Summary Basis of Decision for Ofev
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 Ofev is located below.
Recent Activity for Ofev
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.
Post-Authorization Activity Table (PAAT) for Ofev
Updated: 2024-08-08
The following table describes post-authorization activity for Ofev, a product which contains the medicinal ingredient nintedanib. 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 02443066 – 100 mg, nintedanib, capsule, oral administration
- DIN 02443074 – 150 mg, nintedanib, capsule, oral administration
Post-Authorization Activity Table (PAAT)
Activity/Submission Type, Control Number |
Date Submitted |
Decision and Date |
Summary of Activities |
SNDS # 249336 |
2021-02-08 |
Issued NOC 2021-07-06 |
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 Dosage and Administration and Special Handling Instructions 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 # 241747 |
2020-07-16 |
Issued NOC 2021-06-25 |
Submission filed as a Level I – Supplement to streamline the current three indications into one simplified indication and to update the PM with new safety information. Changes to the indication and the inclusion of data from Study 1199.33 were rejected by Health Canada. Data from Study 1199.247 and Study 1199-0340 were reviewed and added to the PM. As a result of the SNDS, modifications were made to the Warnings and Precautions; Drug Interactions; Clinical Pharmacology; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.An NOC was issued. A Regulatory Decision Summary was published. |
SNDS # 247352 |
2020-12-10 |
Issued NOC 2021-05-11 |
Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information, 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 Warnings and Precautions; Adverse Reactions; and Clinical Trials 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 # 232923 |
2019-10-28 |
Issued NOC 2020-05-20 |
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: OFEV (nintedanib) is indicated for the treatment of other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype (also known as progressive fibrosing ILD). The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published. |
NC # 232837 |
2019-10-23 |
Issued NOL 2020-01-28 |
Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Adverse Reactions section of the PM, and corresponding changes were made to Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
SNDS # 227166 |
2019-04-25 |
Issued NOC 2019-11-22 |
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: Ofev (nintedanib) is indicated to slow the rate of decline in pulmonary function in patients with systemic sclerosis associated interstitial lung disease (SSc-ILD). The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published. |
NC # 216277 |
2018-05-14 |
Issued NOL 2018-08-10
|
Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with safety-related changes. As a result of the NC, changes were made to the Warnings and Precautions, Adverse Reactions, and Drug Interactions sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
NC # 212069 |
2017-12-12 |
Issued NOL 2018-03-20
|
Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with safety-related changes. As a result of the NC, changes were made to the Warnings and Precautions, and Dosage and Administration sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
Dear Healthcare Professional Letter |
Not applicable |
Posted 2018-01-11 |
Dear Healthcare Professional Letter posted containing important safety information for healthcare professionals. |
NC # 207762 |
2017-07-21 |
Issued NOL 2017-10-26
|
Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with safety-related changes. As a result of the NC, changes were made to the Warnings and Precautions, and Adverse Reactions sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
NC # 202904 |
2017-02-15 |
Issued NOL 2017-06-02
|
Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with safety-related changes. As a result of the NC, changes were made to the Warnings and Precautions, and Adverse Reactions sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
SNDS # 194900 |
2016-05-09 |
Issued NOC 2017-04-25
|
Submission filed as a Level I – Supplement to propose a dosing strategy of 100 mg twice daily for patients with mild hepatic impairment (Child Pugh A), and to update safety information regarding patients with hepatic impairment. As a result of the SNDS, changes were made to the Warnings and Precautions, Adverse Reactions, Drug Interactions, and Dosage and Administration sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOC was issued. |
NC # 196957 |
2016-07-21 |
Issued NOL 2016-11-18 |
Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with safety-related changes. As a result of the NC, modifications were made to the Adverse Reactions section of the PM, and corresponding changes were made to the PM Part III: Consumer Information.The submission was reviewed and considered acceptable, and an NOL was issued. |
Drug product (DIN market notification |
Not applicable |
Date of first sale: 2015/06/29 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
NC # 187039 |
2015/08/18 |
Issued No Objection Letter 2015/10/16 |
Submission filed as a Level II (90 day) Notifiable Change (Safety Change) for Product Monograph (PM) changes associated with safety information. As a result of the Notifiable Change (NC), changes were made to the Warnings and Precautions, Action and Clinical Pharmacology, Dosage and Administration, and Dosage Forms, Composition and Packaging sections of the PM. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
Drug product (DIN 02443066) market notification |
Not applicable |
Date of first sale: 2015/06/29 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
NDS # 176043 |
2014/07/09 |
Issued NOC 2015/06/25 |
Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Ofev
Date SBD issued: 2015-08-21
The following information relates to the New Drug Submission for Ofev.
