Summary Basis of Decision for Dacogen

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Dacogen is located below.

Recent Activity for Dacogen

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

The following table describes post-authorization activity for Dacogen, a product which contains the medicinal ingredient decitabine. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Updated: 2025-06-12

Drug Identification Number (DIN):

DIN 02490366 – 50 mg decitabine/vial, powder, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 232860

2019-10-24

Cancellation Letter Received 2019-11-05

Submission filed as a Level I – Supplement to transfer ownership of the drug product from Otsuka Pharmaceutical Co., Ltd. to Taiho Pharma Canada Inc. The changes were not in scope of an SNDS but were considered appropriate for an NDS. The sponsor cancelled the submission administratively.

NDS # 217663

2018-06-29

Issued NOC 2019-07-11

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Dacogen

Date SBD issued: 2019-12-11

The following information relates to the New Drug Submission for Dacogen.

Decitabine

Drug Identification Number (DIN):

  • DIN 02490366 - 50 mg/vial, powder, intravenous administration

Otsuka Pharmaceutical Co., Ltd.

New Drug Submission Control Number: 217663

 

On July 11, 2019, Health Canada issued a Notice of Compliance to Otsuka Pharmaceutical Co., Ltd. for the drug product Dacogen.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-harm-uncertainty profile of Dacogen is favourable for the treatment of adult patients with de novo or secondary myelodysplastic syndrome (MDS), untreated or previously treated with chemotherapy, who are not considered candidates for hematopoietic stem cell transplantation, including:

  • Intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System (IPSS) groups,
  • All French-American-British (FAB) subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia [CMML]).

 

1 What was approved?

 

Dacogen, a pyrimidine analogue, was authorized for the treatment of adult patients with de novo or secondary myelodysplastic syndrome (MDS), untreated or previously treated with chemotherapy, who are not considered candidates for hematopoietic stem cell transplantation, including:

  • Intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System (IPSS) groups,
  • All French-American-British (FAB) subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia [CMML]).

Dacogen is not authorized for use in pediatric patients (<18 years of age), as its safety and efficacy have not been studied in this patient population.

No overall differences in safety or effectiveness were detected between geriatric patients (≥65 years of age) and younger patients. However, a higher frequency of catheter-related infections were reported in patients aged 75 years and older in a Phase III clinical study (5% in patients ≥65 years of age versus 24% in patients ≥75 years of age).

Dacogen is contraindicated in patients who are hypersensitive to this drug (decitabine) or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Dacogen was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Dacogen (50 mg/vial decitabine) is presented as powder. In addition to the medicinal ingredient, the powder contains potassium dihydrogen phosphate and sodium hydroxide.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Dacogen Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Dacogen approved?

 

Health Canada considers that the benefit-harm-uncertainty profile of Dacogen is favourable for the treatment of adult patients with de novo or secondary myelodysplastic syndrome (MDS), untreated or previously treated with chemotherapy, who are not considered candidates for hematopoietic stem cell transplantation, including:

  • Intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System (IPSS) groups,
  • All French-American-British (FAB) subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia [CMML]).

Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases in which the bone marrow does not produce a sufficient amount of healthy, mature blood cells (red blood cells, white blood cells, and platelets). This results in the accumulation of immature blood cells (known as blasts) in the bone marrow and blood, and fewer numbers of mature blood cells. Myelodysplastic syndromes have been associated with various chromosomal changes, and prognosis is generally poor.

The number of new cases of MDS per year is estimated as between 1,800 and 5,900 in Canada. The median age of patients at the time of diagnosis is 65 years. Approximately 30% of MDS patients progress to acute myeloid leukemia (AML).

The survival or progression to AML for individual patients is predicted using the International Prognostic Scoring System (IPSS). The risk categories, in order of increasing severity, are Low (0), Intermediate (INT)-1 (0.5-1.0), INT-2 (1.5-2.0), and High (≥2.5). Scores are based on the number of cytopenias, cytogenetic findings, and proportions of blasts in the bone marrow.

Optimal management of MDS is highly individualized, taking factors including age, severity of cytopenia, performance status, and the anticipated risk of disease progression into account. Allogeneic bone marrow transplant is the only proven curative option for MDS, but is not a viable option for the majority of patients due to advanced age and/or co-morbidities. Drugs authorized in Canada for the treatment of MDS currently include azacitidine, decitabine, and lenalidomide, which are indicated for different subpopulations of MDS patients depending on IPSS risk category, eligibility for stem cell transplantation, and cytogenetic abnormalities.

