Summary Basis of Decision for Zejula
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 Zejula is located below.
Recent Activity for Zejula
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 Zejula, a product which contains the medicinal ingredient niraparib. 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: 2024-08-20
Drug Identification Number (DIN):
DIN 02489783 - 100 mg capsule, niraparib, oral administration
DIN 02530031 - 100 mg tablet, niraparib, oral administration
Post-Authorization Activity Table (PAAT)
|
Activity/Submission Type, Control Number |
Date Submitted |
Decision and Date |
Summary of Activities |
|
SNDS # 262892 |
2022-03-30 |
Issued NOC 2024-01-12 |
Submission filed as a Level I – Supplement to update the PM with the removal of interim overall survival data of the NOVA trial. In response to a Notice of Deficiency issued by Health Canada, the sponsor provided updated overall survival data from the NOVA trial, preliminary overall survival results from the regional phase III NORA trial, and a real-world evidence study. Based on this data, it is recommended that the current indication for niraparib as second line maintenance therapy in recurrent ovarian cancer be maintained, regardless of BRCA status, based on the robust progression-free survival benefit observed in both the BRCA germline mutations (gBRCAmut) and non-gBRCAmut cohorts, the evidence provided in this submission, and a manageable safety profile. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published. |
|
Drug product (DIN 02530031) market notification |
Not applicable |
Date of first sale: 2023-09-13 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
SNDS # 271862 |
2023-01-27 |
Issued NOC 2023-08-17 |
Submission filed as a Level I – Supplement to update the PM following the completion of Study 3000-01-004. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Drug Interactions and Action and Clinical Pharmacology sections of the PM. An NOC was issued. |
|
Health Professional Risk Communication |
Not applicable |
Posted 2023-02-16 |
Health Professional Risk Communication posted (Zejula [niraparib] - Update on the Maintenance Treatment in Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in the Second or Later Line Setting), containing important safety information for healthcare professionals. |
|
SNDS # 259448 |
2021-12-10 |
Issued NOC 2022-08-24 |
Submission filed as a Level I – Supplement for a new immediate-release, film-coated tablet dosage form in a 100 mg strength. The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02530031) was issued for the new dosage form. A Regulatory Decision Summary was published. |
|
SNDS # 260789 |
2022-01-26 |
Issued NOC 2022-06-06 |
Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued. |
|
SNDS # 247584 |
2020-12-17 |
Issued NOC 2021-11-04 |
Submission filed as a Level I – Supplement to update the PM to add a recommended starting dose for patients with moderate hepatic impairment, and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration section of the PM, and corresponding changes were made to Part III Patient Medication Information and to the package insert. An NOC was issued. |
|
SNDS # 237670 |
2020-03-27 |
Issued NOC 2020-10-02 |
Submission filed as a Level I – Supplement for a new indication. The submission was reviewed under the Priority Review of Drug Submissions Policy. The indication authorized was: Zejula (niraparib capsules) is indicated as monotherapy for the maintenance treatment of female adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
Drug product (DIN 02489783 market notification |
Not applicable |
Date of first sale: 2020-01-09 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
NDS # 216792 |
2018-06-04 |
Issued NOC 2019-06-27 |
NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Zejula
Date SBD issued: 2019-11-19
The following information relates to the New Drug Submission for Zejula.
Niraparib
Drug Identification Number (DIN):
- DIN 02489783 - 100 mg capsule, oral administration
GlaxoSmithKline Inc.
New Drug Submission Control Number: 216792
On June 27, 2019, Health Canada issued a Notice of Compliance to GlaxoSmithKline Inc. for the drug product Zejula.
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 Zejula is favourable as monotherapy for the maintenance treatment of female adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
1 What was approved?
Zejula, an antineoplastic agent, was authorized as monotherapy for the maintenance treatment of female adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
The safety and efficacy of Zejula have not been established in pediatric patients (<18 years of age), and it is therefore not authorized for pediatric use.
No overall differences in the safety and efficacy of Zejula were observed between geriatric patients (>65 years of age) and younger patients. However, the possibility of greater sensitivity to niraparib in some older patients cannot be ruled out.
