Summary Basis of Decision for Tabrecta
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 Tabrecta is located below.
Recent Activity for Tabrecta
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.
Summary Basis of Decision (SBD) for Tabrecta
Date SBD issued: 2022-08-30
The following information relates to the new drug submission for Tabrecta.
Capmatinib (supplied as capmatinib hydrochloride)
Drug Identification Number (DIN):
- DIN 02527391 - 150 mg capmatinib, tablet, oral administration
- DIN 02527405 - 200 mg capmatinib, tablet, oral administration
Novartis Pharmaceuticals Canada Inc.
New Drug Submission Control Number: 255972
On May 26, 2022, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Novartis Pharmaceuticals Canada Inc. for the drug product Tabrecta. The product was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow‑up to confirm the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.
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 Tabrecta is favourable for the treatment of adult patients with locally advanced unresectable or metastatic non‑small cell lung cancer (NSCLC) harbouring mesenchymal‑epithelial transition (MET) exon 14 skipping alterations.
1 What was approved?
Tabrecta, a protein kinase inhibitor, was authorized for the treatment of adult patients with locally advanced unresectable or metastatic non‑small cell lung cancer (NSCLC) harbouring mesenchymal‑epithelial transition (MET) exon 14 (METex14) skipping alterations.
Efficacy in patients with NSCLC harbouring METex14 alterations was based on overall response rate and duration of response in a single-arm study. Documentation of the presence of a METex14 alteration based on a validated test is required prior to treatment with Tabrecta.
No data are available to Health Canada with respect to pediatric patients (less than 18 years of age). Therefore, Health Canada has not authorized an indication for pediatric use.
In Study A2201 (GEOMETRY mono-1), 61% of the 373 patients were 65 years of age or older, and 18% were 75 years of age or older. No clinically important differences in safety or efficacy were observed between patients aged 65 years or older and younger patients.
Tabrecta (150 mg and 200 mg capmatinib, supplied as capmatinib hydrochloride) is presented as a tablet. In addition to the medicinal ingredient, the tablet contains microcrystalline cellulose; crospovidone; hypromellose; iron oxide, black (for the 150 mg tablets); iron oxide, red (for the 150 mg tablets); iron oxide, yellow; macrogol 4000; magnesium stearate; mannitol; povidone; silica colloidal anhydrous; sodium laurilsulfate; talc; and titanium dioxide.
The use of Tabrecta is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Tabrecta Product Monograph is available through the Drug Product Database.
For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
2 Why was Tabrecta approved?
Health Canada considers that the benefit-harm-uncertainty profile of Tabrecta is favourable for the treatment of adult patients with locally advanced unresectable or metastatic non‑small cell lung cancer (NSCLC) harbouring mesenchymal‑epithelial transition (MET) exon 14 (METex14) skipping alterations. Tabrecta was authorized under the Notice of Compliance with Conditions (NOC/c) Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit.
Lung cancer is the most commonly diagnosed malignancy and the leading cause of cancer death in Canada. Non-small cell lung cancer accounts for approximately 85% of all lung cancer cases. Mesenchymal‑epithelial transition exon 14 skipping alterations are present in approximately 2‑4% of cases of NSCLC. These genetic alterations typically affect elderly patients and are associated with a poor prognosis.
At the time of authorization of Tabrecta, available therapies used to treat patients with METex14‑altered advanced NSCLC included tepotinib, a kinase inhibitor of MET, which had recently been authorized to treat patients with METex14‑altered advanced NSCLC under the NOC/c Guidance, non‑targeted therapies such as platinum doublet chemotherapy with or without an immune checkpoint inhibitor (ICI), single‑agent chemotherapy, or ICI . However, the effectiveness of the non‑targeted therapies has not been established in this patient population. Additionally, the toxicities associated with chemotherapy can be significant, which is an important consideration for patients who tend to be older and have comorbidities. Capmatinib, the medicinal ingredient in Tabrecta, is an inhibitor of the MET receptor tyrosine kinase. In this New Drug Submission, the sponsor sought an indication for the treatment of adult patients with METex14‑altered advanced NSCLC.
