1、1ANNEX ISUMMARY OF PRODUCT CHARACTERISTICS2This medicine is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section4.8 for how to report adverse reactions.1 NAME OF THE
2、 MEDICINAL PRODUCTDacogen 50mg powder for concentrate for solution for infusion.2 QUALITATIVE AND QUANTITATIVE COMPOSITIONEach vial of powder contains 50mg decitabine.After reconstitution with 10ml of water for injections, each ml of concentrate contains 5mg of decitabine.Excipients with known effec
3、t: Each vial contains 0.5mmol potassium (E340) and 0.29mmol sodium (E524).For the full list of excipients, see section 6.1.3 PHARMACEUTICAL FORMPowder for concentrate for solution for infusion(powder for infusion).White to almost white lyophilized powder.4 CLINICAL PARTICULARS4.1 Therapeutic indicat
4、ionsDacogen is indicated for the treatment of adult patients aged65years and above with newly diagnosed de novo or secondary acute myeloid leukaemia (AML), according to the World Health Organisation (WHO) classification, who are not candidates for standard induction chemotherapy.4.2 Posology and met
5、hod of administrationDacogen administration must be initiated under the supervision of physicians experienced in the use of chemotherapeutic agents.PosologyIn a treatment cycle, Dacogenis administered at a dose of 20mg/m2 body surface area by intravenous infusion over 1 hour repeated daily for 5 con
6、secutive days (i.e., a total of 5doses per treatment cycle). The total daily dose must not exceed 20mg/m2 and the total dose per treatment cycle must not exceed 100mg/m2. If a dose is missed, treatment should be resumed as soon as possible. The cycle should be repeated every 4weeks depending on the
7、patients clinical response and observed toxicity. It is recommended that patients be treated for a minimum of 4cycles; however, a complete or partial remission may take longer than 4 cycles to be obtained. Treatment may be continued as long as the patient shows response, continues to benefit or exhi
8、bits stable disease, i.e., in the absence of overt progression.If after 4cycles, the patients haematological values (e.g., platelet counts or absolute neutrophil count), have not returned to pre-treatment levels or if disease progression occurs (peripheral blast counts are 3increasing or bone marrow
9、 blast counts are worsening), the patient may be considered to be a non-responder and alternative therapeutic options to Dacogen should be considered.Pre-medication for the prevention of nausea and vomiting is not routinely recommended but may be administered if required.Management of myelosuppressi
10、on and associated complicationsMyelosuppression and adverse events related to myelosuppression (thrombocytopaenia, anaemia, neutropaenia, and febrile neutropaenia) are common in both treated and untreated patients with AML. Complications of myelosuppression include infections and bleeding. Treatment
11、 may be delayed at the discretion of the treating physician, if the patient experiencesmyelosuppression-associated complications, such as those described below: Febrile neutropaenia(temperature 38.5C and absolute neutrophil count 60years with AML according to the WHO classification. The primary endp
12、oint was complete remission (CR) rate that was assessed by independent expert review. The secondary endpoint of the study was overall survival. Dacogen was administered as a 1-hour intravenous infusion of 20mg/m2 once daily for 5consecutive days repeated every 4weeks. In the intent-to-treat analysis
13、, a CR rate of 23.6% (95% CI: 13.2,37) was observed in 13/55subjects treated with Dacogen. The median time to CR was 4.1 months, and the median duration of CR was 18.2months. The median overall survival in the intent-to-treat population was 7.6months (95% CI: 5.7, 11.5).The efficacy and safety of Da
14、cogen has not been evaluated in patients with acute promyelocytic leukaemia or CNS leukaemia.Paediatric populationThe European Medicines Agency has deferred the obligation to submit the results of studies with Dacogen in one or more subsets of the paediatric population for the treatment ofacute myel
15、oid leukaemia. See Section 4.2 for information on paediatric use.5.2 Pharmacokinetic propertiesThe population pharmacokinetic (PK) parameters of decitabine were pooled from 3clinical studies in 45patients with AML or myelodysplastic syndrome (MDS) utilizing the 5-Day regimen. In each study, decitabi
16、ne PK was evaluated on the fifth day of the first treatment cycle.DistributionThe pharmacokinetics of decitabine following intravenous administration as a 1-hour infusion weredescribed by a linear two-compartment model, characterised by rapid elimination of the drug from the central compartment and
