Leaflet DACOGEN 50mg powder for concentrate infusion solution

Dacogen 50 mg powder for concentrate for solution for infusion.

Each vial of powder for concentrate for solution for infusion contains 50 mg decitabine.

After reconstitution with 10 ml of water for injections, each ml of concentrate contains 5 mg ofdecitabine.

Each vial contains 0.29 mmol sodium (E524).

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion (powder for infusion).

White to almost white lyophilized powder.

Dacogen is indicated for the treatment of adult patients with newly diagnosed de novo or secondaryacute myeloid leukaemia (AML), according to the World Health Organisation (WHO) classification,who are not candidates for standard induction chemotherapy.

Dacogen administration must be initiated under the supervision of physicians experienced in the use ofchemotherapeutic medicinal products.

In a treatment cycle, Dacogen is administered at a dose of 20 mg/m2 body surface area by intravenousinfusion over 1 hour repeated daily for 5 consecutive days (i.e., a total of 5 doses per treatment cycle).

The total daily dose must not exceed 20 mg/m2 and the total dose per treatment cycle must not exceed100 mg/m2. If a dose is missed, treatment should be resumed as soon as possible. The cycle should berepeated every 4 weeks depending on the patient's clinical response and observed toxicity. It isrecommended that patients be treated for a minimum of 4 cycles; however, a complete or partialremission may take longer than 4 cycles to be obtained. Treatment may be continued as long as thepatient shows response, continues to benefit or exhibits stable disease, i.e., in the absence of overtprogression.

If after 4 cycles, the patient’s 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 areincreasing or bone marrow blast counts are worsening), the patient may be considered to be anon-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 beadministered if required.

Management of myelosuppression and associated complications

Myelosuppression 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 may be delayed at thediscretion of the treating physician, if the patient experiences myelosuppression-associatedcomplications, such as those described below:

- Febrile neutropaenia (temperature ≥ 38.5°C and absolute neutrophil count < 1,000/µL)

- Active viral, bacterial or fungal infection (i.e., requiring intravenous anti-infectives or extensivesupportive care)

- Haemorrhage (gastrointestinal, genito-urinary, pulmonary with platelets < 25,000/µL or anycentral nervous system haemorrhage)

Treatment with Dacogen may be resumed once these conditions have improved or have been stabilisedwith adequate treatment (anti-infective therapy, transfusions, or growth factors).

In clinical studies, approximately one-third of patients receiving Dacogen required a dose-delay. Dosereduction is not recommended.

Dacogen should not be used in children with AML aged < 18 years, because efficacy was notestablished. Currently available data are described in sections 4.8, 5.1, and 5.2.

Studies in patients with hepatic impairment have not been conducted. The need for dose adjustment inpatients with hepatic impairment has not been evaluated. If worsening hepatic function occurs, patientsshould be carefully monitored (see sections 4.4 and 5.2).

Studies in patients with renal impairment have not been conducted. The need for dose adjustment inpatients with renal impairment has not been evaluated (see section 4.4 and 5.2).

Dacogen is administered by intravenous infusion. A central venous catheter is not required.

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 6.6.

Hypersensitivity to decitabine or to any of the excipients, listed in section 6.1.

Breast-feeding (see section 4.6)

Myelosuppression and complications of myelosuppression, including infections and bleeding thatoccur in patients with AML may be exacerbated with Dacogen treatment. Therefore, patients are atincreased risk for severe infections (due to any pathogen such as bacterial, fungal and viral), withpotentially fatal outcome (see section 4.8). Patients should be monitored for signs and symptoms ofinfection and treated promptly.

In clinical studies, the majority of patients had baseline Grade 3/4 myelosuppression. In patients withbaseline Grade 2 abnormalities, worsening of myelosuppression was seen in most patients and morefrequently than in patients with baseline Grade 1 or 0 abnormalities. Myelosuppression caused by

Dacogen is reversible. Complete blood and platelet counts should be performed regularly, as clinicallyindicated and prior to each treatment cycle. In the presence of myelosuppression or its complications,treatment with Dacogen may be interrupted and/or supportive measures instituted (see sections 4.2 and4.8).

Cases of interstitial lung disease (ILD) (including pulmonary infiltrates, organising pneumonia andpulmonary fibrosis) without signs of infectious aetiology have been reported in patients receivingdecitabine. Careful assessment of patients with an acute onset or unexplained worsening of pulmonarysymptoms should be performed to exclude ILD. If ILD is confirmed, appropriate treatment should beinitiated (see section 4.8).