The clinical efficacy of Tabrecta was evaluated in 160 adult patients enrolled in the pivotal multi‑cohort Phase II Study A2201 (GEOMETRY mono‑1) who had locally advanced unresectable (Stage IIIB) or metastatic (Stage IV) NSCLC with METex14 alterations. Patients received Tabrecta 400 mg orally twice daily until disease progression or unacceptable toxicity.
The primary efficacy endpoint was overall response rate (ORR), determined by a blinded independent review committee (BIRC) according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. The key secondary efficacy endpoint was duration of response (DOR) as determined by the BIRC. Among the 60 patients who had not received any prior systemic treatments for advanced disease (i.e., treatment‑naïve patients), the ORR was 66.7% (95% confidence interval [CI]: 53.3, 78.3), and the median DOR was 12.6 months (95% CI: 8.4, not estimable). Among the 100 patients who had received 1 or 2 prior lines of systemic therapy for advanced disease (i.e., previously treated patients), the ORR was 44.0% (95% CI: 34.1, 54.3) and the median DOR was 9.7 months (95% CI: 5.6, 13.0). These efficacy results are considered promising evidence of clinical benefit under the recommended condition of use.
The clinical safety of Tabrecta was evaluated in 373 patients who had advanced NSCLC with MET dysfunction (i.e., METex14 alterations or MET amplification) in the pivotal Study A2201. The median duration of exposure to Tabrecta was 17.9 weeks (range: 0.4 to 251.6 weeks).
The most common adverse reactions (reported in ≥20% of patients [all grades]) were peripheral edema, nausea, fatigue, vomiting, increased blood creatinine, dyspnea, and decreased appetite. The most common Grade 3 or 4 adverse reactions (reported in ≥5% of patients) were peripheral edema, fatigue, dyspnea, increased alanine aminotransferase (ALT), and increased lipase.
Sixty patients (16.2%) permanently discontinued Tabrecta due to an adverse event. Peripheral edema (2.1%), pneumonitis (1.6%), and fatigue (1.3%) were the adverse events most frequently reported to lead to permanent discontinuation (≥1%). Dose interruptions due to an adverse event were reported in 208 patients (55.8%). The adverse events most frequently reported to require dose interruption (>5%) included peripheral edema (10.7%), increased blood creatinine (8.0%), nausea (5.9%), increased lipase (5.1%), and vomiting (5.1%). Dose reductions due to an adverse event were reported in 97 patients (26.0%). The adverse events most frequently reported to lead to dose reduction (>2%) included peripheral edema (9.4%) and increased ALT (3.2%).
A Serious Warnings and Precautions box is included in the Tabrecta Product Monograph to highlight the risks of interstitial lung disease (ILD)/pneumonitis, hepatotoxicity, and embryo‑fetal toxicity.
A Risk Management Plan (RMP) for Tabrecta was submitted by Novartis Pharmaceuticals Canada Inc. to Health Canada. 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. Upon review, the RMP was considered to be acceptable.
The submitted inner and outer labels, package insert, and Patient Medication Information section of the Tabrecta Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements.
The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Tabrecta was accepted.
Tabrecta has an acceptable safety profile based on the non-clinical data and clinical studies in consideration of the intended patient population. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Tabrecta Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring of the use of Tabrecta will be ongoing. Further evaluation will take place upon the submission of the requested studies after they become available.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued 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 Tabrecta?
The sponsor filed a request for Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance for the review of the New Drug Submission (NDS) for Tabrecta. The sponsor presented promising evidence of clinical effectiveness that Tabrecta has the potential to provide effective treatment of a life-threatening disease for which no drug is presently marketed in Canada.
