Summary Basis of Decision for Demylocan
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Demylocan is located below.
Recent Activity for Demylocan
SBDs written for eligible drugs 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. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Demylocan
Updated: 2022-12-14
The following table describes post-authorization activity for Demylocan, 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.
Drug Identification Number (DIN):
DIN 02484811 – decitabine, 50 mg/vial, powder, intravenous administration
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Drug product (DIN 02484811) market notification | Not applicable | Date of first sale: 2021-03-24 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| SNDS # 228391 | 2019-06-04 | Issued NOC 2019-12-30 |
Submission filed as a Level I – Supplement to change the manufacturing process and add an alternate supplier for the drug substance. The data were reviewed and considered acceptable, and an NOC was issued. |
| NDS # 207372 | 2017-12-28 | Issued NOC 2019-01-21 |
NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Demylocan
Date SBD issued: 2019-06-25
The following information relates to the New Drug Submission for Demylocan.
Decitabine
Drug Identification Number (DIN):
- DIN 02484811 - 50 mg/vial, powder, intravenous administration
Pendopharm, Division of Pharmascience Inc.
New Drug Submission Control Number: 207372
On January 21, 2019, Health Canada issued a Notice of Compliance to Pendopharm, Division of Pharmascience Inc. for the drug product Demylocan.
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 Demylocan is favourable for the treatment of adult patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refactory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System (IPSS) groups.
1 What was approved?
Demylocan, a pyrimidine analogue, was authorized for the treatment of adult patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refactory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System (IPSS) groups.
Demylocan is contraindicated for:
- Patients who are hypersensitive to decitabine or to any ingredient in the formulation, including any non-medicinal ingredient or component of the container.
- Breastfeeding women.
Demylocan 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.
Demylocan (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 Demylocan Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Demylocan approved?
Health Canada considers that the benefit-harm-uncertainty profile of Demylocan is favourable for the treatment of adult patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British (FAB) subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refactory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System (IPSS) groups.
Demylocan is not authorized for use in pediatric patients (<18 years of age), as no clinical safety or efficacy data are available for this population.
The majority of MDS patients are 65 years of age or older, which was reflected in the populations of the clinical studies reviewed. However, while MDS is rare in individuals under 50 years old, the pivotal trials included patients as young as 30 years old. There were no significant differences in safety or efficacy identified between geriatric patients (≥65 years of age) and younger patients.
Myelodysplastic syndromes are a heterogeneous group of hematopoietic stem cell disorders, and are estimated to affect 4.8 out of every 100,000 individuals worldwide. They are characterized by peripheral blood cytopenias and dysplastic hematopoiesis, with or without increased blast cells. Significant morbidity and mortality occur in approximately 40% of patients, due to the progression of chronic cytopenias or the transformation of MDS to acute myeloid leukemia (AML).
The IPSS, a widely recognized and accepted standard, evaluates the severity of MDS based on the proportion of leukemic blast cells in the bone marrow, as well as cytogenetic abnormalities and cytopenias. If left untreated, survival rates are estimated at 3.5-5.7 years for low-risk patients (those with low [0] or intermediate-1 [0.5-1.0] IPSS scores), and from several months to slightly over one year for high-risk patients (intermediate-2 [1.5-2.0] or high [≥2.5] IPSS scores).
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. Several treatment options have been authorized in Canada, including growth factors, immunomodulators, immunosuppressive agents, blood product support, allogeneic stem cell transplants, hypomethylating agents, and high-intensity chemotherapy. However, some treatments are not feasible for the majority of patients, and some are only approved for certain subpopulations of patients. Considering these challenges and the poor prognosis for MDS, there remains an unmet need for effective treatment options.