Decitabine (the medicinal ingredient in Dacogen) is a pyrimidine analogue. It is believed to inhibit the growth of neoplastic cells by inhibiting deoxyribonucleic acid (DNA) methylation, thereby restoring normal function to genes that are essential for the regulation of cell differentiation and growth. At the time of authorization in Canada, Dacogen was the second of two drugs in which decitabine is the medicinal ingredient. The safety and efficacy of Dacogen were demonstrated primarily through two pivotal clinical studies, D-0007 and DACO-020. Each study provided the primary support for one of the two approved dosing regimens for Dacogen.

Both studies enrolled adult MDS patients meeting the French-American-British (FAB) classification criteria and IPSS INT-1, INT-2, and high-risk prognostic scores. The clinical studies included patients with blasts between 20% and 30% based on the old FAB classification. This is now considered to be acute myeloid leukemia (AML) according to the World Health Organization (WHO) 2008 classification.

The Phase III pivotal study D-0007 provided data supporting the inpatient dosing regimen, in which patients received a dose of 15 mg/m2 body surface area, administered intravenously over a three-hour period, every eight hours, for three consecutive days. This cycle was repeated every six weeks. Patients were randomized to receive standard medical care alone, or standard medical care along with Dacogen.

The co-primary efficacy endpoints were the overall response rate (ORR; defined as the sum of the complete response [CR] and the partial response [PR]) and the time to AML transformation or death. In an analysis of the intention-to-treat (ITT) population, the ORR was 17% in patients receiving Dacogen and standard medical care. Patient responses were durable. The median duration of response was 288 days, and the median time to response was 93 days. The ORR in patients receiving standard medical care only was zero. The time to AML transformation or death did not reach statistical significance in the ITT population.

The Phase II pivotal study DACO-020 provided data supporting the outpatient dosing regimen, in which patients received a dose of 20 mg/m2 body surface area, administered intravenously over one hour, for five consecutive days. This cycle was repeated every four weeks. This study enrolled patients with any FAB subtype and an IPSS score ≥INT-1. As DACO-020 was a single-arm study, all patients were treated with Dacogen.

The primary efficacy endpoint was the ORR, which was determined to be 16% in the ITT population. Patient responses were durable, with a median duration of 443 days and a median time to response of 162 days.

Due to the designs of the two studies and their similar patient characteristics, it was determined that the results of DACO-020 and D-0007 can be cross-compared. Overall, the outcomes of the clinical review support the efficacy of Dacogen for the approved indication, when administered according to either recommended dosing regimen.

Similar adverse reactions were reported in connection with both dosing regimens. The most commonly reported adverse reactions were related to myelosuppression, and included neutropenia, thrombocytopenia, anemia, and febrile neutropenia. Lower incidences of these adverse reactions were reported in patients undergoing the outpatient regimen. A higher incidence of febrile neutropenia and an increase in adverse events requiring transfusion were observed in the first two treatment cycles, compared with later cycles. Transient dose-related cytopenias were also observed in the early stages of treatment with Dacogen.

Serious infection-related adverse reactions including septic shock, sepsis, and pneumonia were observed in patients treated with Dacogen. Serious adverse reactions related to bleeding were also reported, including central nervous system (CNS) hemorrhage and gastrointestinal hemorrhage, in the context of severe thrombocytopenia. Interstitial lung disease, cardiac arrest, hypersensitivity (anaphylaxis), and intracranial hemorrhage were also reported in patients receiving Dacogen.

A Risk Management Plan (RMP) for Dacogen was submitted by Otsuka Pharmaceutical Co., Ltd. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Dacogen Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Dacogen was accepted. Additionally, the sponsor is expected to submit post-market surveillance data regarding name confusion for the name Dacogen for a period of two years.

Dacogen has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Dacogen Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

3 What steps led to the approval of Dacogen?

 

Submission Milestones: Dacogen

Submission Milestone Date
Pre-submission meeting: 2018-05-29
Submission filed: 2018-06-28
Screening  
Screening Deficiency Notice issued: 2018-08-17
Response filed: 2018-08-30
Screening Acceptance Letter issued: 2018-09-17
Review  
Review of Risk Management Plan complete: 2019-06-28
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2019-07-08
Quality Evaluation complete: 2019-07-08
Clinical/Medical Evaluation complete: 2019-07-09
Notice of Compliance issued by Director General, Therapeutic Products Directorate: 2019-07-11

 

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

The sponsor has additionally committed to providing reports regarding name confusion for the brand name Dacogen for a period of two years. The reporting period will begin with market notification of Dacogen.

