^PrESBRIET

Contact: Bureau of Cardiology, Allergy, and Neurological Sciences

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

Recent activity for ESBRIET

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorisation 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 decision was negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for ESBRIET

Updated: 2013/05/06

The following table describes post-authorization activity for Esbriet, a product which contains the medicinal ingredient pirfenidone. 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.

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

Drug Identification Number (DIN):
DIN 02393751 - 267 mg pirfenidone, capsule, oral

Post Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number	Date Submitted	Decision and Date	Summary of Activities
(The most recent activity is listed first)
Drug product [Drug Identification Number (DIN) 02393751] market notification	Not applicable	Date of first sale 2013/01/08	The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the  Food and Drug Regulations.
NDS # 159211	2012/10/05	Issued NOC 2012/10/29	Submission filed to transfer ownership of product from InterMune International AG to InterMune Canada Inc.
NDS # 153849	2012/03/02	Issued NOC 2012/10/01	Notice of Compliance issued for New Drug Submission.

Summary Basis of Decision (SBD) for ESBRIET

The following information relates to the original authorization of the new drug submission for Esbriet.

Date SBD Issued: 2012/11/21

Pirfenidone
267 mg, capsule, oral
Drug Identification Number: 02393751
InterMune International AG
New Drug Submission Control Number: 153849

On October 1, 2012, Health Canada issued a Notice of Compliance to InterMune International AG for the drug product, Esbriet.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (safety and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Esbriet is favourable for the treatment of mild to moderate idiopathic pulmonary fibrosis in adults.

1. What was approved?
2. Why was Esbriet approved?
3. What steps led to the approval of Esbriet?
4. What follow-up measures will the company take?
5. What post-authorization activity has taken place for Esbriet?
6. What other information is available about drugs?
7. What was the scientific rationale for Health Canada's decision?

1. What was approved?

Esbriet, an anti-fibrotic and anti-inflammatory agent, was authorized for the treatment of mild to moderate idiopathic pulmonary fibrosis in adults.

Esbriet is contraindicated for patients with the following conditions:

• Hypersensitivity to this drug or to any ingredient in the formulation or component of the container.
• Concomitant use of strong inhibitors of the cytochrome P450 (CYP) isoenzyme CYP1A2 such as fluvoxamine and ciprofloxacin.
• Severe hepatic impairment or end-stage liver disease.
• Severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease requiring dialysis.

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

Esbriet (267 mg pirfenidone) is presented as a hard gelatin two-piece capsule. In addition to the medicinal ingredient, the capsule contains black iron oxide, croscarmellose sodium, gelatin, indigo carmine, magnesium stearate, microcrystalline cellulose, povidone, red iron oxide, shellac, titanium dioxide, and yellow iron oxide.

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 Esbriet Product Monograph, approved by Health Canada and available through the Drug Product Database.

2. Why was Esbriet approved?

Health Canada considers that the benefit/risk profile of Esbriet is favourable for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF) in adults.

Idiopathic pulmonary fibrosis is a rare, fatal disease of unknown etiology characterized by progressive fibrosis of the lung interstitium, leading to decreased lung volumes and progressive pulmonary insufficiency. No accurate prevalence data are available for Canada; however, based on the United States data, estimates suggest that there are approximately 5,000-10,000 patients with IPF in Canada. Median survival, as described across a range of studies, is approximately 2-5 years from the time of diagnosis. At the present time, there are no therapies or medications marketed in Canada that are specifically indicated for the treatment of IPF.

Esbriet (pirfenidone 2,403 mg/day) has been shown to be efficacious in the treatment of IPF in two similarly designed pivotal studies with 692 patients. In one of the pivotal studies, decline in lung function, as measured by forced vital capacity (FVC), a prognostic marker for IPF, was significantly reduced in patients receiving Esbriet as compared to those receiving placebo. The absolute difference in the mean change in percent predicted FVC from Baseline at Week 72 of treatment was 4.4% between treatment groups, representing a relative difference of 35.5%. Treatment with Esbriet also significantly reduced the decline of percent predicted FVC from Baseline at Weeks 24, 36, 48, and 60. At Week 72, a decline from Baseline in percent predicted FVC of ≥10% (a threshold indicative of the risk of mortality in IPF) was seen in 20% of patients receiving Esbriet compared to 35% receiving placebo. The other pivotal study failed to show a statistically significant FVC treatment effect of Esbriet at Week 72; however, there was evidence of treatment effect at Week 24, 36, and 48. Beneficial treatment effects were also observed in the categorical analysis of FVC, the analyses of disease progression, and the six minute walk test.

