in Studies TRA100773A and TRA100773B were combined with data from 111 healthy adult subjects in a population PK analysis. Plasma eltrombopag AUC(0-) and Cmax estimates for ITP patients are presented (Table 6). Table 6: Geometric mean (95 % confidence intervals) of steady-state plasma eltrombopag pharmacokinetic parameters in adults with ITP
Plasma eltrombopag concentration-time data collected in 590 subjects with HCV enrolled in Phase III studies TPL103922/ENABLE 1 and TPL108390/ENABLE 2 were combined with data from patients with HCV enrolled in the Phase II study TPL102357 and healthy adult subjects in a population PK analysis. Plasma eltrombopag Cmax AUC(0-) estimates for patients with HCV enrolled in the Phase 3 studies are presented for each dose studied in Table 7. Table 7 Geometric mean (95 % CI) steady-state plasma eltrombopag pharmacokinetic parameters in patients with chronic HCV
AUC (0-) and Cmax based on population PK post-hoc estimates at the highest dose in the data for each patient. Absorption and bioavailability Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Administration of eltrombopag concomitantly with antacids and other products containing polyvalent cations such as dairy products and mineral supplements significantly reduces eltrombopag exposure (see section 4.2). The absolute oral bioavailability of eltrombopag after administration to humans has not been established. Based on urinary excretion and metabolites eliminated in faeces, the oral absorption of drug-related material following administration of a single 75 mg eltrombopag solution dose was estimated to be at least 52 %. Distribution Eltrombopag is highly bound to human plasma proteins (> 99.9 %), predominantly to albumin. Eltrombopag is a substrate for BCRP, but is not a substrate for P-glycoprotein or OATP1B1. Biotransformation Eltrombopag is primarily metabolized through cleavage, oxidation and conjugation with glucuronic acid, glutathione, or cysteine. In a human radiolabel study, eltrombopag accounted for approximately 64 % of plasma radiocarbon AUC0-∞. Minor metabolites due to glucuronidation and oxidation were also detected. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for oxidative metabolism of eltrombopag. Uridine diphosphoglucuronyl transferase UGT1A1 and UGT1A3 are responsible for glucuronidation, and bacteria in the lower gastrointestinal tract may be responsible for the cleavage pathway. Elimination Absorbed eltrombopag is extensively metabolised. The predominant route of eltrombopag excretion is via faeces (59 %) with 31 % of the dose found in the urine as metabolites. Unchanged parent compound (eltrombopag) is not detected in urine. Unchanged eltrombopag excreted in faeces accounts for approximately 20 % of the dose. The plasma elimination half-life of eltrombopag is approximately 21-32 hours. Pharmacokinetic interactions Based on a human study with radiolabelled eltrombopag, glucuronidation plays a minor role in the metabolism of eltrombopag. Human liver microsome studies identified UGT1A1 and UGT1A3 as the enzymes responsible for eltrombopag glucuronidation. Eltrombopag was an inhibitor of a number of UGT enzymes in vitro. Clinically significant drug interactions involving glucuronidation are not anticipated due to limited contribution of individual UGT enzymes in the glucuronidation of eltrombopag. Approximately 21 % of an eltrombopag dose could undergo oxidative metabolism. Human liver microsome studies identified CYP1A2 and CYP2C8 as the enzymes responsible for eltrombopag oxidation. Eltrombopag does not inhibit or induce CYP enzymes based on in vitro and in vivo data (see section 4.5). In vitro studies demonstrate that eltrombopag is an inhibitor of the OATP1B1 transporter and an inhibitor of the BCRP transporter and eltrombopag increased exposure of the OATP1B1 and BCRP substrate rosuvastatin in a clinical drug interaction study (see section 4.5). In clinical studies with eltrombopag, a dose reduction of statins by 50 % was recommended. Eltrombopag chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, selenium and zinc (see sections 4.2 and 4.5). Administration of a single 50 mg dose of eltrombopag with a standard high-calorie, high-fat breakfast that included dairy products reduced plasma eltrombopag AUC(0-∞) and Cmax. Whereas, low-calcium food [< 50 mg