Subsequent review led to the decision to issue the sponsor market authorization under the NOC/c Guidance, in recognition of the promising but unconfirmed evidence of clinical effectiveness in the submission. In keeping with the provisions of the NOC/c Guidance, the sponsor agreed to provide additional information to confirm the clinical benefit.
The New Drug Submission for Tabrecta was reviewed under Project Orbis, an initiative of the United States Food and Drug Administration (FDA) Oncology Center of Excellence. The project is an international partnership designed to give cancer patients faster access to promising cancer treatments. The submission for Tabrecta was classified as a Project Orbis Type C submission, in which the FDA had already issued a positive decision and subsequently shared their completed review documents with Health Canada. The Canadian regulatory decision on the Tabrecta NDS was made independently based on a critical assessment of the data package submitted to Health Canada, along with the reviews completed by the FDA as described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. Methods 2 and 3 were used for the review of the clinical data, Method 3 was used for the review of non-clinical data, and Method 2 was used for the review of the quality data.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Submission Milestones: Tabrecta
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2021-06-08 |
| Advance Consideration under the Notice of Compliance with Conditions Guidance accepted | 2021-08-09 |
| New Drug Submission filed | 2021-08-19 |
| Screening | |
| Screening Acceptance Letter issued | 2021-09-14 |
| Review | |
| Non-clinical evaluation completed | 2022-03-17 |
| Quality evaluation completed | 2022-03-25 |
| Review of Risk Management Plan completed | 2022-03-29 |
| Labelling review completed | 2022-03-29 |
| Clinical/medical evaluation completed | 2022-03-30 |
| Notice of Compliance with Conditions Qualifying Notice issued | 2022-04-04 |
| Review of Response to Notice of Compliance with Conditions Qualifying Notice: | |
| Response filed (Letter of Undertaking) | 2022-05-12 |
| Labelling review completed | 2022-05-17 |
| Clinical/medical evaluation completed | 2022-05-19 |
| Notice of Compliance issued by Director General, Pharmaceutical Products Directorate under the Notice of Compliance with Conditions Guidance | 2022-05-26 |
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations and in the Notice of Compliance with Conditions (NOC/c) Guidance. Notably, the sponsor has agreed to provide the following:
Confirmatory Studies
Study CINC280A2201 (GEOMETRY Mono-1)
The sponsor has committed to providing an interim study report for Study CINC280A2201 (GEOMETRY Mono‑1) as a Supplement to a New Drug Submission ‑ Confirmatory (SNDS-C). This report is expected to confirm and further characterize the clinical benefit of capmatinib in patients with non‑small cell lung cancer (NSCLC) harbouring mesenchymal‑epithelial transition (MET) exon 14 skipping alterations by providing a more precise estimation of the overall response rate and duration of response as assessed by blinded independent central review. It should contain data from treatment‑naïve patients after all responders have been followed for at least 12 months from the date of initial response or until disease progression, whichever occurs first. It should also contain data from previously treated patients after all responders have been followed for at least 6 months from the date of initial response or until disease progression, whichever occurs first. The sponsor has committed to submitting this SNDS‑C by the third quarter (Q3) of 2022.
The sponsor has also committed to providing annual status reports on the progress of ongoing confirmatory trials.
Additional Studies
The sponsor has agreed to submit the primary analysis report of Study CINC280A2301, an ongoing, randomized Phase III study comparing capmatinib to docetaxel in patients with advanced NSCLC harbouring MET exon 14 skipping alterations who have previously received systemic therapy. The sponsor has committed to submitting this report by the first quarter (Q1) of 2026.
Post-Market Safety Monitoring
Periodic Safety Update Reports ‑ Confirmatory (PSUR‑C) or Periodic Benefit-Risk Evaluation Reports ‑ Confirmatory (PBRER‑C) are to be submitted annually until such time as conditions associated with the market authorisation are removed.
The sponsor is expected to comply with the requirements for reporting on specific issues of concern, reporting adverse drug reactions occurring in Canada and internationally, and risk management measures as described in the NOC/c Guidance.