Use in patients with hepatic impairment has not been established. Caution should be exercised in theadministration of Dacogen to patients with hepatic impairment and in patients who develop signs orsymptoms of hepatic impairment. Liver function tests should be performed prior to initiation oftherapy and prior to each treatment cycle, and as clinically indicated (see sections 4.2 and 5.2).

Use in patients with severe renal impairment has not been studied. Caution should be exercised in theadministration of Dacogen to patients with severe renal impairment (Creatinine Clearance [CrCl]< 30 ml/min). Renal function tests should be performed prior to initiation of therapy and prior to eachtreatment cycle, and as clinically indicated (see section 4.2).

Cardiac disease

Patients with a history of severe congestive heart failure or clinically unstable cardiac disease wereexcluded from clinical studies and therefore, the safety and efficacy of Dacogen in these patients hasnot been established. Cases of cardiomyopathy with cardiac decompensation, in some cases reversibleafter treatment discontinuation, dose reduction or corrective treatment, have been reported in thepostmarketing setting. Patients, especially those with cardiac disease history, should be monitored forsigns and symptoms of heart failure.

Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported inpatients receiving decitabine. Differentiation syndrome may be fatal (see section 4.8). Treatment withhigh-dose IV corticosteroids and haemodynamic monitoring should be considered at first onset ofsymptoms or signs suggestive of differentiation syndrome. Temporary discontinuation of Dacogenshould be considered until resolution of symptoms and if resumed, caution is advised.

This medicine contains 0.5 mmol potassium per vial. After reconstitution and dilution of the solutionfor intravenous infusion, this medicine contains less than 1 mmol (39 mg) of potassium per dose, i.e.essentially ‘potassium- free’.

This medicine contains 0.29 mmol (6.67 mg) sodium per vial. After reconstitution and dilution of thesolution for intravenous infusion, this medicine contains between 13.8 mg-138 mg (0.6-6 mmol)sodium per dose (depending on the infusion fluid for dilution), equivalent to 0.7-7% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

No formal clinical drug interaction studies with decitabine have been conducted.

There is the potential for a drug-drug interaction with other agents which are also activated bysequential phosphorylation (via intracellular phosphokinase activities) and/or metabolised by enzymesimplicated in the inactivation of decitabine (e.g., cytidine deaminase). Therefore, caution should beexercised if these active substances are combined with decitabine.

Impact of co-administered medicinal products on decitabine

Cytochrome (CYP) 450-mediated metabolic interactions are not anticipated as decitabine metabolismis not mediated by this system but by oxidative deamination.

Impact of decitabine on co-administered medicinal products

Given its low in vitro plasma protein binding ( 1%), decitabine is unlikely to displaceco-administered medicinal products from their plasma protein binding. Decitabine has been shown tobe a weak inhibitor of P-gp mediated transport in vitro and is therefore, also not expected to affect

P-gp mediated transport of co-administered medicinal products (see section 5.2).

Women of childbearing potential/Contraception in men and women

Due to the genotoxic potential of decitabine (see section 5.3), women of childbearing potential mustuse effective contraceptive measures and avoid becoming pregnant while being treated with Dacogenand for 6 months following completion of treatment. Men should use effective contraceptive measuresand be advised to not father a child while receiving Dacogen, and for 3 months following completionof treatment (see section 5.3).

The use of decitabine with hormonal contraceptives has not been studied.

There are no adequate data on the use of Dacogen in pregnant women. Studies have shown thatdecitabine is teratogenic in rats and mice (see section 5.3). The potential risk for humans is unknown.

Based on results from animal studies and its mechanism of action, Dacogen should not be used duringpregnancy and in women of childbearing potential not using effective contraception. A pregnancy testshould be performed on all women of childbearing potential before treatment is started. If Dacogen isused during pregnancy, or if a patient becomes pregnant while receiving this medicinal product, thepatient should be apprised of the potential hazard to the foetus.

It is not known whether decitabine or its metabolites are excreted in breast milk. Dacogen iscontraindicated during breast-feeding; therefore, if treatment with this medicine is required,breast-feeding must be discontinued (see section 4.3).