calcium] did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content (see sections 4.2 and 4.5). Special patient populations Renal impairment The pharmacokinetics of eltrombopag has been studied after administration of eltrombopag to adult subjects with renal impairment. Following administration of a single 50 mg-dose, the AUC0-∞ of eltrombopag was 32 % to 36 % lower in subjects with mild to moderate renal impairment, and 60 % lower in subjects with severe renal impairment compared with healthy volunteers. There was substantial variability and significant overlap in exposures between patients with renal impairment and healthy volunteers. Unbound eltrombopag (active) concentrations for this highly protein bound medicinal product were not measured. Patients with impaired renal function should use eltrombopag with caution and close monitoring, for example by testing serum creatinine and/or urine analysis (see section 4.2). The efficacy and safety of eltrombopag has not been established in subjects with both moderate to severe renal impairment and hepatic impairment. Hepatic impairment The pharmacokinetics of eltrombopag has been studied after administration of eltrombopag to adult subjects with hepatic impairment. Following the administration of a single 50 mg dose, the AUC0-∞ of eltrombopag was 41 % higher in subjects with mild hepatic impairment and 80 % to 93 % higher in subjects with moderate to severe hepatic impairment compared with healthy volunteers. There was substantial variability and significant overlap in exposures between patients with hepatic impairment and healthy volunteers. Unbound eltrombopag (active) concentrations for this highly protein bound medicinal product were not measured. 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 were with mild hepatic impairment, 67 with moderate hepatic impairment, and 2 with severe hepatic impairment. Compared to healthy volunteers, patients with mild hepatic impairment had approximately 111 % (95 % CI: 45 % to 283 %) higher plasma eltrombopag AUC(0-) values and patients with moderate hepatic impairment had approximately 183 % (95 % CI: 90 % to 459 %) higher plasma eltrombopag AUC(0-) values. Therefore, eltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥ 5) unless the expected benefit outweighs the identified risk of portal venous thrombosis (see sections 4.2 and 4.4). For patients with HCV initiate eltrombopag at a dose of 25 mg once daily (see section 4.2). Race The influence of East Asian ethnicity on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 healthy adults (31 East Asians) and 88 patients with ITP (18 East Asians). Based on estimates from the population pharmacokinetic analysis, East Asian (i.e. Japanese, Chinese, Taiwanese and Korean) ITP patients had approximately 87 % higher plasma eltrombopag AUC(0-) values as compared to non-East Asian patients who were predominantly Caucasian, without adjustment for body weight differences (see section 4.2). The influence of East Asian ethnicity (such as Chinese, Japanese, Taiwanese, Korean, and Thai) on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 635 patients with HCV (145 East Asians and 69 Southeast Asians). Based on estimates from the population pharmacokinetic analysis, East Asian patients had approximately 55 % higher plasma eltrombopag AUC(0-) values as compared to patients of other races who were predominantly Caucasian (see section 4.2). Gender The influence of gender on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 healthy adults (14 females) and 88 patients with ITP (57 females). Based on estimates from the population pharmacokinetic analysis, female ITP patients had approximately 50 % higher plasma eltrombopag AUC(0-) as compared to male patients, without adjustment for body weight differences. The influence of gender on eltrombopag pharmacokinetics was evaluated using population pharmacokinetics analysis in 635 patients with HCV (260 females). Based on model estimate, female HCV patient had approximately 41 % higher plasma eltrombopag AUC(0-) as compared to male patients. Age The influence of age on eltrombopag pharmacokinetics was evaluated using population pharmacokinetics analysis in 28 healthy subjects, 673 patients with HCV, and 41 patients with chronic liver disease of other aetiology ranging from 19 to 74 years old. There are no PK data on the use of eltrombopag in patients ≥ 75 years. Based on model estimate, elderly (≥ 65 years) patients had approximately 41 % higher plasma eltrombopag AUC(0-) as compared to younger patients (see section 4.2). 