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
As described above, the review of the clinical component of the New Drug Submission (NDS) for Tabrecta was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration as a Project Orbis Type C submission. Additionally, the review of the clinical component of the NDS for Tabrecta was conducted as per Methods 2 and 3 as described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
Clinical Pharmacology
Capmatinib is an inhibitor of the mesenchymal‑epithelial transition (MET) receptor tyrosine kinase. Capmatinib inhibits MET phosphorylation (both autophosphorylation and phosphorylation triggered by the ligand hepatocyte growth factor [HGF]), MET‑mediated phosphorylation of downstream signaling proteins, as well as proliferation and survival of MET‑dependent cancer cells. Treatment with capmatinib resulted in the regression of tumor xenograft models derived from lung cancer, including all alterations leading to MET exon 14 (MET ex14) skipping mutations.
Capmatinib exhibited dose‑proportional increases in systemic exposure as measured by the area under the concentration‑time curve from time zero to infinity (AUCinf) and the maximum concentration (Cmax) across the dose range of 200 mg twice daily to 400 mg twice daily. Steady‑state is expected to be achieved after 3 days of oral dosing at 400 mg twice daily, with a geometric mean accumulation ratio of 1.39 (coefficient of variation 42.9%).
The major aspects of absorption, distribution, metabolism, and elimination were characterized in patients and in healthy subjects. The absorption of capmatinib after oral administration is estimated to be greater than 70%. In cancer patients, the Cmax was reached 1‑2 hours after a 400 mg dose. Tabrecta can be administered with or without food, as food was not found to affect the bioavailability of capmatinib to a clinically meaningful extent. Capmatinib is 96% bound to human plasma proteins, independent of concentration. The apparent mean volume of distribution at steady-state (Vss/F) is 164 L in cancer patients. Capmatinib is metabolized primarily by cytochrome P450 (CYP) 3A4 and aldehyde oxidase. The most abundant circulating metabolite, M16, is not pharmacologically active. The effective elimination half‑life is 6.54 hours, and capmatinib is eliminated mainly through the fecal route.
Studies were conducted to evaluate the effects of hepatic and renal impairment on the pharmacokinetics of capmatinib. Mild, moderate, or severe hepatic impairment and mild or moderate renal impairment had no clinically significant effect on the exposure of capmatinib. Capmatinib has not been studied in patients with severe renal impairment (creatinine clearance of 15 to 29 mL/min).
Following the coadministration of capmatinib with a strong CYP3A inhibitor, a 42% increase was observed in exposure as measured by the AUC, although no change was observed in the Cmax. Patients should therefore be closely monitored during coadministration with a strong CYP3A inhibitor, as this may increase the incidence and severity of adverse drug reactions.
A 67% decrease in the AUC and a 56% decrease in the Cmax were observed when capmatinib was coadministered with a strong CYP3A inducer. As this may decrease the anti‑tumour activity of capmatinib, coadministration with a strong CYP3A inducer should be avoided. Additionally, physiologically‑based pharmacokinetic modelling predicted a 44% decrease in capmatinib AUC and a 34% decrease in Cmax for coadministration with a moderate CYP3A inducer. This should therefore also be avoided.
Following the coadministration of capmatinib with a CYP1A2 substrate, a 134% increase was observed in the substrate AUC. The coadministration of capmatinib with a P‑glycoprotein (P‑gp) substrate increased the substrate AUC by 47% and the Cmax by 74%. The coadministration of capmatinib with a breast cancer resistance protein (BCRP) substrate increased the substrate AUC by 108% and the Cmax by 204%. Based on in vitro data, capmatinib may inhibit multidrug and toxin extrusion protein (MATE) 1 and MATE2K transporters at clinically relevant concentrations, which may increase the exposure of their substrates. If coadministration of Tabrecta with any of these substrates (CYP1A2, P‑gp, BCRP, MATE1, or MATE2K) is unavoidable where minimal substrate concentration changes may lead to serious adverse reactions, the dose of the substrate should be decreased in accordance with the approved Product Monograph for the substrate.