Zejula is contraindicated in:
- patients who are hypersensitive to this drug (niraparib) or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container, and
- patients who are breastfeeding.
Zejula 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.
Zejula (100 mg niraparib) is presented as a capsule. In addition to the medicinal ingredient, the capsule contains FD&C Blue #1, FD&C Red #3, FD&C Yellow #5, gelatin, lactose monohydrate, magnesium stearate, pharmaceutical grade printing ink, and titanium dioxide.
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 Zejula Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Zejula approved?
Health Canada considers that the benefit-harm-uncertainty profile of Zejula is favourable as monotherapy for the maintenance treatment of female adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
Ovarian cancer is often diagnosed at advanced stages, as the disease is asymptomatic in earlier stages. The later diagnosis results in poor prognosis. The five-year overall survival rate for all stages of ovarian cancer is approximately 46%. First- and second-line therapies against ovarian cancer are usually platinum-based. With subsequent lines of therapy, the length of time prior to relapse and the need for a new line of treatment tends to become progressively shorter.
Ovarian cancer, along with breast cancer, fallopian tube cancer, and primary peritoneal cancer, has been associated with mutations in the BRCA1 and BRCA2 genes. Niraparib, the medicinal ingredient in Zejula, is a highly selective inhibitor of the poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP)-1 and PARP-2 enzymes, which have roles in DNA repair. Niraparib has also shown 25- to 200-fold increased selectivity against cancer cell lines harbouring a BRCA1 or BRCA2 mutation and cancer cell lines that are homologous recombination-deficient (HRD) via BRCA1 or BRCA2 silencing.
The market authorization of Zejula was based primarily on results of the pivotal Phase III study ENGOT-OV16/NOVA (NOVA), which provided evidence of efficacy and safety. This study was conducted in 553 female adult patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. Patients were assigned to one of two cohorts depending on the presence of a deleterious germline mutation in either the BRCA1 or BRCA2 gene. All 553 patients were randomized in a 2:1 ratio to receive either 300 mg Zejula once daily, or the placebo.
Progression-free survival (PFS) was the primary efficacy endpoint, determined mainly by central independent assessment according to version 1.1 of the Response Evaluation Criteria in Solid Tumours (RECIST). A statistically significant increase in PFS was observed in both cohorts of patients treated with Zejula compared to those who received the placebo.
Overall survival was designated as a secondary efficacy endpoint. However, the available overall survival data were limited at the time of PFS analysis, with deaths occurring in 17% of the patient population.
In the overall safety analysis population, patients treated with Zejula reported a higher frequency of Grade 3 or 4 treatment-emergent adverse events (TEAEs), serious adverse events, and TEAEs leading to treatment interruption, dose reduction, or discontinuation.
In patients receiving Zejula, the most frequently reported adverse reactions (in ≥10% of patients) include nausea, thrombocytopenia, fatigue/asthenia, anemia, constipation, vomiting, abdominal pain/distension, neutropenia, insomnia, headache, decreased appetite, nasopharyngitis, rash, mucositis/stomatitis, diarrhea, dyspnea, hypertension, myalgia, dyspepsia, back pain, dizziness, leukopenia, cough, urinary tract infection, arthralgia, anxiety, palpitations, dry mouth, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevation, and dysgeusia.
Treatment-emergent thrombocytopenia and anemia were the most frequently reported serious adverse reactions (in >1% of patients). One on-treatment death was reported during this trial, and was associated with acute myeloblastic leukemia.
A Serious Warnings and Precautions box is included in the Zejula Product Monograph to highlight specific safety concerns. These include the risk of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML, including some cases that have been fatal), bone marrow suppression, hypertension (including hypertensive crisis), and the potential to cause fetal harm if administered to a pregnant woman.
Dose modification (interruption or reduction) or discontinuation may be considered as options to manage intolerable adverse events. The Zejula Product Monograph contains comprehensive instructions on dose modification, based on the individual tolerance of the patient as well as results of hematological laboratory tests.
A Risk Management Plan (RMP) for Zejula was submitted by GlaxoSmithKline Inc. 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 Zejula 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 Zejula was accepted.