Nintedanib, 100 mg and 150 mg, capsules, oral
Drug Identification Number (DIN):
- DIN 02443066 - 100 mg, capsule
- DIN 02443074 - 150 mg, capsule
Boehringer Ingelheim Canada Ltd. Ltee
New Drug Submission Control Number: 176043
On June 25, 2015, Health Canada issued a Notice of Compliance to Boehringer Ingelheim (Canada) Ltd. Ltee for the drug product Ofev.
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/risk profile of Ofev is favourable for the treatment of Idiopathic Pulmonary Fibrosis (IPF).
1 What was approved?
Ofev, a protein kinase inhibitor, was authorized for the treatment of Idiopathic Pulmonary Fibrosis (IPF).
The safety and efficacy of Ofev in pediatric patients have not been evaluated in clinical studies and therefore, Ofev should not be used in patients under 18 years of age. No dose adjustment is necessary in patients 65 years and older.
Ofev is contraindicated in patients with known hypersensitivity to nintedanib, peanut or soya, or any of the excipients. The use of Ofev is also contraindicated during pregnancy. Ofev was approved for use under the conditions stated in the Ofev Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Ofev (100 mg and 150 mg, nintedanib) is presented as capsules. In addition to the medicinal ingredient, the capsule contains: gelatin, glycerol, hard fat, iron oxide black, iron oxide red, iron oxide yellow, medium chain triglycerides, propylene glycol, shellac glaze, soya lecithin, 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 Ofev Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Ofev approved?
Health Canada considers that the benefit/risk profile of Ofev is favourable for the treatment of Idiopathic Pulmonary Fibrosis (IPF).
Idiopathic pulmonary fibrosis is a specific form of chronic, progressive fibrotic interstitial lung disease of unknown cause that leads to fibrosis and thickening of the interstitium. This leads to decreased lung function and declining quality of life. IPF occurs primarily in older adults, is limited to the lungs, and is associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia. Idiopathic pulmonary fibrosis is the most common idiopathic interstitial lung disease, however, it is a rare and fatal disease and the natural history is variable and unpredictable. The overall prevalence of IPF in Canada is estimated to be about 10,000 people. The median survival is 2 to 3 years following diagnosis.
In Canada, there is one other pharmacologic treatment currently available for IPF. Other pharmacologic options have not been proven efficacious in clinical studies, and none are indicated for the treatment of IPF. Lung transplantation is the only globally accepted therapy available for the treatment of IPF.
Ofev, 150 mg nintedanib twice daily, has been shown to reduce the decline in lung function over one year in adult patients with IPF. The market authorization was based on two replicate Phase III, 52-week, randomized, double-blind, placebo-controlled, parallel-group studies (study 1199.32 and study 1199.34) in patients with IPF. In addition, a supportive 52-week dose-ranging study (Study 1199.30) also demonstrated the efficacy of Ofev.
The primary endpoint for the two replicate Phase III studies was the annual rate of decline in forced vital capacity (FVC), the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. The key secondary endpoints were change from baseline in St. George's Respiratory Questionnaire (SGRQ - a tool to measure the impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease) total score at 52 weeks and time to first acute IPF exacerbation over 52 weeks.
With respect to the primary endpoint, Ofev demonstrated a consistent and statistically significant benefit in reducing the decline in FVC in patients with IPF by 125 mL/year and 94 mL/year, in Studies 1199.32 and 1199.34, respectively, as compared to placebo. The rate of decline in FVC was similar in both studies, and was more gradual over the 52 weeks than the decline observed in the placebo treatment group, suggesting benefit over time. The reduced rate of decline in lung function was supported by the treatment difference in the absolute change in FVC and FVC % of predicted normal values, which reduces variability due to demographic factors such as age and gender. Divergent results between the replicate studies were observed for SGRQ and time to first acute IPF exacerbation. In one study, there was no difference between the treatment groups for both SGRQ and IPF exacerbation, whereas in the second study, nintedanib was statistically significantly favourable over placebo for both SGRQ and acute IPF exacerbations.