For further details, please refer to the Tabrecta Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Tabrecta was assessed in 160 adult patients with locally advanced unresectable (Stage IIIB) or metastatic (Stage IV) NSCLC with METex14 alterations in the pivotal multi‑cohort Phase II Study A2201 (GEOMETRY mono‑1). Patients received Tabrecta 400 mg orally twice daily until disease progression or unacceptable toxicity.
The primary efficacy endpoint was overall response rate (ORR), determined by a blinded independent review committee (BIRC) according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. The key secondary efficacy endpoint was duration of response (DOR) as determined by the BIRC. Among the 60 patients who had not received any prior systemic treatments for advanced disease (i.e., treatment‑naïve patients), the ORR was 66.7% (95% confidence interval [CI]: 53.3, 78.3), and the median DOR was 12.6 months (95% CI: 8.4, not estimable). Among the 100 patients who had received 1 or 2 prior lines of systemic therapy for advanced disease (i.e., previously treated patients), the ORR was 44.0% (95% CI: 34.1, 54.3) and the median DOR was 9.7 months (95% CI: 5.6, 13.0). These efficacy results are considered promising evidence of clinical benefit under the recommended condition of use.
Indication
Health Canada approved the following indication:
- Tabrecta (capmatinib tablets) is indicated for the treatment of adult patients with locally advanced unresectable or metastatic non-small cell lung cancer (NSCLC) harbouring mesenchymal-epithelial transition (MET) exon 14 skipping alterations.
The efficacy of Tabrecta in patients with NSCLC harbouring METex14 skipping alterations was based on overall response rate and duration of response in a single-arm study. Documentation of the presence of a METex14 alteration based on a validated test is required prior to treatment with Tabrecta.
The sponsor’s proposed indication was modified slightly based on Health Canada’s recommendation to better align with the characteristics of patients enrolled in the pivotal study. Additional information was added following the indication statement to describe the basis of the authorization and to emphasize proper patient selection.
For more information, refer to the Tabrecta Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The primary safety population in which the clinical safety of Tabrecta was evaluated consisted of 373 patients who had advanced NSCLC with MET dysfunction in the pivotal Study A2201. The median duration of exposure to Tabrecta was 17.9 weeks (range: 0.4 to 251.6 weeks).
The most common adverse reactions (reported in ≥20% of patients [all grades]) were peripheral edema, nausea, fatigue, vomiting, increased blood creatinine, dyspnea, and decreased appetite. The most common Grade 3 or 4 adverse reactions (reported in ≥5% of patients) were peripheral edema, fatigue, dyspnea, increased alanine aminotransferase (ALT), and increased lipase.
Sixty patients (16.2%) permanently discontinued Tabrecta due to an adverse event. Peripheral edema (2.1%), pneumonitis (1.6%), and fatigue (1.3%) were the adverse events most frequently reported to lead to permanent discontinuation (≥1%). Dose interruptions due to an adverse event were reported in 208 patients (55.8%). The adverse events most frequently reported to require dose interruption (>5%) included peripheral edema (10.7%), increased blood creatinine (8.0%), nausea (5.9%), increased lipase (5.1%), and vomiting (5.1%). Dose reductions due to an adverse event were reported in 97 patients (26.0%). The adverse events most frequently reported to lead to dose reduction (>2%) included peripheral edema (9.4%) and increased ALT (3.2%).
A Serious Warnings and Precautions box is included in the Tabrecta Product Monograph to highlight the risks of interstitial lung disease (ILD)/pneumonitis, hepatotoxicity, and embryo‑fetal toxicity.
Based on the data reviewed, Tabrecta presents an acceptable and manageable safety profile for the intended patient population. The overall benefit‑harm-uncertainty profile of Tabrecta for the approved indication is favourable under the Notice of Compliance with Conditions (NOC/c) Guidance Document. Additional clinical data are needed to verify the clinical benefit of Tabrecta.