Zejula has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through adequate monitoring and dose modification (interruption or reduction) or discontinuation. Appropriate warnings and precautions are in place in the Zejula 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 Zejula?
The New Drug Submission (NDS) for Zejula was reviewed as part of the New Chemical Entities Work Sharing Trial (NCEWST), a work-sharing initiative between Canada, Australia, Singapore, and Switzerland. This partnership aims to promote collaboration between regulatory agencies, optimize the use of resources, reduce duplication, and enhance each agency's ability to ensure consumers have timely access to safe, effective, and high-quality therapeutic products.
For this submission, Health Canada completed the clinical and quality reviews of Zejula, while Australia's Therapeutic Goods Administration (TGA) completed the non-clinical review. Although the review of the submission was collaborative, each jurisdiction made their regulatory decision independently of the others.
Submission Milestones: Zejula
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2018-01-24 |
| Submission filed: | 2018-05-31 |
| Screening | |
| Screening Deficiency Notice issued: | 2018-07-19 |
| Response filed: | 2018-08-30 |
| Screening Acceptance Letter issued: | 2018-09-27 |
| Review | |
| Biostatistics Evaluation complete: | 2019-01-08 |
| Review of Risk Management Plan complete: | 2019-04-18 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2019-05-21 |
| Quality Evaluation complete: | 2019-05-09 |
| Clinical/Medical Evaluation complete: | 2019-06-26 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2019-06-27 |
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
The clinical review of Zejula was completed by Health Canada as part of a work-sharing initiative with Australia, Singapore, and Switzerland. The review of the submission was collaborative, with each regulatory agency sharing the outcome of their review with the others. However, each regulatory agency made their decision regarding authorization independently.
Clinical Pharmacology
Niraparib, the medicinal ingredient in Zejula, is an inhibitor of the poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, which are involved in deoxyribonucleic acid (DNA) repair.
The results of in vitro studies indicate that niraparib may inhibit PARP enzymatic activity, promoting the formation of PARP-DNA complexes which then lead to DNA damage, apoptosis, and cell death.
Niraparib may affect pulse rate and blood pressure in patients receiving the recommended dose of 300 mg once daily. This may be due to pharmacological inhibition of the dopamine, norepinephrine, and serotonin transporters. In the pivotal study (described in the Clinical Efficacy section below), increases in the mean pulse rate and blood pressure were observed in patients treated with niraparib compared to patients receiving the placebo at all on-study assessments.
A separate clinical study was conducted to examine whether niraparib can prolong the QTc interval. Patients were randomized to receive either 300 mg niraparib once daily (number of patients [n] = 367) or a placebo (n = 179). No large differences in the mean QTc interval (>20 ms) were detected in the patients receiving niraparib.
The major pharmacokinetic aspects of niraparib have been well characterized. Systemic exposure to niraparib was observed to increase in a dose-proportional manner within a range of 30 mg to 400 mg, which corresponds to 0.1 times to 1.3 times the recommended dose, respectively. The absolute bioavailability of niraparib is approximately 73%, and the peak plasma concentration is reached after approximately three hours. Niraparib is 83% bound to human plasma proteins.
Niraparib is metabolized by carboxylesterases, with M1 and M10 as the major circulating metabolites. The half-life of niraparib was determined to be approximately 48 hours. Niraparib and its metabolites are eliminated through multiple pathways, including liver metabolism, hepatobiliary excretion, and renal elimination.
Mild hepatic impairment and mild to moderate renal impairment did not have clinically significant effects on the pharmacokinetics of niraparib. The effects of moderate to severe hepatic impairment, severe renal impairment, and end-stage renal disease on the pharmacokinetics of niraparib remain unknown.
Overall, the clinical pharmacological data support the use of Zejula for the approved indication.
For further details, please refer to the Zejula Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Zejula was evaluated primarily in the pivotal Phase III study ENGOT-OV16/NOVA (NOVA). The NOVA study was conducted in 553 female adult patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. To be eligible for this trial, patients must have already undergone at least two platinum-based treatment regimens. One of these platinum-based treatment regimens must also have been the patient's most recent therapy, to which she had a partial or complete response.