 

5 What post-authorization activity has taken place for Dacogen?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Dacogen is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Decitabine, the medicinal ingredient in Dacogen, is believed to inhibit the growth of neoplastic cells by inhibiting deoxyribonucleic acid (DNA) methylation. This has been observed in vitro and in vivo, and is believed to occur following the activation of decitabine by phosphorylation and its integration into DNA. In neoplastic cells, the reduced methylation of DNA may restore normal function to genes that are essential for regulating cellular differentiation and growth. Decitabine integrated into DNA may also form covalent adducts with DNA methyltransferase (which methylates DNA), thereby inhibiting its activity.

Data was submitted to support the two proposed dosing regimens for Dacogen. Through the inpatient dosing regimen, patients receive 15 mg/m2 Dacogen intravenously over three hours, every eight hours for three days. This cycle is repeated every six weeks. Through the outpatient dosing regimen, patients receive 20 mg/m2 Dacogen intravenously over one hour, once daily for five days. This cycle is repeated every four weeks.

The major pharmacokinetic aspects of distribution, metabolism, and elimination of decitabine have been characterized for the two dosage regimens. Decitabine has a short half-life, which was determined to be approximately 37 minutes with the inpatient dosing regimen and 32 minutes with the outpatient dosing regimen. Consistent with a short half-life, the results of a Phase I pharmacokinetics study indicated that there was no systemic accumulation of the drug when administered according to the inpatient dosing regimen.

Decitabine is a prodrug, which requires phosphorylation by deoxycytidine kinase to become active, and is deactivated by cytidine deaminase in the liver, kidney, intestinal epithelium, and blood. Drug interaction studies with decitabine have not been carried out, but there is potential for decitabine to interact with other agents requiring activation and/or inactivation by the same enzymes as decitabine.

There were no studies submitted involving patients with hepatic or renal impairment. Results from mass-balance studies indicate that the cytochrome P450 (CYP) enzymes are not likely to be involved in the metabolism of decitabine, and that approximately 90% of the administered dose is eliminated in the urine, primarily as metabolites. The major circulating metabolites of decitabine are not known to be pharmacologically active.

Overall, the pharmacokinetic data support the use of Dacogen for the approved indication. For further details, please refer to the Dacogen Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Dacogen was demonstrated primarily through two pivotal clinical studies, D-0007 and DACO-020. Each study provided the primary support for one of the two approved dosing regimens for Dacogen.

Both studies enrolled adult patients with myelodysplastic syndromes (MDS) meeting the French-American-British (FAB) classification criteria and International Prognostic Scoring System (IPSS) intermediate (INT)-1, INT-2, and high-risk prognostic scores. The clinical studies included patients with blasts between 20% and 30% based on the old FAB classification. This is now considered to be acute myeloid leukemia (AML) according to the World Health Organization (WHO) 2008 classification.

D-0007: Inpatient dosing regimen

The Phase III pivotal study D-0007 provided data supporting the inpatient dosing regimen, in which patients received a dose of 15 mg/m2 body surface area, administered intravenously over a three-hour period, every eight hours, for three consecutive days. This cycle was repeated every six weeks, depending on toxicity and the patient's clinical response. Dose reductions were allowed if needed. This study was conducted in 170 patients, who were randomized to receive standard medical care alone (81 patients), or standard medical care along with Dacogen (89 patients randomized, only 83 patients received Dacogen). Standard medical care included blood and blood product transfusions, prophylactic antibiotics, and hematopoietic growth factors. Patient demographics, disease characteristics, and baseline performance were similar between the two treatment groups.

The co-primary efficacy endpoints were the overall response rate (ORR; defined as the sum of the complete response [CR] and the partial response [PR]) and the time to AML transformation or death. Responses were classified according to the MDS International Working Group (IWG) criteria (2000). Patients were required to be red blood cell and platelet transfusion-independent during the time of response.

In an analysis of the intention-to-treat (ITT) population, the ORR was 17% (15 out of 89 patients) in patients receiving Dacogen along with the standard medical care, and patient responses were durable. The median duration of response was 288 days (range: 116-388 days). The median time to response was 93 days (range: 55-272 days). The ORR in patients receiving standard medical care only was zero.