For more information, refer to the Tabrecta Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
As described above, the review of the non‑clinical component of the New Drug Submission (NDS) for Tabrecta was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration as a Project Orbis Type C submission. Additionally, the review of the non-clinical component of the NDS for Tabrecta was conducted as per Method 3 as described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
Results from non‑clinical pharmacodynamics studies indicated that capmatinib is a selective and specific inhibitor of the mesenchymal‑epithelial transition (MET) receptor tyrosine kinase. At the intended therapeutic dose, capmatinib exhibits anti‑tumour activity and low potential for off‑target activity. The major circulating metabolite, M16, was found to be pharmacologically inactive.
Similar pharmacokinetic profiles were observed across the tested animals, except for the dog. Capmatinib was efficiently metabolized by cytochrome P450 (CYP) 1A1 and CYP3A4, and was eliminated via metabolism and predominantly excreted in feces. In repeat‑dose toxicity studies in rats and cynomolgus monkeys, signs of toxicity were observed in the liver, pancreas, kidneys, and brain/central nervous system.
Carcinogenicity studies with capmatinib have not been conducted. Capmatinib is not considered genotoxic based on findings from an in vitro bacterial reverse mutation assay (Ames test), an in vitro chromosome aberration assay in human peripheral blood lymphocytes, and an in vivo bone marrow micronucleus test in rats.
Capmatinib is considered potentially teratogenic to humans based on embryo‑fetal development studies conducted in rats and rabbits. During the period of organogenesis, pregnant rats received oral doses of capmatinib up to 30 mg/kg/day, and pregnant rabbits received oral doses up to 60 mg/kg/day. At 30 mg/kg/day in rats and 60 mg/kg/day in rabbits, the maternal systemic exposures (as measured by the area under the concentration‑time curve [AUC]) were approximately 1.4 and 1.5 times, respectively, the exposure in humans at the maximum recommended human dose (MRHD) of 400 mg twice daily. In rats, signs of maternal toxicity (reduced body weight gain and food consumption) were observed at 30 mg/kg/day. Fetal effects including reduced fetal weights, irregular/incomplete ossification, and increased incidences of fetal malformations were observed at doses of ≥10 mg/kg/day. In rabbits, no maternal effects were observed at doses up to 60 mg/kg/day. Fetal effects including small lung lobe were observed at ≥5 mg/kg/day, and reduced fetal weights, irregular/incomplete ossification and increased incidences of fetal malformations were observed at the dose of 60 mg/kg/day.
Capmatinib was found to have the potential for photosensitization based on observations from in vitro and in vivo photosensitization assays. The no‑observed-adverse-effect level (NOAEL) for in vivo photosensitization was 30 mg/kg/day, which corresponds to approximately 2.9 times the human maximum concentration (Cmax) at the 400 mg twice daily dose.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Tabrecta Product Monograph. Considering the intended use of Tabrecta, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Tabrecta Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
As described above, the review of the quality component of the New Drug Submission (NDS) for Tabrecta was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration as a Project Orbis Type C submission. Additionally, the review of the quality component of the NDS for Tabrecta was conducted as per Method 2 as described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
The chemistry and manufacturing information submitted for Tabrecta 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 36 months is acceptable. Tabrecta should not be stored above 25 °C.
Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies).
All sites involved in production are compliant with good manufacturing practices.
None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.
None of the excipients used in the formulation of Tabrecta are of human or animal origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| TABRECTA | 02527391 | NOVARTIS PHARMACEUTICALS CANADA INC | CAPMATINIB (CAPMATINIB HYDROCHLORIDE) 150 MG |
| TABRECTA | 02527405 | NOVARTIS PHARMACEUTICALS CANADA INC | CAPMATINIB (CAPMATINIB HYDROCHLORIDE) 200 MG |