Patients were assigned to one of two cohorts depending on the presence of a deleterious germline mutation in either the BRCA1 or BRCA2 gene. These genes have been implicated in the development of breast cancer and ovarian cancer, as well as fallopian tube cancer and primary peritoneal cancer. Patients assigned to the germline BRCA mutation (gBRCAmut) cohort tested positive or were suspected for the mutation (number of patients [n] = 203). Patients without this mutation (n = 350) were assigned to the non-germline BRCA mutation (non-gBRCAmut) cohort.
All 553 patients were randomized in a 2:1 ratio to receive either 300 mg Zejula once daily, or the placebo. Patients were monitored through consecutive 28-day cycles, for a median duration of 250 days.
The primary efficacy endpoint was progression-free survival (PFS), determined mainly by central independent assessment according to version 1.1 of the Response Evaluation Criteria in Solid Tumours (RECIST). In some cases, other criteria were also applied to evaluate PFS. These included clinical signs and symptoms, as well as increasing levels of cancer antigen 125 (CA125) in the blood.
A statistically significant increase in PFS was observed in both cohorts in patients treated with Zejula, compared to those who received the placebo. In the gBRCAmut cohort, the median PFS was 21.0 months in patients treated with Zejula, versus 5.5 months in patients who received the placebo (hazard ratio [HR] = 0.26; p<0.0001). In the non-gBRCAmut cohort, the median PFS was 9.3 months in patients who received Zejula, and 3.9 months in patients who received the placebo (HR = 0.45; p<0.0001).
Overall survival was designated as a secondary efficacy endpoint. However, the available overall survival data were limited at the time of PFS analysis, with deaths occurring in 17% of the patient population.
Indication
| Sponsor's proposed indication | Health Canada-approved indication |
| Zejula is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. | Zejula (niraparib capsules) is indicated as monotherapy for the maintenance treatment of female adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. |
The proposed indication was revised to better reflect the patient population in the pivotal study in which Zejula was shown to be an effective treatment.
For more information, refer to the Zejula Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The outcomes of the NOVA study have established both the clinical safety and efficacy of Zejula in the intended patient population, and are described in the Clinical Efficacy section.
In the overall safety population, the following events were reported at a higher frequency in patients receiving Zejula than in patients receiving the placebo: Grade 3 or 4 treatment-emergent adverse events (TEAEs; 74% versus 23%), serious adverse events (30% versus 15%), TEAEs leading to treatment interruption (69% versus 5%), TEAEs leading to dose reduction (67% versus 15%), and TEAEs leading to treatment discontinuation (15% versus 2%).
In patients receiving Zejula, the most frequently reported adverse reactions (in ≥10% of patients) include nausea, thrombocytopenia, fatigue/asthenia, anemia, constipation, vomiting, abdominal pain/distension, neutropenia, insomnia, headache, decreased appetite, nasopharyngitis, rash, mucositis/stomatitis, diarrhea, dyspnea, hypertension, myalgia, dyspepsia, back pain, dizziness, leukopenia, cough, urinary tract infection, arthralgia, anxiety, palpitations, dry mouth, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevation, and dysgeusia.
Treatment-emergent thrombocytopenia and anemia were the most frequently reported serious adverse reactions (in >1% of patients). One on-treatment death was reported during this trial, and was associated with acute myeloblastic leukemia.
Grade 3 and 4 hematologic TEAEs reported in patients who received Zejula occurred most commonly in the initial days and weeks of treatment. These events were managed through strict dose adjustments based on the individual tolerability of each patient.
The most common hematologic TEAEs of any grade in both treatment arms (Zejula or placebo) were anemia (49% versus 7%), thrombocytopenia (46% versus 3%), and neutropenia (18% versus 3%). The most common non-hematologic TEAEs of any grade were nausea (74% versus 35%), fatigue (46% versus 32%), constipation (40% versus 20%), and vomiting (34% versus 16%).
Due to the adverse events observed with the 300 mg starting dose, a post hoc analysis was conducted by the sponsor with the objective of providing evidence to support a lower starting dose of 200 mg based on the baseline platelet counts and body weight of the patients. However, the analysis did not provide sufficient evidence that a niraparib starting dose other than the 300 mg, used in the pivotal study, would produce the required efficacy in the patient population for which Zejula is intended. Therefore, the dosing recommendations were not changed. However, the Product Monograph states that clinicians may consider a starting dose of 200 mg for patients weighing less than 58 kg, as Grade 3 and 4 adverse reactions were observed to be more common in patients with low body weight.