No human data on the effect of decitabine on fertility are available. In non-clinical animal studies,decitabine alters male fertility and is mutagenic. Because of the possibility of infertility as aconsequence of Dacogen therapy, men should seek advice on conservation of sperm and femalepatients of childbearing potential should seek consultation regarding oocyte cryopreservation prior toinitiation of treatment.

Dacogen has moderate influence on the ability to drive and use machines. Patients should be advisedthat they may experience undesirable effects such as anaemia during treatment. Therefore, cautionshould be recommended when driving a car or operating machines.

The most common adverse drug reactions (≥ 35%) reported are pyrexia, anaemia andthrombocytopaenia.

The most common Grade 3/4 adverse drug reactions (≥ 20%) included pneumonia,thrombocytopaenia, neutropaenia, febrile neutropaenia and anaemia.

In clinical studies, 30% of patients treated with Dacogen and 25% of patients treated in the comparatorarm had adverse events with an outcome of death during treatment or within 30 days after the last doseof study drug.

In the Dacogen treatment group, there was a higher incidence of treatment discontinuation due toadverse events in women compared to men (43% versus 32%).

Tabulated list of adverse drug reactions

Adverse drug reactions reported in 293 AML patients treated with Dacogen are summarised in

Table 1. The following table reflects data from AML clinical studies and from post-marketingexperience. The adverse drug reactions are listed by frequency category. Frequency categories aredefined as follows: 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 (frequency cannot beestimated from the available data).

Within each frequency grouping, adverse drug reactions are presented in order of decreasingseriousness.

Table 1: Adverse drug reactions identified with Dacogen

Frequency

Frequency All Gradesa Grades 3-4a

System Organ Class (all Grades) Adverse Drug Reaction (%) (%)

Infections and Very common pneumonia* 24 20infestations urinary tract infection* 15 7

All other infections (viral, 63 39bacterial, fungal)*, b, c, d

Common septic shock* 6 4sepsis* 9 8sinusitis 3 1

Neoplasms benign, Not known differentiation syndrome Not known Not knownmalignant andunspecified (incl.cysts and polyps)

Blood and lymphatic Very common febrile neutropaenia* 34 32disorders neutropaenia* 32 30thrombocytopaenia*, e 41 38anaemia 38 31leukopaenia 20 18

Uncommon pancytopaenia* < 1 < 1

Immune system Common hypersensitivity including 1 < 1disorders anaphylactic reactionf

Metabolism and Very common hyperglycaemia 13 3nutrition disorders

Nervous system Very common headache 16 1disorders

Cardiac disorders Uncommon cardiomyopathy < 1 < 1

Respiratory, thoracic Very common epistaxis 14 2and mediastinal Not known interstitial lung disease Not known Not knowndisorders

Gastrointestinal Very common diarrhoea 31 2disorders vomiting 18 1nausea 33 < 1

Common stomatitis 7 1

Not known enterocolitis, including Not known Not knownneutropaenic colitis,caecitis*

Hepatobiliary Very common hepatic function abnormal 11 3disorders Common hyperbilirubinaemiag 5 <1

Skin and Uncommon acute febrile neutrophilic < 1 NAsubcutaneous tissue dermatosis (Sweet’sdisorders syndrome)

General disorders and Very common pyrexia 48 9administration siteconditionsa Worst National Cancer Institute Common Terminology Criteria for Adverse Events Grade.b Excluding pneumonia, urinary tract infection, sepsis, septic shock and sinusitis.c The most frequently reported 'other infections' in study DACO-016 were: oral herpes, oral candidiasis, pharyngitis,upper respiratory tract infection, cellulitis, bronchitis, nasopharyngitis.d Including enterocolitis infectious.e Including haemorrhage associated with thrombocytopaenia, including fatal cases.f Including preferred terms hypersensitivity, drug hypersensitivity, anaphylactic reaction, anaphylactic shock,anaphylactoid reaction, anaphylactoid shock.g In clinical studies in AML and myelodysplastic syndrome (MDS), the reporting frequency for hyperbilirubinaemiawas 11% for All Grades and 2% for Grade 3-4.

* Includes events with a fatal outcome.

NA = Not applicable

Description of selected adverse drug reactions

Haematologic adverse drug reactions

The most commonly reported haematologic adverse drug reactions associated with Dacogen treatmentincluded febrile neutropaenia, thrombocytopaenia, neutropaenia, anaemia and leukopaenia.