Overall, Esbriet was generally well-tolerated. Commonly seen adverse drug reactions included skin disorders (rash and photosensitivity reaction) and gastrointestinal disorders (nausea, vomiting, dyspepsia, gastroesophageal reflux disease, stomach discomfort, and abdominal pain) as well as weight loss, fatigue, dizziness, anorexia, pharyngolaryngeal pain, insomnia, urinary tract infection, and hot flush. In general, these events were not serious. The proportion of patients with serious adverse events was similar in patients taking Esbriet compared to those taking placebo, with IPF being the most common.

A number of major safety issues were identified in this submission. Elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the upper limit of normal have been reported in patients treated with Esbriet. Pharmacology studies demonstrated that there was a mean increase of 60% in Esbriet exposure in patients with moderate hepatic impairment. Co-administration of pirfenidone and fluvoxamine (a strong inhibitor of the cytochrome P450 (CYP) isoenzyme CYP1A2) resulted in a significant increase in the exposure of pirfenidone. These safety issues were adequately addressed through appropriate labelling in the Esbriet Product Monograph.

A Risk Management Plan was submitted by the sponsor and was reviewed by Health Canada. The sponsor is required to carry out post-marketing surveillance activities to ensure continuous monitoring of adverse events associated with the use of Esbriet.

Overall, the therapeutic benefits seen in the pivotal studies are promising and the benefits of Esbriet therapy seem to outweigh the risks. Currently, there are no approved therapies in Canada for the treatment of IPF. Health Canada considers that the benefit and risk balance of Esbriet (pirfenidone capsule 267 mg) is favourable for the proposed indication for the treatment of mild to moderate IPF in adults and the dosing regimen of 2403 mg/day, three 267 mg capsules three-times a day.

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 Esbriet?

The drug submission for Esbriet was reviewed under the Priority Review Policy. The sponsor presented sufficient preliminary evidence that the drug may provide effective treatment for a serious, life-threatening disease for which no drug is presently marketed in Canada.

Submission Milestones: Esbriet

Submission Milestone	Date
Pre-submission meeting:	2011/08/03
Request for priority status
Filed:	2011/12/02
Approval issued by Director of Bureau of Cardiology, Allergy, and Neurological Sciences:	2012/01/05
Submission filed:	2012/03/02
Screening
Screening Acceptance Letter issued:	2012/04/04
Review
Biopharmaceutics Evaluation complete:	2012/09/24
Quality Evaluation complete:	2012/08/31
Clinical Evaluation complete:	2012/09/24
Labelling Review complete:	2012/09/24
Notice of Compliance issued by Director General, Therapeutic Products Directorate:	2012/10/01

The Canadian regulatory decision on the non-clinical and clinical review of Esbriet was based on a critical assessment of the Canadian data package. The foreign review completed by the European Union's centralized procedure European Medicines Agency (EMA) was used as an added reference.

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?

As part of the marketing authorization for Esbriet, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to) to conduct post-marketing surveillance activities to ensure the continuous monitoring of adverse events associated with the use of Esbriet.

5. What post-authorization activity has taken place for Esbriet?

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

The PAAT for Esbriet is found above.

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

6. What other information is available about drugs?

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

• 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?

Clinical Basis for Decision

Clinical Pharmacology

The mechanisms of action of pirfenidone, the active substance in Esbriet, have not been fully established. Non-clinical studies with a variety of in vitro systems and animal models of pulmonary fibrosis suggest that pirfenidone exerts anti-fibrotic and anti-inflammatory properties.

The clinical pharmacology portion consisted of 7 studies conducted in healthy, hepatic impaired, and renal impaired subjects. These studies primarily provided safety and pharmacokinetic data for patients and healthy subjects exposed to pirfenidone. The clinical pharmacological data support the use of Esbriet for the recommended indication.

For further details, please refer to the Esbriet Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Esbriet (pirfenidone 267 mg oral capsules) was assessed in two pivotal Phase III, multicentre, randomized, double-blind, placebo-controlled studies (PIPF-004 and PIPF-006) in patients with idiopathic pulmonary fibrosis (IPF). Both studies compared treatment with Esbriet 2,403 mg/day to placebo. The studies were nearly identical in design and pooled data analysis was pre-defined. In both studies, treatment was administered three-times daily for a minimum of 72 weeks. In Study PIPF-004, 174 patients received Esbriet and 174 patients received placebo; while in Study PIPF-006, 171 patients received Esbriet and 173 patients received placebo. The primary efficacy endpoint in both studies was the change from Baseline to Week 72 in percent predicted Forced Vital Capacity (FVC), the maximum amount of air that a person can forcefully exhale. Secondary efficacy endpoints included categorical analysis of FVC, progression-free survival (PFS), and the 6 minute-walk test (6MWT).