The reduction in the decline in FVC was similar in the 52-week dose-ranging study (Study 1199.30) with nintedanib 150 mg given twice daily (reduction of 131 mL/year).
The benefit of Ofev in reducing the decline in lung function was consistent over the three 52 week clinical studies and is considered robust; however, there is uncertainty regarding the effect of nintedanib on the quality of life and acute exacerbation, which was not consistent. The pathophysiology and symptoms of IPF are predominantly due to the loss of lung function, and therefore, slowing of the rate of decline in lung function may be expected to have secondary benefits on quality of life and potentially IPF exacerbations. There is also uncertainty in the validity of SGRQ as an outcome for patients with IPF as it has not been validated in this patient population. In addition, the Minimal Clinical Important Difference (MCID) for SGRQ total score in chronic obstructive pulmonary disease (COPD) is 4 points, however, the difference from placebo was <3 points in both Phase III clinical studies. Patients with acute IPF exacerbations have a very poor outcome, and the clinical benefit of nintedanib in reducing exacerbations is not robust, however, for adjudicated IPF exacerbations, a numerical benefit of nintedanib over placebo was observed in both pivotal clinical studies. There is also uncertainty regarding the long-term efficacy of the 100 mg twice-daily dose, which did not significantly reduce the rate of decline in FVC in the dose-ranging study. In the pivotal clinical studies, 26-29% of patients had a dose reduction for 4 months on average. Some patients may need to stay on the reduced dose for longer periods of time to manage adverse reactions that may occur with the higher dose.
The safety profile of Ofev was characterized mainly by gastrointestinal disorders and hepatic injury. The most common adverse reactions reported were diarrhea, nausea, vomiting, abdominal pain, decreased appetite and weight, and increased liver enzymes. The adverse reactions were generally well managed by dose reductions or treatment interruptions. Due to the anti-angiogenic activity of nintedanib, there is also the potential for serious adverse reactions including bleeding and gastrointestinal perforations. Myocardial infarction was also observed infrequently with nintedanib. All of the potential adverse reactions are addressed in the Product Monograph, and monitoring of liver enzymes is recommended for patients.
In non-clinical studies, impaired female fertility was observed in rats and embryo fetal lethality and teratogenicity were observed in rats and rabbits. As a result, Ofev is contraindicated during pregnancy and is appropriately labelled in the Product Monograph.
Due to the older population with IPF and common co-morbidities, there may be uncertainties regarding the cause of adverse events due to treatment; however, the gastrointestinal adverse reactions and increased liver enzyme elevations that may lead to liver damage are evidently linked to treatment with nintedanib.
Ofev has demonstrated robust clinical benefit in reducing the decline of lung function in patients with IPF. Ofev is the second pharmacological treatment for IPF, which is a disease with a poor prognosis and an unmet medical need. Management of adverse reactions is available and appropriately addressed in the Product Monograph with the recommendation of dose reduction (to 100 mg twice daily) or temporary or permanent treatment discontinuation as required.
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 Ofev?
The sponsor filed a request for Priority Review Status under the Priority Review Policy for the review of the New Drug Submission (NDS) for Ofev. An assessment was conducted to determine if sufficient evidence was provided demonstrating that the drug provides:
- an effective treatment, prevention or diagnosis of a disease or condition for which no drug is presently marketed in Canada; or
- a significant increase in efficacy and/or significant decrease in risk such that the overall benefit/risk profile is improved over existing therapies, preventatives or diagnostic agents for idiopathic pulmonary fibrosis (IPF), a disease or condition that is not adequately managed by a drug marketed in Canada.
The efficacy results provided from the pivotal studies did not provide evidence of a significant increase in efficacy over existing therapies. In addition, from the safety data provided, it was not possible to judge what safety advantage, if any, is provided by the use of Ofev as opposed to other existing therapeutic options. For these reasons, the review bureau determined that the submission did not meet the criteria for Priority Review and therefore the request was denied. The submission was subsequently filed and reviewed as a regular NDS.