Serious bleeding-related adverse drug reactions, some of which lead to a fatal outcome, such as centralnervous system (CNS) haemorrhage (2%) and gastrointestinal (GI) haemorrhage (2%), in the contextof severe thrombocytopaenia, were reported in patients receiving decitabine.

Haematological adverse drug reactions should be managed by routine monitoring of complete bloodcounts and early administration of supportive treatments as required. Supportive treatments include,administration of prophylactic antibiotics and/or growth factor support (e.g., G-CSF) for neutropaeniaand transfusions for anaemia or thrombocytopaenia according to institutional guidelines. For situationswhere decitabine administration should be delayed, see section 4.2.

Infections and infestations adverse drug reactions

Serious infection-related adverse drug reactions, with potentially fatal outcome, such as septic shock,sepsis, pneumonia, and other infections (viral, bacterial and fungal) were reported in patients receivingdecitabine.

Occurrences of enterocolitis, including neutropaenic colitis, caecitis have been reported duringtreatment with decitabine. Enterocolitis may lead to septic complications and may be associated withfatal outcome.

Cases of interstitial lung disease (including pulmonary infiltrates, organising pneumonia andpulmonary fibrosis) without signs of infectious aetiology have been reported in patients receivingdecitabine.

Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported inpatients receiving decitabine. Differentiation syndrome may be fatal and symptoms and clinicalfindings include respiratory distress, pulmonary infiltrates, fever, rash, pulmonary oedema, peripheraloedema, rapid weight gain, pleural effusions, pericardial effusions, hypotension and renal dysfunction.

Differentiation syndrome may occur with or without concomitant leucocytosis. Capillary leaksyndrome and coagulopathy can also occur (see section 4.4).

The safety assessment in paediatric patients is based on the limited safety data from a Phase I/II studyto evaluate pharmacokinetics, safety and efficacy of Dacogen in paediatric patients (aged 1 to14 years) with relapsed or refractory AML (n = 17) (see section 5.1). No new safety signal wasobserved in this paediatric study.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no direct experience of human overdose and no specific antidote. However, early clinicalstudy data in published literature at doses greater than 20 times higher than the current therapeuticdose, reported increased myelosuppression including prolonged neutropaenia and thrombocytopaenia.

Toxicity is likely to manifest as exacerbations of adverse drug reactions, primarily myelosuppression.

Treatment for overdose should be supportive.

5 PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents, antimetabolites, pyrimidine analogues; ATC Code:

L01BC08

Decitabine (5-aza-2-deoxycytidine) is a cytidine deoxynucleoside analogue that selectively inhibits

DNA methyltransferases at low doses, resulting in gene promoter hypomethylation that can result inreactivation of tumour suppressor genes, induction of cellular differentiation or cellular senescencefollowed by programmed cell death.

The use of Dacogen was studied in an open-label, randomised, multicentre Phase III study(DACO-016) in subjects with newly diagnosed de novo or secondary AML according to the WHOclassification. Dacogen (n = 242) was compared to treatment choice (TC, n = 243) which consisted ofpatient’s choice with physician’s advice of either supportive care alone (n = 28, 11.5%) or 20 mg/m2cytarabine subcutaneously once daily for 10 consecutive days repeated every 4 weeks(n = 215, 88.5%). Dacogen was administered as a 1-hour intravenous infusion of 20 mg/m2 once dailyfor 5 consecutive days repeated every 4 weeks.

Subjects who were considered candidates for standard induction chemotherapy were not included inthe study as shown by the following baseline characteristics. The median age for the intent-to-treat(ITT) population was 73 years (range 64 to 91 years). Thirty-six percent of subjects had poor-riskcytogenetics at baseline. The remainder of the subjects had intermediate-risk cytogenetics. Patientswith favourable cytogenetics were not included in the study. Twenty-five percent of subjects had an

ECOG performance status ≥ 2. Eighty-one percent of subjects had significant comorbidities (e.g.,infection, cardiac impairment, pulmonary impairment). The number of patients treated with Dacogenby racial group was White 209 (86.4%) and Asian 33 (13.6%).

The primary endpoint of the study was overall survival. The secondary endpoint was completeremission rate that was assessed by independent expert review. Progression-free survival and

Event-free survival were tertiary endpoints.