The results of subgroup analyses indicate that the observed difference in ORR between the two treatment groups is robust and remains consistent across IPSS risk groups, gender, age, FAB classifications (except for refractory anemia with ringed sideroblasts [RARS]), type of MDS (de novo versus secondary), and in patients with a history of prior treatment for MDS (prior treatment versus therapy naïve).

The time to AML transformation or death did not reach statistical significance in the ITT population.

DACO-020: Outpatient dosing regimen

The Phase II pivotal study DACO-020 provided data supporting the outpatient dosing regimen, in which patients received a dose of 20 mg/m2 body surface area, administered intravenously over one hour, for five consecutive days. This cycle was repeated every four weeks. This study enrolled 99 patients with MDS, with any FAB subtype and an IPSS score ≥INT-1. As DACO-020 was a single-arm study, all patients were treated with Dacogen.

The primary efficacy endpoint was the ORR, which was determined to be 16% in the ITT population. Patient responses were durable, with a median duration of 443 days and a median time to response of 162 days. In the full patient population of DACO-020, the overall improvement rate (based on CR, PR or hematologic improvement) was 43%.

The results of subgroup analyses indicate that overall responses were observed in patients with all IPSS and FAB classifications, except for patients with refractory anemia with excess blasts in transformation (RAEB-t). However, one out of six RAEB-t patients experienced overall improvement.

Due to the designs of the two studies and their similar patient characteristics, it was determined that the results of DACO-020 and D-0007 can be cross-compared. Overall, the outcomes of the clinical review support the efficacy of Dacogen for the approved indication, when administered according to either recommended dosing regimen.

Indication

The New Drug Submission for Dacogen was filed by the sponsor with the following indication, which Health Canada subsequently approved:

Dacogen (decitabine for injection) is indicated for the treatment of adult patients with de novo or secondary myelodysplastic syndrome (MDS), untreated or previously treated with chemotherapy, who are not considered candidates for hematopoietic stem cell transplantation, including:

  • Intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System (IPSS) groups,
  • All French-American-British (FAB) subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia [CMML]).

For more information, refer to the Dacogen Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Dacogen was evaluated primarily in the studies D-0007 and DACO-020, which provided evidence supporting the inpatient and outpatient dosing regimens, respectively. The outcomes of both clinical studies are described in the Clinical Efficacy section.

Neutropenia, thrombocytopenia, and the potential for fetal harm are listed in a Serious Warnings and Precautions box in the Product Monograph for Dacogen. The risk of fetal harm was identified during the non-clinical review.

D-0007: Inpatient dosing regimen

The inpatient dosing regimen was evaluated in the clinical study D-0007. Patients who were treated with Dacogen through this study received a dose of 15 mg/m2 body surface area, administered intravenously over a three-hour period, every eight hours for three consecutive days. This cycle was repeated every six weeks, depending on toxicity and the patient's clinical response. Dose reductions were allowed if needed.

In this study, the most frequently reported adverse reactions in patients who received Dacogen were neutropenia (90%), thrombocytopenia (89%), anemia (82%), fatigue (48%), pyrexia (53%), nausea (42%), cough (40%), petechiae (39%), constipation (35%), diarrhea (34%), and hyperglycemia (33%).

Serious adverse reactions were observed in 69% of patients receiving Dacogen and the standard medical care, and in 56% of patients receiving the standard medical care only. The serious adverse reactions reported in D-0007 most commonly fell into the following categories: blood and lymphatic system disorders, general disorders and administrative site conditions, infections and infestations, and cardiac disorders.

Ten percent (10%) of patients discontinued treatment due to toxicity. The adverse reactions which led to permanent discontinuation include thrombocytopenia, neutropenia, cardiopulmonary arrest, pneumonia NOS, lymphadenopathy, elevated total bilirubin, elevated alanine aminotransferase (ALT), Mycobacterium avium complex infection, subarachnoid hemorrhage, cardio-respiratory arrest, increased blood bilirubin, intracranial hemorrhage, and abnormal liver function tests. Approximately one third of patients receiving Dacogen required dose delay or dose reduction. The overall incidence of death was similar between the two treatment arms over the study period and long-term follow-up (71% of patients treated with Dacogen, and 68% of patients receiving standard medical care only).