A Serious Warnings and Precautions box is included in the Zejula Product Monograph to highlight specific safety concerns. These include the risk of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML, including some cases that have been fatal), bone marrow suppression, hypertension (including hypertensive crisis), and the potential to cause fetal harm if administered to a pregnant woman.
Dose modification (interruption or reduction) or discontinuation may be considered as options to manage intolerable adverse events. The Zejula Product Monograph contains comprehensive instructions on dose modification, based on the individual tolerance of the patient as well as results of hematological laboratory tests. During the NOVA study, the adverse events that most often led to dose reduction were thrombocytopenia (31%), anemia (18%), and decreased platelet count (10%).
Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified for Zejula, and to promote its safe and effective use. Overall, the benefit-harm-uncertainty profile of Zejula is favourable. For more information, refer to the Zejula 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 Zejula was completed by Australia's Therapeutic Goods Administration (TGA) as part of a work-sharing initiative with Canada, Singapore, and Switzerland. The review of the submission was collaborative, with each regulatory agency sharing the outcome of their review with the others. However, each regulatory agency made their decision regarding authorization independently.
The cytotoxic effects of niraparib, the medicinal ingredient in Zejula, are attributed to its ability to prevent DNA repair by inhibiting the PARP-1 and PARP-2 enzymes. These effects were observed in tumour cell lines both with and without mutations in the BRCA1 or BRCA2 genes.
In in vivo studies, niraparib reduced tumour growth in mouse xenograft models with tumours characterized by defective BRCA1/2 function or homologous recombination deficiency, as well as tumours with wild-type (normal) BRCA genes without detectable homologous recombination deficiency.
Niraparib crossed the blood-brain barrier in preclinical models.
Off-target effects of niraparib were observed at clinically relevant concentrations during non-clinical studies, inhibiting the monoamine transporters for dopamine, norepinephrine, and serotonin. Hypertension has been observed as an adverse reaction in patients, and may be related to these effects. Other hemodynamic parameters may also be affected at clinical exposures due to the off-target effects on monoamine transporters.
Signs of toxicity were identified in the hematopoietic system, gastrointestinal tissue, and the male reproductive system. Septicemia was also observed in male rats, and was most likely caused by bone marrow depression and lymphoid depletion. No specific hazards affecting the respiratory system were identified in safety pharmacology studies with niraparib.
Niraparib had clastogenic effects in both in vitro and in vivo studies, which is expected due to its intended pharmacological activity (inhibiting DNA repair). No dedicated carcinogenicity studies were conducted.
No reproductive or developmental toxicity studies were conducted. However, there is sufficient evidence that niraparib adversely affects embryo-fetal development and fertility based on observations from repeat-dose toxicity studies in rats and dogs. The observed signs of reproductive toxicity include reduced spermatogenesis and testicular germ cell depletion in male animals.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Zejula Product Monograph. Considering the intended use of Zejula, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Zejula Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The quality review of Zejula was completed by Health Canada as part of a work-sharing initiative with Australia, Singapore, and Switzerland. The review of the submission was collaborative, with each regulatory agency sharing the outcome of their review with the others. However, each regulatory agency made their decision regarding authorization independently.
The Chemistry and Manufacturing information submitted for Zejula 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 20ºC to 25ºC.
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. Zejula contains two excipients of animal origin, lactose monohydrate and gelatin. Both excipients are obtained from sources that are not considered a risk for transmitting bovine spongiform encephalopathy (BSE) or transmissible spongiform encephalopathy (TSE). Certification letters attesting to these claims were provided by the sponsor.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ZEJULA | 02489783 | GLAXOSMITHKLINE INC | NIRAPARIB (NIRAPARIB TOSYLATE) 100 MG |
| ZEJULA | 02530031 | GLAXOSMITHKLINE INC | NIRAPARIB (NIRAPARIB TOSYLATE) 100 MG |