17、by relatively slow distribution from the peripheral compartment. For a typical patient (weight 70 kg/body surface area1.73m2) the decitabine pharmacokinetic parameters are listed in the Table3below.Table 3: Summary of population PK analysis for a typical patient receiving daily 1-hour infusions of D
18、acogen 20mg/m2 over 5 days every 4weeksParametera Predicted Value 95%CICmax (ng/ml) 107 88.5-129AUCcum (ng.h/ml) 580 480-695t1/2 (min) 68.2 54.2-79.6Vdss (L) 116 84.1-153CL (L/h) 298 249-359a The total dose per cycle was 100mg/m211Decitabine exhibits linear PK and following the intravenous infusion,
19、 steady-state concentrations are reached within 0.5hour. Based on model simulation, PK parameters were independent of time (i.e., did not change from cycle to cycle) and no accumulation was observed with this dosing regimen. Plasma protein binding of decitabine is negligible ( 200L/h with moderate i
20、nter-subject variability (Coefficient of variation CVis approximately 50%). Excretion of unchanged drug appears to play only a minor role in the elimination of decitabine.Results from a mass balance study with radioactive 14C-decitabine in cancer patients showed that 90% of the administered dose of
21、decitabine (4% unchanged drug) is excreted in the urine.Additional information on special populationsThe effects of renal or hepatic impairment, gender, age or race on the pharmacokinetics of decitabine have not been formally studied. Information on special populations was derived from pharmacokinet
22、ic data from the 3studies noted above, and from one Phase I study in MDS subjects,(N= 14; 15mg/m2 x3-hours q8hx3 days).Older peoplePopulation pharmacokinetic analysis showed that decitabine pharmacokinetics are not dependent on age (range studied 40to87years; median 70years).GenderPopulation pharmac
23、okinetic analysis of decitabine did not show any clinically relevant difference between men and women.RaceMost of the patients studied were Caucasian. However, the population pharmacokinetic analysis of decitabine indicated that race had no apparent effect on the exposure to decitabine.Hepatic impai
24、rmentThe PK of decitabine have not been formally studied in patients with hepatic impairment. Results from a human mass-balance study and in vitro experiments mentioned above indicated that the CYP enzymes are unlikely to be involved in the metabolism of decitabine. In addition,the limited data from
25、 the population PK analysis indicated no significant PK parameter dependencies on total bilirubin concentration despite a wide range of total bilirubin levels. Thus, decitabine exposure is not likely to be affected in patients with impaired hepatic function.12Renal impairmentThe PK of decitabine hav
26、e not been formally studied in patients with renal insufficiency. The population PK analysis on the limited decitabine data indicated no significant PK parameter dependencies on normalized creatinine clearance, an indicator of renal function. Thus, decitabine exposure is not likely to be affected in
27、 patients with impaired renal function.5.3 Preclinical safety dataFormal carcinogenicity studies have not been performed with decitabine. Evidence from the literature indicates that decitabine has carcinogenic potential. The available data from in vitro and in vivo studies provide sufficient evidenc
28、e that decitabine has genotoxic potential. Data from the literature also indicate that decitabine has adverse effects on all aspects of the reproductive cycle, including fertility, embryo-foetal development and post-natal development. Multi-cycle repeat-dose toxicity studies in rats and rabbits indi
29、cated that the primary toxicity was myelosuppression, including effects on bone marrow, which was reversible on cessation of treatment. Gastrointestinal toxicity was also observed and in males, testicular atrophy which did not reverse over the scheduled recovery periods. Decitabine administration to
30、 neonatal/juvenile rats showed a comparable general toxicity profile as in older rats. Neurobehavioural development and reproductive capacity were unaffected when neonatal/juvenile rats were treated at dose levels inducing myelosuppression.See section4.2 for information on paediatric use.6 PHARMACEU
31、TICAL PARTICULARS6.1 List of excipientsPotassium dihydrogen phosphate(E340)Sodium hydroxide(E524)Hydrochloric acid (for pH adjustment)6.2 IncompatibilitiesThis medicinal product must not be mixed with other medicinal productsexcept those mentioned in section6.6.6.3 Shelf lifeUnopened vial3years.Reco
32、nstitutedand dilutedsolutionWithin 15minutes of reconstitution,the concentrate(in 10ml of sterile water for injections) must be further diluted with cold (2C -8C) infusion fluids. This prepared diluted solutionfor intravenous infusion canbe stored at 2C -8C for up to a maximum of 3hours, followed by