Submission Milestones: Ofev
Submission Milestone | Date |
---|---|
Pre-submission meeting: | 2014-04-03 |
Request for priority status | |
Filed: | 2014-04-22 |
Rejection issued by Director, Bureau of Cardiology, Allergy and Neurological Sciences: | 2014-05-30 |
Submission filed: | 2014-07-09 |
Screening | |
Screening Acceptance Letter issued: | 2014-08-29 |
Review | |
Biopharmaceutics Evaluation complete: | 2015-03-05 |
Quality Evaluation complete: | 2015-06-17 |
Clinical Evaluation complete: | 2015-06-24 |
Labelling Review complete: | 2015-06-24 |
Notice of Compliance (NOC) issued by Director General: | 2015-06-25 |
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 and have been market notified (that is, the company has told Health Canada the product is being marketed).
- 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
Nintedanib (the medicinal ingredient in Ofev) is a small molecule that inhibits multiple receptor tyrosine kinases including: platelet-derived growth factor receptor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, and vascular endothelial growth factor receptor (VEGFR) 1-3. Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signalling. Activation of FGFR and PDGFR signalling cascades is critically involved in proliferation and migration of lung fibroblasts/myofibroblasts, the hallmark cells in the pathology of idiopathic pulmonary fibrosis (IPF). The potential impact of VEGFR inhibition on IPF pathology is currently not fully elucidated. In addition, nintedanib inhibits non-tyrosine kinases including: Fms-like tyrosine kinase-3 (Flt-3), Lck, Lyn and Src kinases. In vivo studies have shown that nintedanib demonstrates potent anti-fibrotic and anti-inflammatory activity.
Nintedanib clinical pharmacology was investigated in both healthy volunteers and cancer patients and included a food-effect study. The proposed dosing regimen for Ofev is 150 mg twice daily. Nintedanib 200 mg twice daily was the maximum-tolerated dose. The dose-limiting toxicities were gastrointestinal disorders and severe liver enzyme increase.
Age, body weight, and race/patient origin were intrinsic factors that were found to significantly affect nintedanib pharmacokinetics (PK). There was a trend for elevated exposure to nintedanib in patients with hepatic impairment. No dedicated studies were performed in hepatically or renally impaired patients. Based on a population PK analysis, the bioavailability of nintedanib was lower in current smokers compared to ex-smokers and never-smokers. Nintedanib exposure increased by approximately 20% after administration under fed conditions compared to fasted conditions. In the Product Monograph, the dosing instructions indicate that nintedanib should be taken with food.
Nintedanib was a P-glycoprotein (P-gp) substrate in vitro. Co-administration of nintedanib with the potent P-gp and CYP3A4 inhibitor, ketoconazole, increased nintedanib exposure by 1.83 fold for maximum plasma concentration (Cmax). The potent P-gp and CYP 3A4 inducer, rifampicin, decreased exposure to nintedanib by 60% based on Cmax.
For further details, please refer to the Ofev Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of nintedanib has been studied in patients with IPF in two replicate Phase III, randomised, double-blind, placebo-controlled studies with identical design (Studies 1199.32 and 1199.34). In addition, a supportive 52-week dose-ranging study (Study 1199.30) also demonstrated the efficacy of Ofev.
Patients enrolled in the two replicate Phase III studies were randomised in a 3:2 ratio for twice-daily treatment with nintedanib 150 mg or placebo. A dose reduction to 100 mg twice daily and dose interruptions were allowed in order to manage adverse events.
The two Phase III studies included male and female patients 40 years of age and older, with a diagnosis of IPF [American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) criteria] for <5 years. Diagnoses were centrally adjudicated based on radiological and, if available, histopathological confirmation. Patients were required to have a forced vital capacity (FVC - the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible) ≥50% of predicted normal values and a diffusing capacity of the lung for carbon monoxide (DLCO, corrected for hemoglobin) of 30% to 79% of predicted normal values.
The primary endpoint in Studies 1199.32 and 1199.34 was the annual rate of decline in FVC. The key secondary endpoints were change from baseline in St. George's Respiratory Questionnaire (SGRQ - a tool to measure the impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease) total score at 52 weeks and time to first acute IPF exacerbation.