The median overall survival in the --ITT population was 7.7 months in subjects treated with Dacogencompared to 5.0 months for subjects in the TC arm (hazard ratio 0.85; 95% CI: 0.69, 1.04,p = 0.1079). The difference did not reach statistical significance, however, there was a trend forimprovement in survival with a 15% reduction in the risk of death for subjects in the Dacogen arm(Figure 1). When censored for potentially disease modifying subsequent therapy (i.e., inductionchemotherapy or hypomethylating agent) the analysis for overall survival showed a 20% reduction inthe risk of death for subjects in the Dacogen arm [HR = 0.80, (95% CI: 0.64, 0.99),p-value = 0.0437)].

Figure 1. Overall survival (ITT population).

N Death (%) Median 95% CI

DACOGEN 242 197 (81) 7.7 (6.2, 9.2)

Total TC 243 199 (82) 5.0 (4.3, 6.3)

HR (95% CI): 0.85 (0.69, 1.04)

Logrank p-value: 0.10790 6 12 18 24 30 36

Time (Months)

No. of Subjects at Risk

DACOGEN 242 137 65 28 12 1 0

Total TC 243 107 55 19 7 4 0os.itt.s Wed Jan 12 17:56:26 2011

In an analysis with an additional 1 year of mature survival data, the effect of Dacogen on overallsurvival demonstrated a clinical improvement compared to the TC arm (7.7 months vs. 5.0 months,respectively, hazard ratio = 0.82, 95% CI: 0.68, 0.99, nominal p-value = 0.0373, Figure 2).

Percent of Subjects Alive

Figure 2. Analysis of mature overall survival data (ITT population).

N Death (%) Median 95% CI

DACOGEN 242 219 (90) 7.7 (6.2, 9.2)

Total TC 243 227 (93) 5.0 (4.3, 6.3)

HR (95% CI): 0.82 (0.68, 0.99)

Logrank p-value: 0.03730 6 12 18 24 30 36 42 48

Time (Months)

No. of Subjects at Risk

DACOGEN 242 137 78 50 28 11 2 0 0

Total TC 243 107 68 35 20 10 4 2 0

Based on the initial analysis in the ITT population, a statistically significant difference in completeremission rate (CR + CRp) was achieved in favour of subjects in the Dacogen arm, 17.8% (43/242)compared to the TC arm, 7.8% (19/243); treatment difference 9.9% (95% CI: 4.07; 15.83), p = 0.0011.

The median time to best response and median duration of best response in patients who achieved a CRor CRp were 4.3 months and 8.3 months, respectively. Progression-free survival was significantlylonger for subjects in the Dacogen arm, 3.7 months (95% CI: 2.7, pct. 4.6) compared with subjects in the

TC arm, 2.1 months (95% CI: 1.9, 3.1); hazard ratio 0.75 (95% CI: 0.62, 0.91), p = 0.0031. Theseresults as well as other endpoints are shown in Table 2.

Table 2: Other efficacy endpoints for Study DACO-016 (ITT population)

TC (combined

Dacogen group)

Outcomes n = 242 n = 243 p-value

CR + CRp 43 (17.8%) 19 (7.8%) 0.0011

OR = 2.5(1.40, 4.78)b

CR 38 (15.7%) 18 (7.4%) -

EFSa 3.5 2.1 0.0025(2.5, 4.1)b (1.9, 2.8)b

HR = 0.75(0.62, 0.90)b

PFSa 3.7 2.1 0.0031(2.7, pct. 4.6)b (1.9, 3.1)b

HR = 0.75(0.62, 0.91)b

Percent of Subjects Alive

CR = complete remission; CRp = complete remission with incomplete platelet recovery, EFS = event-free survival,

PFS = progression-free survival, OR = odds ratio, HR = hazard ratio

- = Not evaluablea Reported as median monthsb 95% confidence intervals

Overall survival and complete remission rates in pre-specified disease-related sub-groups (i.e.,cytogenetic risk, Eastern Cooperative Oncology Group [ECOG] score, age, type of AML, and baselinebone marrow blast count) were consistent with results for the overall study population.

The use of Dacogen as initial therapy was also evaluated in an open-label, single-arm, Phase II study(DACO-017) in 55 subjects > 60 years with AML according to the WHO classification. The primaryendpoint was complete remission (CR) rate that was assessed by independent expert review. Thesecondary endpoint of the study was overall survival. Dacogen was administered as a 1-hourintravenous infusion of 20 mg/m2 once daily for 5 consecutive days repeated every 4 weeks. In the

ITT analysis, a CR rate of 23.6% (95% CI: 13.2, 37) was observed in 13/55 subjects treated with

Dacogen. The median time to CR was 4.1 months, and the median duration of CR was 18.2 months.