The New Drug Submission (NDS) for Demylocan was filed as a Submission Relying on Third-Party Data (SRTD), for which the evidence of safety and efficacy is based heavily on published literature and market experience. The review of the NDS for Demylocan involved a comprehensive analysis of regulatory reviews conducted by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
The clinical studies submitted for review were conducted over a span of 20 years, and contain inherent differences due to developments in the understanding of MDS and the available technology. However, all those that were classified as core studies have used internationally recognized standards. Two studies were considered pivotal: Study D-0007 and the Alternative Dosing for Outpatient Treatment (ADOPT) Trial. Additional information on both studies is provided in the Clinical Efficacy section.
Study D-0007 was a Phase III study which compared the efficacy of the standard medical care (SC) alone (number of patients [n] = 81) to that of the SC along with Demylocan administered intravenously (n = 89). Patients receiving Demylocan were given a 15 mg/m2 dose intravenously over a three-hour period, every eight hours, for three consecutive days. This was defined as the inpatient dosing regimen, and repeated every six weeks. The overall response rate (ORR) among patients receiving Demylocan was 17%, including 9% of patients with a complete response. There were no responders in the SC treatment arm (p-value [p] <0.001). Median time to AML transformation or death was 12.1 months in patients receiving Demylocan with the SC treatment, versus 7.8 months in patients receiving the SC treatment only (p = 0.16).
The ADOPT Trial provided evidence supporting the efficacy of an outpatient dosing regimen for decitabine. This dosing regimen was organized into four-week-long cycles, in which patients received 20 mg/m2 Demylocan intravenously over one hour, on days 1-5 of the first week of the cycle. Based on the most recent International Working Group (IWG) criteria (2006), the ORR was 32%. Fifteen out of 99 patients had a complete response. Response rates were similar across all FAB subtypes and IPSS risk categories, and consistent with those observed in Study D-0007.
The outcomes of the two pivotal studies support the efficacy of Demylocan for the approved indication, when administered according to either recommended dosing regimen.
The clinical safety of Demylocan was reviewed using a safety database containing data from MDS patients from all of the core studies, who received at least one dose of decitabine on either dosing regimen. The most frequently reported adverse events across all studies were hematologic in nature, and generally indicative of myelosuppression. Hematologic toxicities complicated the safety assessment of Demylocan as they are associated with myelosuppression and are also characteristics of MDS. Important risk mitigation strategies include monitoring patients for cytopenias or complications arising from myelosuppression, and assessing the need for treatment with growth factors or antimicrobial agents. The most common non-hematologic adverse events were gastrointestinal events, and were generally below Grade 3 in terms of severity. The outcomes of the clinical safety review are described in further detail in the Clinical Safety section.
Neutropenia, thrombocytopenia, the potential for fetal harm, and the potential for infertility are listed in a Serious Warnings and Precautions box in the Product Monograph for Demylocan. The risks of fetal harm and infertility were detected during the non-clinical review.
A Risk Management Plan (RMP) for Demylocan was submitted by Pendopharm, Division of Pharmascience Inc. to Health Canada, and was considered acceptable upon review. 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 implemented to minimize risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Demylocan Product Monograph meet the necessary regulatory labelling, plain language and design element requirements. The first brand name proposed was not accepted due to its high similarity to the name of the medicinal ingredient. Demylocan was the second name proposed, and was accepted following a Look-alike Sound-alike brand name assessment.
Demylocan 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 Demylocan 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 Demylocan?
The New Drug Submission for Demylocan was filed as a Submission Relying on Third-Party Data (SRTD), according to the Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience).
Decitabine, the medicinal ingredient in Demylocan, was first authorized for the treatment of myelodysplastic syndromes (MDS) in the United States and marketed under the brand name Dacogen. Dacogen was later authorized in the European Union. The formulation authorized in Canada as Demylocan is the sponsor's generic product, Decitabine, which is authorized as a therapeutic equivalent to Dacogen in the United States.
Review reports of the sponsor's generic product from the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were consulted during the review of Demylocan.