5.3 Preclinical safety data Eltrombopag does not stimulate platelet production in mice, rats or dogs because of unique TPO receptor specificity. Therefore, data from these animals do not fully model potential adverse effects related to the pharmacology of eltrombopag in humans, including the reproduction and carcinogenicity studies. Treatment-related cataracts were detected in rodents and were dose and time-dependent. At ≥ 6 times the human clinical exposure in ITP patients at 75 mg/day and 3 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC, cataracts were observed in mice after 6 weeks and rats after 28 weeks of dosing. At ≥ 4 times the human clinical exposure in ITP patients at 75 mg/day and 2 times the human exposure in HCV patients at 100 mg/day, based on AUC, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing. Cataracts have not been observed in dogs after 52 weeks of dosing (at 2 times the human clinical exposure in ITP patients at 75 mg/day and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on AUC). Renal tubular toxicity was observed in studies of up to 14 days duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2 year oral carcinogenicity study in mice at doses of 25, 75 and 150 mg/kg/day. Effects were less severe at lower doses and were characterized by a spectrum of regenerative changes. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 0.6 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC. Renal effects were not observed in rats after 28 weeks or in dogs after 52 weeks at exposures 4 and 2 times, the human clinical exposure in ITP patients at 75 mg/day and 2 times and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on AUC. Hepatocyte degeneration and/or necrosis, often accompanied by increased serum liver enzymes, was observed in mice, rats and dogs at doses that were associated with morbidity and mortality or were poorly tolerated. No hepatic effects were observed after chronic dosing in rats (28 weeks) and in dogs (52 weeks) at 4 or 2 times the human clinical exposure in ITP patients at 75 mg/day and 2 times and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on AUC. At poorly tolerated doses in rats and dogs (> 10 times the human clinical exposure in ITP patients at 75 mg/day and > 4 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC), decreased reticulocyte counts and regenerative bone marrow erythroid hyperplasia (rats only) were observed in short term studies. There were no effects of note on red cell mass or reticulocyte counts after dosing for up to 28 weeks in rats, 52 weeks in dogs and 2 years in mice or rats at maximally tolerated doses which were 2 to 4 times human clinical exposure in ITP patients at 75 mg/day and ≤ 2 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC. Endosteal hyperostosis was observed in a 28 week toxicity study in rats at a non-tolerated dose of 60 mg/kg/day (6 times the human clinical exposure in ITP patients at 75 mg/day and 3 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC). There were no bone changes observed in mice or rats after lifetime exposure (2 years) at 4 times the human clinical exposure in ITP patients at 75 mg/day and 2 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC. Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure in ITP patients at 75 mg/day and 2 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure in ITP patients at 75 mg/day and 7 times the human clinical exposure in HCV patients at 100 mg/day, based on Cmax). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (< 3-fold increase in mutation frequency). These in vitro and in vivo findings suggest that eltrombopag does not pose a genotoxic risk to humans. Eltrombopag did not affect female fertility, early embryonic development or embryofoetal development in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure in ITP patients at 75 mg/day and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on AUC). Also there was no effect on embryofoetal development in rabbits at doses up to 150 mg/kg/day, the highest dose tested (0.3 to 0.5 times the human clinical exposure in ITP patients at 75 mg/day and HCV patients at 100 mg/day, based on AUC). However, at a maternally toxic dose of 60 mg/kg/day (6 times the human clinical exposure in ITP patients at 75 mg/day and 3 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC) in rats, eltrombopag treatment was associated with embryo lethality (increased pre- and post-implantation loss), reduced foetal body weight and gravid uterine weight in the female fertility study and a low incidence of cervical ribs and reduced foetal body weight in the embryofoetal development study. Eltrombopag should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus (see section 4.6). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure in ITP patients at 75 mg/day and 2 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC). In the pre- and post-natal development study in rats, there were no undesirable effects on pregnancy, parturition or lactation of F0 female rats at maternally non-toxic doses (10 and 20 mg/kg/day) and no effects on the growth, development, neurobehavioral or reproductive function of the offspring (F1). Eltrombopag was detected in the plasma of all F1 rat pups for the entire 22 hour sampling period following administration of medicinal product to the F0 dams, suggesting that rat pup exposure to eltrombopag was likely via lactation. In vitro studies with eltrombopag suggest a potential phototoxicity risk; however, in rodents there was no evidence of cutaneous phototoxicity (10 times the human clinical exposure in ITP patients at 75 mg/day and 5 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC) or ocular phototoxicity (≥ 5 times the human clinical exposure in ITP patients at 75 mg/day and 3 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC). Furthermore, a clinical pharmacology study in 36 subjects showed no evidence that photosensitivity was increased following administration of eltrombopag 75 mg. This was measured by delayed phototoxic index. Nevertheless, a potential risk of photoallergy cannot be ruled out since no specific preclinical study could be performed. 6. Pharmaceutical particulars 6.1 List of excipients Tablet core Magnesium stearate Mannitol (E421) Microcrystalline cellulose Povidone (K30) Sodium starch glycolate Type A Tablet coating (25 mg) Hypromellose Macrogol 400 Polysorbate 80 Titanium dioxide (E171) Tablet coating (50mg) Hypromellose Iron oxide red (E172) Iron oxide yellow (E172) Macrogol 400 Titanium dioxide (E171) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 4 years. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container 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. 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder GlaxoSmithKline Trading Services Limited Currabinny Carrigaline County Cork Ireland 8. Marketing authorisation number(s) 25 mg (14 tablets) EU/1/10/612/001 25 mg (28 tablets) EU/1/10/612/002 25 mg (84 tablets) EU/1/10/612/003 50mg (14 tablets) EU/1/10/612/004 50mg (28 tablets) EU/1/10/612/005 50 mg (84 tablets) EU/1/10/612/006 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 11 March 2010 10. Date of revision of the text 22 May 2014 POM Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.ema.europa.eu/. --------------------------------------------------------------- 产地国家: 英国 原产地英文商品名: Revolade 25MG 14 TABLETS. 原产地英文药品名: LTROMBOPAG OLAMINE 中文参考商品译名: Revolade 25毫克/片 14片/盒 中文参考药品译名: 艾曲波帕乙醇胺 生产厂家中文参考译名: 葛兰素史克 生产厂家英文名: GlaxoSmithKline --------------------------------------------------------------- 产地国家: 英国 原产地英文商品名: Revolade 50 MG 14TABLETS. 原产地英文药品名: LTROMBOPAG OLAMINE 中文参考商品译名: Revolade 50毫克/片 14片/盒 中文参考药品译名: 艾曲波帕乙醇胺 生产厂家中文参考译名: 葛兰素史克 生产厂家英文名: GlaxoSmithKline --------------------------------------------------------------- 产地国家: 美国 原产地英文商品名: PROMACTA 12.5 MG 30 TABLETS 原产地英文药品名: ELTROMBOPAG OLAMINE 中文参考商品译名: 艾曲波帕 12.5毫克/片 30片/盒 中文参考药品译名: 伊屈泼帕乙醇胺 生产厂家中文参考译名: 葛兰素史克 生产厂家英文名: GLAXOSMITHKLINE --------------------------------------------------------------- 产地国家: 美国 原产地英文商品名: PROMACTA 25 MG 30 TABLETS 原产地英文药品名: ELTROMBOPAG OLAMINE 中文参考商品译名: 艾曲波帕 25毫克/片 30片/盒 中文参考药品译名: 伊屈泼帕乙醇胺 生产厂家中文参考译名: 葛兰素史克 生产厂家英文名: GLAXOSMITHKLINE
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艾曲波帕片|Revolade（ELTROMBOPAG OLAMINE TABLETS）简介：
2013年9月27日，葛兰素史克（GSK），Revolade（eltrombopag，艾曲波帕）新适应症申请获欧盟委员会（EC）批准，用于治疗慢性丙型肝炎（HCV）成人患者的血小板减少症（thrombocytopenia），从而使得这些患 ... 责任编辑：admin |
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