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英文药名：Revolade(Revolade film-coated Tablets) 中文药名：艾曲波帕片 生产厂家：葛兰素史克
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 eva luated 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). 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. The risk of thromboembolic events (TEEs) has been found to be increased in thrombocytopenic patients (platelet count < 50,000/ µl) with chronic liver disease (CLD), without concomitant ITP, treated with 75 mg eltrombopag once daily for two weeks in preparation for invasive procedures (see sections 4.4 and 4.8). Paediatric population Revolade is not recommended for use in children and adolescents below age 18 due to insufficient data on safety and efficacy. Elderly There are limited data on the use of eltrombopag in patients aged 65 years and older. 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. East Asian patients Initiation of eltrombopag at a reduced dose of 25 mg once daily may be considered for patients of East Asian ancestry (such as Chinese, Japanese, Taiwanese or Korean) (see section 5.2). Patient platelet count should continue to be monitored and the standard criteria for further dose modification followed. Method of administration The tablets should be 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. 4.4 Special warnings and precautions for use The diagnosis of ITP in adults and elderly patients should have been confirmed by the exclusion of other clinical entities presenting with thrombocytopenia. 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. The effectiveness and safety of eltrombopag have not been established for use in other thrombocytopenic conditions including chemotherapy-induced thrombocytopenia and myelodysplastic syndromes (MDS). Risk of hepatotoxicity 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 eva luated 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: • 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. 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 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 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 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). Bleeding following discontinuation of eltrombopag 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. Bone marrow reticulin formation and risk of bone marrow fibrosis 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 Malignancies and progression of malignancies 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 theoretical concern that they may stimulate the progression of existing haematopoietic malignancies such as MDS. Cataracts 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. 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. 4.5 Interaction with other medicinal products and other forms of interaction Effects of eltrombopag on other medicinal products 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 % 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. 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. 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. Effects of other medicinal products on eltrombopag 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 section 4.2). 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 section 4.2). 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 Pregnancy and lactation Pregnancy There are no or limited amount of data from the use of eltrombopag in pregnant women. Studies in animals haveshown 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. 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. 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. 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 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) Infections and infestations Uncommon
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 3: 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. 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) (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Pharmacokinetics The plasma eltrombopag concentration-time data collected in 88 subjects 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 subjects are presented (Table 4). Table 4: Geometric mean (95 % confidence intervals) of steady-state plasma eltrombopag pharmacokinetic parameters in adults with ITP
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. Metabolism 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). 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 eva luated using a population pharmacokinetic analysis in 28 healthy adults and 79 patients with chronic liver disease (37 mild hepatic impairment, 40 with moderate hepatic impairment, and 2 with severe hepatic impairment). Based on estimates from the population pharmacokinetic analysis, patients with hepatic impairment had higher plasma eltrombopag AUC(0-) values as compared to healthy volunteers, and AUC(0-) increased with increased Child-Pugh score. Compared to healthy volunteers, patients with mild hepatic impairment had approximately 87% to 110% higher plasma eltrombopag AUC (0- ) values and patients with moderate hepatic impairment had approximately 141% to 240% 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). Race The influence of East Asian ethnicity on the pharmacokinetics of eltrombopag was eva luated 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). Gender The influence of gender on the pharmacokinetics of eltrombopag was eva luated 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. 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 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 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 (2 times the human clinical exposure based on AUC). The clinical relevance of these findings is unknown (see section 4.4). 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. Renal effects were not observed in rats after 28 weeks or in dogs after 52 weeks at exposures 4 and 2 times respectively, the human clinical exposure based on AUC. The clinical relevance of these findings is unknown. 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) or dogs (52 weeks) at exposures up to 4 or 2 times, respectively, the human clinical exposure based on AUC. At poorly tolerated doses in rats and dogs (> 10 times maximum human clinical exposure 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 maximum human clinical exposure 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 maximum human clinical exposure based on AUC). There were no bone changes observed in mice or rats after lifetime exposure (2 years) at 4 times maximum human clinical exposure 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 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 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 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 (0.5 times the human clinical exposure based on AUC). However, at a maternally toxic dose of 60 mg/kg/day (6 times the human clinical exposure 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 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 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 F 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 based on AUC) or ocular phototoxicity ( 5 times the human clinical exposure 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 Revolade 25mg film-coated tablets: Tablet coating Hypromellose Macrogol 400 Polysorbate 80 Titanium dioxide (E171) Revolade 50mg film-coated tablets: Tablet coating 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 containg 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 product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER GlaxoSmithKline Trading Services Limited 6900 Cork Airport Business Park Kinsale Road Cork Ireland 8. MARKETING AUTHORISATION NUMBER(S) EU/1/10/612/001 EU/1/10/612/002 EU/1/10/612/003 EU/1/10/612/004 EU/1/10/612/005 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 02 May 2011 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.
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Revolade(Revolade film-coated Tablets)简介：
英文药名：Revolade(Revolade film-coated Tablets)
中文药名：艾曲波帕片
生产厂家：葛兰素史克药品介绍【研发公司】葛兰素史克；目前已在美国、英国、德国、澳大利亚上市；【剂型规格】片剂：25mg、 ... 责任编辑：admin |
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