Submission Milestones: Demylocan
| Submission Milestone | Date |
|---|---|
| Submission filed: | 2017-12-21 |
| Screening | |
| Screening Deficiency Notice issued: | 2018-02-09 |
| Response filed: | 2018-02-15 |
| Screening Acceptance Letter issued: | 2018-03-27 |
| Review | |
| Review of Risk Management Plan complete: | 2018-12-05 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2018-12-21 |
| Quality Evaluation complete: | 2019-01-15 |
| Clinical/Medical Evaluation complete: | 2019-01-17 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2019-01-21 |
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?
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision
Clinical Pharmacology
Decitabine, the medicinal ingredient in Demylocan, 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 Demylocan. Through the inpatient dosing regimen, patients receive 15 mg/m2 Demylocan 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 Demylocan 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 in the pivotal studies. A biexponential decline was observed following an intravenous infusion. Decitabine has a short half-life of approximately 35 minutes, and is therefore not expected to accumulate in the body with successive doses of 15 mg/m2 once every eight hours, or of 20 mg/m2 once daily. Both the total exposure per dose (as measured by the area under the concentration-time curve [AUC∞]) and the weekly cumulative AUC were higher following the inpatient dosing regimen (15 mg/m2) than following the outpatient dosing regimen (20 mg/m2).
Decitabine is a prodrug, which requires phosphorylation by deoxycytidine kinase to become active, and is deactivated by cytidine deaminase. There is a potential for drug interactions with other agents requiring activation and/or inactivation by the same enzymes as decitibine. In vitro tests were therefore conducted to assess the potential of decitabine to induce or inhibit a wide range of cytochrome P450 (CYP) enzymes. A strong positive induction effect of decitabine was observed for CYP2E1 from the primary hepatocyte culture of one donor in vitro. As general anaesthetics are substrates of CYP2E1, efficacy of these drugs may be reduced in patients treated with decitabine who require general anaesthesia. Precautionary statements were added to the Product Monograph regarding concurrent use of Demylocan with this class of drugs.
There were no studies submitted involving patients with renal or hepatic impairment, and no information is available regarding dose modification in these patient populations. Patients with renal or hepatic impairment should be closely monitored for toxicities including declines in liver function, as decitabine is metabolized by enzymes found in the liver and excreted mainly through the kidneys.
Overall, the pharmacokinetic data support the use of Demylocan for the approved indication. For further details, please refer to the Demylocan Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical review of Demylocan relied strongly on the regulatory reviews of the sponsor's generic drug product conducted by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA). As a Submission Relying on Third-Party Data (SRTD), the evidence of clinical efficacy was obtained primarily from published literature and other publicly available references.
Data were submitted from numerous clinical studies, conducted over a 20-year period. There are variations among the studies in diagnostic and response criteria as well as the approach to dosing, as the available technologies and knowledge of myelodysplastic syndromes (MDS) have advanced over time. However, all core studies reviewed for this submission have used internationally recognized standards including the French-American-British (FAB) and World Health Organization (WHO) classification systems for MDS, the International Prognostic Scoring System (IPSS) score, and the International Working Group (IWG) response criteria. The IWG response criteria are used to assess patient response, and were employed in all studies except for those classified as early Phase II studies.
Two studies were identified as pivotal: Study D-0007 and the Alternative Dosing for Outpatient Treatment (ADOPT) Trial.
Study D-0007 was an open-label, randomized, controlled Phase III study, which compared the efficacy of the standard medical care (SC) alone (number of patients [n] = 81) to that of the SC along with intravenous Demylocan (n = 89). All patients in this study were adults with MDS, with any FAB classification and an IPSS score of ≥intermediate-1. At study initiation, patient demographics were well balanced between the two treatment arms. In patients receiving Demylocan, 15 mg/m2 were administered intravenously over a three-hour period, every eight hours, for three consecutive days. This was defined as the inpatient dosing regimen, and repeated every six weeks. The number of treatment cycles administered to each patient ranged from zero to nine, with a median of three cycles.
The primary endpoints in this study were the overall response rate (ORR, defined as the complete response plus the partial response), and the time to acute myeloid leukemia (AML) transformation or death. A maximum p-value (p) of 0.024 was set as the criterion for a statistically significant response, using a two-sided analysis for either of the primary endpoints.