33、 up to 1hourat room temperature(20C -25C) before administration.From a microbiological point of view, the product should be used within the time period recommended above. It is the responsibility of the user to follow the recommended storage times and conditions and ensure that reconstitution has ta
34、ken place in aseptic conditions.6.4 Special precautions for storageDo not store above 25C.For storage conditions of the reconstituted and diluted medicinal product,see section 6.3.136.5 Nature and contents of containerClear colourless Type I 20ml glassvial sealed with a bromobutyl rubber stopper and
35、 an aluminium seal with plastic flip-off capcontaining 50mg decitabine.Pack size: 1vial.6.6 Special precautions for disposal and other handlingRecommendations for safe handlingSkin contact with the solution should be avoided and protective gloves must be worn. Standard procedures for dealing with an
36、ticancer agents should be adopted.Reconstitution procedureThe powder should be aseptically reconstituted with 10ml of water for injections. Upon reconstitution, each ml contains approximately 5mg of decitabine at pH6.7to 7.3. Within 15minutes of reconstitution, the solution must be further diluted w
37、ith cold infusion fluids sodium chloride 9mg/ml (0.9%) solution for injection or 5% glucose solution forinjectionto a final concentration of 0.1to1.0 mg/ml.For the shelf-life and the precaution for storage after reconstitution, see section6.3.Dacogen should not be infused through the same intravenou
38、s access/line withother medicinal products.DisposalThis medicinal product is for single use only. Any unused product or waste material should be disposed of in accordance with local requirements.7 MARKETING AUTHORISATION HOLDERJanssen-Cilag International NVTurnhoutseweg 30B-2340 BeerseBelgium8 MARKE
39、TING AUTHORISATION NUMBEREU/1/12/792/0019 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATIONDate of first authorisation: 20 September 201210 DATE OF REVISION OF THE TEXTDetailed information on this medicinal product is available on the website of the European Medicines Agency (EMA) http:/www.e
40、ma.europa.eu/14ANNEX IIA. MANUFACTURER RESPONSIBLE FOR BATCH RELEASEB. CONDITIONS ORRESTRICTIONS REGARDING SUPPLY AND USEC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATIOND. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT15A. MANUFACTURE
41、R RESPONSIBLE FOR BATCH RELEASEName and address of the manufacturer responsible for batch releaseJanssen Pharmaceutica N.V.Turnhoutseweg 30B-2340 BeerseBelgiumB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USEMedicinal product subject to restricted medical prescription (see Annex I: Summary of P
42、roduct Characteristics, section4.2).C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION Periodic Safety Update ReportsThe marketing authorisation holder shall submit periodic safety update reports for this product in accordance with the requirements set out in the list of Union refer
43、ence dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal.D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT Risk Management Plan (RMP)The MAH shall perform the required pharmacov
44、igilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.An updated RMP should be submitted: At the request of the European Medicines Agency; Whenever the risk management system is modified,
45、 especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.If the dates for submission of a PSUR and the update of a RMP coincide, they
46、 can be submitted at the same time.16ANNEX IIILABELLING AND PACKAGE LEAFLET17A. LABELLING18PARTICULARS TO APPEAR ON THE OUTER PACKAGINGOUTER CARTON1. NAME OF THE MEDICINAL PRODUCTDacogen 50mg powder for concentrate for solutionfor infusiondecitabine2. STATEMENT OF ACTIVE SUBSTANCE(S)Eachvial contain
47、s 50 mg decitabine.After reconstitution, 1ml concentratecontains 5 mg decitabine.3. LIST OF EXCIPIENTSExcipients: potassium dihydrogen phosphate (E340), sodium hydroxide(E524), and hydrochloric acidSee the package leaflet for further information.4. PHARMACEUTICAL FORM AND CONTENTSPowder for concentr
48、ate for solutionfor infusion.1vial5. METHOD AND ROUTE OF ADMINISTRATIONRead the package leaflet before use.For single use only.Intravenous use.6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDRENKeep out of the sightand reach of children.7. OTHER SPECIA
49、L WARNING(S), IF NECESSARYCytotoxic8. EXPIRY DATEEXP9. SPECIAL STORAGE CONDITIONSUnopened vial: Do not store above 25C.19Read the leaflet for the shelf-life of the reconstituted and diluted product.10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDERJanssen-Cilag International NVTurnhoutseweg 30B-2340 BeerseBelgium12. MARKETING AUTHORISATION NUMBEREU/1/12/792/00113. BATCH NUMBERLot14. GENERAL CLASSIFICATION FOR SUPPLYMedicinal prod