The median overall survival in the ITT population was 7.6 months (95% CI: 5.7, 11.5).

The efficacy and safety of Dacogen has not been evaluated in patients with acute promyelocyticleukaemia or CNS leukaemia.

A Phase I/II open-label, multicentre study evaluated the safety and efficacy of Dacogen in sequentialadministration with cytarabine in children aged 1 month to < 18 years with relapsed or refractory

AML. A total of 17 subjects were enrolled and received Dacogen 20 mg/m2 in this study, of which9 subjects received cytarabine 1 g/m2 and 8 subjects received cytarabine administered at the maximumtolerable dose of 2 g/m2. All subjects discontinued the study treatment. The reasons for treatmentdiscontinuation included disease progression (12 [70.6%] subjects), subjects proceeding to transplant(3 [17.6%]), investigator decision (1 [5.9%]), and “other” (1 [5.9%]). Reported adverse events wereconsistent with the known safety profile of Dacogen in adults (see section 4.8). Based on thesenegative results, Dacogen should not be used in children with AML aged < 18 years, because efficacywas not established (see section 4.2).

The population pharmacokinetic (PK) parameters of decitabine were pooled from 3 clinical studies in45 patients with AML or myelodysplastic syndrome (MDS) utilizing the 5-Day regimen. In eachstudy, decitabine PK was evaluated on the fifth day of the first treatment cycle.

The pharmacokinetics of decitabine following intravenous administration as a 1-hour infusion weredescribed by a linear two-compartment model, characterised by rapid elimination from the centralcompartment and by relatively slow distribution from the peripheral compartment. For a typicalpatient (weight 70 kg/body surface area 1.73 m2) the decitabine pharmacokinetic parameters are listedin the Table 3 below.

Table 3: Summary of population PK analysis for a typical patient receiving daily 1-hourinfusions of Dacogen 20 mg/m2 over 5 days every 4 weeks

Parameter a Predicted Value 95% CI

Cmax (ng/ml) 107 88.5 - 129

AUCcum (ng.h/ml) 580 480 - 695t1/2 (min) 68.2 54.2 - 79.6

Vdss (L) 116 84.1 - 153

CL (L/h) 298 249 - 359a The total dose per cycle was 100 mg/m2

Decitabine exhibits linear PK and following the intravenous infusion, steady-state concentrations arereached within 0.5 hour. 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 (< 1%). Decitabine Vdss in cancer patients is largeindicating distribution into peripheral tissues. There was no evidence of dependencies on age,creatinine clearance, total bilirubin, or disease.

Intracellularly, decitabine is activated through sequential phosphorylation via phosphokinase activitiesto the corresponding triphosphate, which is then incorporated by the DNA polymerase. In vitrometabolism data and the human mass balance study results indicated that the cytochrome P450 systemis not involved in the metabolism of decitabine. The primary route of metabolism is likely throughdeamination by cytidine deaminase in the liver, kidney, intestinal epithelium and blood. Results fromthe human mass-balance study showed that unchanged decitabine in plasma accounted forapproximately 2.4% of total radioactivity in plasma. The major circulating metabolites are notbelieved to be pharmacologically active. The presence of these metabolites in urine together with thehigh total body clearance and low urinary excretion of unchanged decitabine in the urine (~4% of thedose) indicate that decitabine is appreciably metabolised in vivo. In vitro studies show that decitabinedoes not inhibit nor induce CYP 450 enzymes up to more than 20-fold of the therapeutic maximumobserved plasma concentration (Cmax). Thus; CYP-mediated metabolic drug interactions are notanticipated, and decitabine is unlikely to interact with agents metabolised through these pathways. Inaddition, in vitro data show that decitabine is a poor P-gp substrate.

Mean plasma clearance following intravenous administration in cancer subjects was > 200 L/h withmoderate inter-subject variability (coefficient of variation [CV] is approximately 50%). Excretion ofunchanged 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 decitabine (4% unchanged drug) is excreted in the urine.