A total of 1,061 patients were treated in studies 1199.32 and 1199.34 with 638 patients treated with nintedanib 150 mg twice daily. The decline in FVC [that is (i.e.), decline in lung function] was statistically significantly lower for patients treated with nintedanib compared to placebo. The treatment difference for the annual rate of decline in FVC was 125 mL/year) [95% confidence interval (CI): 77.68, 172.84; p <0.0001] and 94 mL/year (95% CI: 44.78, 142.68; p = 0.0002) in the two studies. The results of the primary analysis were supported by the statistically significantly lower absolute and relative changes from baseline in FVC and FVC % of predicted normal values for nintedanib compared to placebo.
The outcomes of the key secondary endpoints of SGRQ total score and acute IPF exacerbations were divergent for the two clinical studies. In Study 1199.32, there was no statistically significant difference between the treatment groups for change in SGRQ total score (treatment difference between nintedanib and placebo: -0.05; p = 0.9657) and the time to first acute IPF exacerbation led to a not statistically significant hazard ratio (HR) of 1.15 (p = 0.6728). Based on the hierarchical testing procedure, the results for the IPF exacerbations were descriptive in Study 1199.32. In Study 1199.34, the treatment difference was statistically significantly in favour of nintedanib for SGRQ (treatment difference: -2.69, p = 0.0197) and acute IPF exacerbation (HR: 0.38; p = 0.0050). In the pooled analysis for time to first acute IPF exacerbation, a numerically lower risk was observed with nintedanib compared to placebo (HR: 0.64; 95% CI: 0.39, 1.05). The proportion of investigator reported acute IPF exacerbations that were adjudicated as 'confirmed' or 'suspected' acute IPF exacerbations over 52 weeks was numerically lower in both clinical studies for nintedanib (2.3% in Study 1199.32 and 1.5% in Study 1199.34) compared with placebo (3.9% and 7.3%).
Supportive Studies
The Phase II dose-ranging study (Study 1199.30) provided supportive evidence for the efficacy of Ofev. This was a randomised, placebo-controlled, double-blind, 52-week dose-escalation study that evaluated four dose strategies of nintedanib in patients with IPF. A total of 428 patients were treated, with 85-86 patients per group treated with placebo or nintedanib 50 mg once daily, nintedanib 50 mg twice daily, nintedanib 100 mg twice daily or nintedanib150 mg twice daily. The primary endpoint was the annual rate of decline in FVC compared to placebo. The difference from placebo in the annual rate of decline in FVC was highest for the 150 mg twice-daily group (reduction in the rate of decline in FVC by 0.131 L/year, 95% CI: 0.027, 0.235; p = 0.0136) which was comparable to the Phase III studies. The difference from placebo was not statistically significant for the other doses.
For more information, refer to the Ofev Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The primary clinical safety database consisted of pooled data from the two 52-week pivotal clinical studies (1199.32 and 1199.34), described in the Clinical Efficacy section, and included all patients with IPF who had taken at least one dose of study medication. Supportive safety data were derived from the 52-week treatment period of the dose ranging study, 1199.30.
In the 52-week studies, the most frequently reported adverse reactions that were more common with treatment with nintedanib were gastrointestinal disorders that included diarrhea [62% of patients treated with nintedanib versus (vs.) 18% of patients treated with placebo], nausea (24% vs. 7%), and abdominal pain (15% vs. 6%). Other more frequently reported adverse reactions with nintedanib were liver enzyme elevation (14% vs. 3%), vomiting (12% vs. 3%), decreased appetite (11% vs. 6%) and weight decrease (10% vs. 4%). Less frequent adverse reactions were headache and hypertension. The majority of adverse reactions were manageable with dose reductions or dose interruptions. Adverse events leading to dose reduction or discontinuation of study medication that occurred more frequently with nintedanib treatment (vs. placebo treatment) included diarrhea, nausea, vomiting, decreased appetite and abdominal pain.