There were no overall differences in the safety or effectiveness of Dacogen between geriatric patients (≥65 years of age) and younger patients. However, a higher frequency of catheter-related infections was observed in patients 75 years and older (5% in patients aged 65 and over, versus 24% in patients aged 75 and over).

DACO-020: Outpatient dosing regimen

The outpatient dosing regimen was evaluated in the clinical study DACO-020, in which patients received a dose of 20 mg/m2 body surface area, administered intravenously over one hour, for five consecutive days. This cycle was repeated every four weeks. Dose reduction was not permitted with this treatment regimen.

The most commonly reported Grade 3 or 4 adverse reactions were neutropenia (37%), thrombocytopenia (24%), and anemia (22%). Dose delays were required for 78% of patients, primarily due to hematologic toxicities. Nineteen patients (20%) discontinued treatment due to adverse reactions. Adverse reactions had fatal outcomes for eight patients, resulting from infection and/or bleeding. Seven of these occurred in the clinical setting of myelosuppression, and are considered at least possibly related to the treatment.

Certain adverse reactions were observed at a higher frequency in patients aged 70 and over, compared with patients aged 65-69. These include anemia (40.0% vs. 26.5%), neutropenia (48.6% vs. 32.7%), thrombocytopenia (42.9% vs. 20.4%), pneumonia (31.4% vs. 14.3%), dizziness (34.3% vs. 12.2%), confusional state (17.1% vs. 0%), and pollakiuria (11.4% vs. 0%).

For more information, refer to the Dacogen Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

The effects of decitabine on postnatal development and fertility were detected through studies in mice. A 3 mg/m2 intraperitoneal injection (approximately 7% of the recommended daily clinical dose) was administered to female mice on day 10 of gestation. Significantly reduced body weights were observed in both male and female offspring exposed to decitabine in utero, relative to controls. There were no consistent effects on fertility when female mice exposed to decitabine in utero were mated to untreated male mice. However, untreated females mated to males exposed in utero displayed signs of decreased fertility at three and five months of age.

Effects on fertility were also observed in male mice following repeated doses of 0.15, 0.30, or 0.45 mg/m2 decitabine, corresponding to 0.3% to 1% of the recommended clinical dose. Signs of reproductive toxicity were observed at doses of 0.30 mg/m2 and above, including reduced testes weights, abnormal histology, and significant decreases in sperm number. Females mated to males dosed with ≥0.30 mg/m2 decitabine also displayed signs of reproductive toxicity, including reduced pregnancy rate and a significant increase in preimplantation losses.

The non-clinical toxicology profile of decitabine is based on studies in mice, dogs, and monkeys (single dose) and in mice, rats, dogs, and rabbits (repeated dose). Ataxia and convulsions were observed in mice following a single dose of 62.5 mg/kg or higher. The main finding in repeated dose studies was myelosuppression. Body weight loss, gastrointestinal toxicity, and atrophy of the lymphoid organs and testes were also observed. Similar toxicity profiles were observed in all three species following repeat dosing.

Decitabine did not produce any effects on potassium currents in human ether-a-go-go-related gene (hERG)-transfected human embryonic kidney (HEK) 293 cells at concentrations up to 6.8 mcg/ml. Decitabine did not have effects on cardiovascular or respiratory parameters in cynomolgus monkeys following continuous intravenous infusion for one hour at a dose of 52.4 mg/kg (628.8 mg/m2).

The results of in vitro studies indicate that decitabine produces no inhibition of the cytochrome (CYP) P450 enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP2C8.

In vitro permeability studies in a Caco-2 monolayer and in MDR1-MDCK cells show that decitabine is expected to have low permeability in the human intestine, and that it is neither a P-glycoprotein (P-gp) substrate or inhibitor.

The results of experiments in in vitro and in vivo systems including mouse lymphoma cells, decitabine-treated mice, and the larvae of fruit flies indicate that decitabine is mutagenic. No dedicated carcinogenicity studies were conducted for decitabine.

Considering the intended use of Dacogen, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Dacogen Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

The Chemistry and Manufacturing information submitted for Dacogen has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 48 months is acceptable when the unopened vial is stored at room temperature (15ºC to 30ºC). Dacogen must be used within 15 minutes of reconstitution. Alternatively, the diluted solution must be prepared with cold (2-8°C) infusion fluids and stored at 2-8°C. This solution remains stable for up to four hours.

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

None of the excipients used in the formulation of Dacogen is of human or animal origin.

 

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