Additional information on special populations

The effects of renal or hepatic impairment, gender, age or race on the pharmacokinetics of decitabinehave not been formally studied. Information on special populations was derived from pharmacokineticdata from the 3 studies noted above, and from one Phase I study in MDS subjects, (N = 14;15 mg/m2 x 3-hours q8h x 3 days).

Population pharmacokinetic analysis showed that decitabine pharmacokinetics are not dependent onage (range studied 40 to 87 years; median 70 years).

Population PK analysis of decitabine showed that after accounting for body size, there is no differencebetween decitabine PK parameters in paediatric AML patients versus adults with AML or MDS.

Population pharmacokinetic analysis of decitabine did not show any clinically relevant differencebetween men and women.

Most of the patients studied were Caucasian. However, the population pharmacokinetic analysis ofdecitabine indicated that race had no apparent effect on the exposure to decitabine.

The PK of decitabine have not been formally studied in patients with hepatic impairment. Results froma human mass-balance study and in vitro experiments mentioned above indicated that the CYPenzymes are unlikely to be involved in the metabolism of decitabine. In addition, the limited data fromthe population PK analysis indicated no significant PK parameter dependencies on total bilirubinconcentration despite a wide range of total bilirubin levels. Thus, decitabine exposure is not likely tobe affected in patients with impaired hepatic function.

The PK of decitabine have not been formally studied in patients with renal insufficiency. Thepopulation PK analysis on the limited decitabine data indicated no significant PK parameterdependencies on normalised creatinine clearance, an indicator of renal function. Thus, decitabineexposure is not likely to be affected in patients with impaired renal function.

Formal carcinogenicity studies have not been performed with decitabine. Evidence from the literatureindicates that decitabine has carcinogenic potential. The available data from in vitro and in vivo studiesprovide sufficient evidence that decitabine has genotoxic potential. Data from the literature alsoindicate 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 inrats and rabbits indicated that the primary toxicity was myelosuppression, including effects on bonemarrow, which was reversible on cessation of treatment. Gastrointestinal toxicity was also observedand in males, testicular atrophy which did not reverse over the scheduled recovery periods. Decitabineadministration to neonatal/juvenile rats showed a comparable general toxicity profile as in older rats.

Neurobehavioural development and reproductive capacity were unaffected when neonatal/juvenile ratswere treated at dose levels inducing myelosuppression. See section 4.2 for information on paediatricuse.

6 PHARMACEUTICAL PARTICULARS

Potassium dihydrogen phosphate (E340)

Sodium hydroxide (E524)

Hydrochloric acid (for pH adjustment)

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vial3 years.

Reconstituted and diluted solution

Within 15 minutes of reconstitution, the concentrate (in 10 ml of sterile water for injections) must befurther diluted with cold (2°C - 8°C) infusion fluids. This prepared diluted solution for intravenousinfusion can be stored at 2°C - 8°C for up to a maximum of 3 hours, followed by up to 1 hour at roomtemperature (20°C - 25°C) before administration.

From a microbiological point of view, the product should be used within the time periodrecommended above. It is the responsibility of the user to follow the recommended storage times andconditions and ensure that reconstitution has taken place in aseptic conditions.

Do not store above 25°C.

For storage conditions of the reconstituted and diluted medicinal product, see section 6.3.

20 ml clear colourless Type I glass vial sealed with a butyl rubber stopper and an aluminium seal withplastic flip-off cap containing 50 mg decitabine.

Pack size: 1 vial.

Skin contact with the solution should be avoided and protective gloves must be worn. Standardprocedures for dealing with cytotoxic medicinal products should be adopted.

The powder should be aseptically reconstituted with 10 ml of water for injections. Uponreconstitution, each ml contains approximately 5 mg of decitabine at pH 6.7 to 7.3. Within 15 minutesof reconstitution, the solution must be further diluted with cold infusion fluids (sodium chloride9 mg/ml [0.9%] solution for injection or 5% glucose solution for injection) to a final concentration of0.15 to 1.0 mg/ml. For the shelf-life and the precaution for storage after reconstitution, see section 6.3.

Dacogen should not be infused through the same intravenous access/line with other medicinalproducts.

This medicinal product is for single use only. Any unused medicinal product or waste material shouldbe disposed of in accordance with local requirements.

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/12/792/001

Date of first authorisation: 20 September 2012

Date of latest renewal: 22 May 2017

Detailed information on this medicinal product is available on the website of the European Medicines

Agency (EMA) http://www.ema.europa.eu/