Among patients who received decitabine along with the SC treatment, the ORR was 17%, including 9% of patients with a complete response, compared with no responders in the SC treatment arm (p<0.001). In patients who received decitabine and were deemed evaluable for response, the ORR was 21%. The population of evaluable patients excluded those who were diagnosed as having AML at baseline, who did not receive study drug, or who did not complete Cycle 2. The median time to AML transformation or death was 12.1 months in patients receiving Demylocan with the SC treatment, versus 7.8 months in patients receiving the SC treatment only (p = 0.16). Of note, nine patients treated with Demylocan had an adjudicated diagnosis of AML at baseline, and five of these patients had a complete or partial response. There were no responses in the three patients receiving the SC treatment only with the same diagnosis at baseline.
Hematologic improvement was observed in 13% of Demylocan-treated patients, versus 7% of patients treated with the SC only. Out of 15 patients who responded to treatment with decitabine (completely or partially), 10 were transfusion-dependent at baseline, and were red blood cell and platelet transfusion-independent in the absence of treatment with growth factors at the time of response. The reduced need for transfusions is clinically beneficial due to the associated risks and the negative impact on quality of life. Responses were observed in patients with each of the FAB subtypes, including one of the six patients with chronic myelomonocytic leukemia.
The ADOPT Trial provided evidence supporting the efficacy of an outpatient dosing regimen for decitabine. It was designed as an open-label, single-arm study in 99 patients with any FAB subtype of MDS, and an IPSS score of ≥INT-1. The outpatient dosing regimen was structured into four-week-long cycles, in which patients received 20 mg/m2 Demylocan intravenously over a one-hour period, on days 1-5 of the first week of the cycle. Patients were treated for one to 17 cycles, with a median of five cycles.
The primary endpoint used to assess efficacy was the ORR, which was 32% based on the most recent IWG criteria (2006). A complete response was observed in 15 patients. Response rates were similar across all FAB subtypes and IPSS risk categories, and consistent with those observed in Study D-0007. Cytogenetic responses and a reduction in transfusion dependence were also indicative of efficacy.
Evaluating the time to AML progression or death was challenging, as it is complicated by the heterogeneous nature of MDS and the older age of most patients. However, the results of core studies involving an inpatient dosing regimen supported the results of Study D-0007, and the results of core studies administering an outpatient dosing regimen were consistent with those of the ADOPT Trial. Additionally, data from subgroup analyses were interpreted cautiously due to small numbers of patients. Overall, the outcomes of the clinical review support the efficacy of Demylocan for the approved indication, when administered according to either recommended dosing regimen.
Indication
The New Drug Submission for Demylocan was filed by the sponsor with the following indication, which Health Canada subsequently approved:
Demylocan is indicated for the treatment of adult patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refactory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System (IPSS) groups.
For more information, refer to the Demylocan Product Monograph, approved by Health Canada and available through the Drug Product Database
Clinical Safety
The clinical safety review of Demylocan was conducted using a safety database including data from MDS patients from all nine core studies. The two pivotal studies are described in the Clinical Efficacy section. All patients included in the database received at least one dose of decitabine on either the inpatient or outpatient dosing regimen. The most frequently reported serious and non-serious adverse events were hematologic, and generally indicative of myelosuppression. The most common non-hematologic adverse events were gastrointestinal events, and were generally below Grade 3 with respect to severity.
Serious adverse event and toxicity data were also available from clinical studies in other hematologic patient populations. While they were considered, these data could not be fully integrated because patients received decitabine through dosing regimens other than those recommended for Demylocan for the current indication. Additionally, there are no clinical safety data available in pregnant or nursing women, or in pediatric patients.