The incidence of serious adverse reactions was balanced between treatment groups (30.4% in the nintedanib treatment group and 30.0% in the placebo treatment group). Serious adverse reactions that were more common with nintedanib treatment than placebo were bronchitis (1.3% of patients treated with nintedanib vs. 0.5% of patients treated with placebo) and myocardial infarction (1.6% vs. 0.5%). Gastrointestinal perforation, a class effect (a drug effect produced by all members of a chemically related group of medications and not only by a single drug from that class), was reported by two patients treated with nintedanib. There were 68 deaths during the pivotal studies with fewer deaths in the nintedanib group. The most frequently reported event leading to death was IPF (including events of worsening of disease as well as exacerbations of IPF) which was more common in the placebo group than in the nintedanib group. The most common adverse events leading to death that were more common in the nintedanib group than the placebo group (all reported at <1%) were pneumonia, lung neoplasm malignant, and myocardial infarction.
The safety of nintedanib was also evaluated in three on-going long-term safety extension studies for which interim analyses were available. No new safety concerns were identified from these interim analyses. The safety profile for nintedanib in these studies was similar to the safety profile in the controlled clinical studies.
Based on experience using other tyrosine kinase inhibitors to treat non-IPF indications, impaired immune and kidney function, intestinal perforation, increased blood pressure, bleeding, and thrombotic events could potentially occur with nintedanib treatment. These safety issues have been addressed in the Product Monograph.
For more information, refer to the Ofev Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
In vitro studies demonstrated that nintedanib is a potent adenosine triphosphate (ATP)-competitive inhibitor of vascular endothelial growth factor receptors (VEGFR) 1-3, fibroblast growth factor receptors (FGFR) 1-3, and platelet-derived growth factor receptors (PDGFR) α and β. Nintedanib also inhibited members of the Src family of non-receptor tyrosine kinases (Src, Lyn, and Lck) and Fms-like tyrosine kinase 3 (Flt-3). Preventive and therapeutic administration of nintedanib in mouse and rat models of lung fibrosis reduced bleomycin and silica induced fibrosis and inflammation.
With repeat dosing, dose-limiting toxicity of nintedanib was achieved in virtually all studies. Clinical signs following nintedanib administration in rodents were consistent with manifestations of poor general condition. Dentopathy observed in rats and mice resulted in difficulty eating and, thus, decreased food consumption due to damaged incisors. Treatment-related clinical findings in monkeys and dogs included signs indicative of gastrointestinal toxicity.
There were relatively minor hematology effects in rodents and monkeys. Generally mild elevations in hepatic aminotransferase activities and sometimes other liver biomarker enzyme activities were detected in different animals given nintedanib. Other organs/body systems affected included: kidneys, digestive system (esophagus, stomach, intestines, and pancreas), hematopoietic system (bone marrow, spleen), lymphoid system (spleen, thymus, and lymph nodes), endocrine system (adrenals), female reproductive system (ovaries), teeth, and bone/cartilage.
In rats, nintedanib was embryolethal, embryotoxic, and teratogenic at low doses. In rabbits, nintedanib was embryolethal and teratogenic at higher doses. Distribution studies have shown that a low percentage (<0.5% of administered dose) of nintedanib-related radioactivity is excreted into maternal milk. In the Product Monograph, Ofev is contraindicated during pregnancy and precautions are included for women of childbearing potential to use contraceptive measures while taking Ofev.
The results of in vitro and in vivo assays demonstrated that nintedanib was not genotoxic. Nintedanib was not carcinogenic following long-term administration in mice and rats.
For more information, refer to the Ofev 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 Ofev 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.
Proposed limits of drug-related impurities are considered adequately qualified [that is (i.e.) within International Conference on Harmonisation (ICH) limits and/or qualified from toxicological studies].
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.
Regarding the risk of bovine spongiform encephalopathy (BSE)/transmissible spongiform encephalopathy (TSE), the excipients used for the manufacture of the drug product are not of animal origin except gelatin used to manufacture the soft gelatin capsules for these formulations. The gelatin is exclusively obtained from pig skin; therefore, a risk of transmitting BSE/TSE can be excluded according to current European regulation, the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products (EMEA/410/01, Revision 3).
Related Drug Products
Product name | DIN | Company name | Active ingredient(s) & strength |
---|---|---|---|
OFEV | 02443074 | BOEHRINGER INGELHEIM (CANADA) LTD LTEE | NINTEDANIB (NINTEDANIB ESILATE) 150 MG |
OFEV | 02443066 | BOEHRINGER INGELHEIM (CANADA) LTD LTEE | NINTEDANIB (NINTEDANIB ESILATE) 100 MG |