All patients in Study D-0007 reported adverse events. Neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia were each reported in over 30% of patients. Additionally, 69% of patients who received decitabine and 56% of patients who received only the SC treatment reported at least one serious adverse event. In decitabine-treated patients, the most frequently reported Grade 3 or 4 adverse events were neutropenia (87%), thrombocytopenia (85%), febrile neutropenia (23%), and leukopenia (22%). Infections associated with serious adverse events were reported more often in patients treated with decitabine (34%) than in those who received only the SC treatment. Bone marrow suppression was the most common cause of dose reduction, delay, or discontinuation. Fatal events occurred in six patients, which were associated with myelosuppression and the underlying disease, and considered at least possibly related to treatment.
In the ADOPT Trial, adverse events of fatigue, nausea, neutropenia, pyrexia, and anemia were each reported in over 30% of patients. The most frequently reported serious adverse events (Grade 3 or 4) were neutropenia (37%), thrombocytopenia (24%), and anemia (22%). The infections most often associated with serious adverse events were pneumonia, sepsis, and septic shock, and were contracted primarily by patients with additional risk factors. Hematologic toxicities and infections were the most common causes of dose delay and discontinuation. Fatal events related to infection or bleeding occurred in eight patients, and were considered at least possibly related to the treatment. Seven of the fatal events occurred in the clinical setting of myelosuppression.
Hematologic toxicities associated with myelosuppression were the most commonly reported serious and non-serious adverse events across all the studies reviewed. They are also characteristics of MDS, which complicated the safety assessment of Demylocan as a treatment for MDS. Increased frequency and severity of these events were observed in Demylocan-treated patients relative to those who did not receive Demylocan. However, the incidence of hematologic toxicities did not decrease with successive cycles in patients that did not respond to the treatment. Important risk mitigation strategies include monitoring patients for cytopenias or complications arising from myelosuppression, and assessing the need for treatment with growth factors or antimicrobial agents.
Neutropenia, thrombocytopenia, the potential for fetal harm, and the potential for infertility are listed in a Serious Warnings and Precautions box in the Product Monograph for Demylocan. The risks of fetal harm and infertility were identified during the non-clinical review.
Collectively, the data from the pivotal and non-pivotal studies are consistent with respect to the safety profile of Demylocan.
For more information, refer to the Demylocan Product Monograph, approved by Health Canada and available through the Drug Product Database
7.2 Non-Clinical Basis for Decision
The non-clinical review of decitabine, the medicinal ingredient in Demylocan, was based primarily on review reports from the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA), as well as other published literature.
The main toxicities identified through the non-clinical review were myelosuppression and reproductive toxicity, which both occurred with multiple cycles of intravenous infusion of decitabine in mice, rats, dogs, and rabbits. Signs of reproductive toxicity included irreversible testicular toxicity with testicular atrophy, and decreased numbers of germ cells and spermatozoa in male animals. Myelosuppression and irreversible testicular toxicity were also observed in neonatal and juvenile rats.
Decitabine is mutagenic and clastogenic in vitro and in vivo. Although no dedicated carcinogenicity studies were carried out, decitabine displayed clear carcinogenic potential in a study with a protocol similar to the conventional carcinogenicity two-year study.
Studies in pregnant mice and rats showed that decitabine is teratogenic. Signs of teratogenicity and embryo-fetal toxicity were apparent at doses considerably lower than the recommended clinical dose (<20 times), although no signs of toxicity were observed in the mothers. While there were no fertility studies carried out in female animals, reduced mating and fertility rates were observed in female mice exposed to decitabine in utero. However, this behaviour was more pronounced in male mice.
Collectively, the non-clinical data submitted for decitabine demonstrated that it is genotoxic, carcinogenic, teratogenic, and may impair fertility in males and females. As toxic effects have been observed at doses well below the recommended clinical dose, appropriate warnings and precautionary measures are listed in the Demylocan Product Monograph to address the safety concerns.
Considering the intended use of Demylocan, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Demylocan 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 Demylocan 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 24 months is acceptable when the drug product is stored at 20°C to 25°C.
Proposed limits of drug-related impurities are considered adequately qualified.
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 Demylocan is of human or animal origin.