Primary Efficacy Endpoint

In Study PIPF-004, decline in lung function, as measured by percent predicted FVC from Baseline at Week 72 of treatment, was significantly reduced in patients that received Esbriet [pirfenidone 2,403 mg/day; number of patients (n) = 174] compared with patients that received placebo [n = 174; probability (p) = 0.001]. The absolute difference in the mean change in percent predicted FVC was 4.4% between treatment groups, representing a relative difference of 35.5%. Treatment with Esbriet also significantly reduced the decline of percent predicted FVC from Baseline at Weeks 24 (p = 0.014), 36 (p <0.001), 48 (p <0.001), and 60 (p <0.001). At Week 72, a decline from Baseline in percent predicted FVC of ≥10% (a threshold indicative of the risk of mortality in IPF) was seen in only 20% of patients that received Esbriet compared to 35% that received placebo.

In Study PIPF-006, there was no statistically significant difference between treatment with Esbriet (n = 171) and placebo (n = 173) in the reduction of the decline of percent predicted FVC from Baseline at Week 72 (p = 0.501). However, treatment with Esbriet reduced the decline in lung function, as measured by percent predicted FVC from Baseline at Weeks 24 (p <0.001), 36 (p = 0.011), and 48 (p = 0.005). At Week 72, a decline in FVC of ≥10% was seen in 23% of patients that received Esbriet and 27% that received placebo.

The primary endpoint analysis of the pooled population also showed an Esbriet treatment effect on percent predicted FVC at Week 72 (p = 0.005). The absolute difference in the mean change in percent predicted FVC was 2.5% between the two treatment groups, representing a relative difference of 22.8%. At Week 72, a decline from Baseline in percent predicted FVC of ≥10% was seen in 21.4% of patients that received Esbriet compared to 30.5% that received placebo.

Secondary Efficacy Endpoints

In Study PIPF-004, treatment with Esbriet significantly reduced the combined risk of death or disease progression [i.e., PFS] by 36% compared to placebo [hazard ratio (HR) 0.64 (0.44-0.95); p = 0.023]. In Study PIPF-006, there was no difference in PFS between the two treatment arms [HR 0.84 (0.58-1.22); p = 0.355]. In the pooled analysis, treatment with Esbriet 2,403 mg/day resulted in a 26% reduction in PFS compared with placebo, with a HR of 0.74 [95% Confidence Interval (CI) 0.57-0.96; p = 0.025].

In Study PIPF-004, there was no difference between patients that received Esbriet compared to placebo, in change from Baseline to Week 72 of distance walked during a 6MWT (p = 0.171). The difference in the mean decline in the 6MWT distance between the treatment groups at Week 72 was 16.4 metres. In Study PIPF-006, the decline in 6MWT distance from Baseline to Week 72 was significantly reduced compared to placebo (p <0.001). The difference in the mean decline in the 6MWT distance between the treatment groups at Week 72 was 31.8 metres.

The pivotal studies were not adequately powered to assess the effect of Esbriet on mortality. In Study PIPF-004, there was a 39% relative reduction in the risk of death in the Esbriet group compared with placebo (HR 0.61; 95% CI 0.28-1.29; p = 0.191). In Study PIPF-006, a similar proportion of patients died in the Esbriet and placebo groups (9.4% and 9.8%, respectively) (HR 0.95; 95% CI 0.48-1.87; p = 0.872). In a pooled analysis of survival, the mortality rate with the Esbriet group was 7.8% (n = 27) compared with 9.8% (n = 34) with placebo (HR 0.77; 95% CI 0.47-1.28). A further ad hoc analysis of the pooled data was conducted considering IPF-related treatment-emergent deaths. A 52% reduction was observed in the risk of IPF-related death in Esbriet patients compared with the placebo patients (HR 0.48; 95% CI 0.24-0.95; p = 0.030), with 3.5% and 7.2% of patients in the two groups dying of IPF-related causes. Since survival data were captured as an exploratory efficacy endpoint and the cause of death was not adjudicated, the overall effect of Esbriet on all-cause mortality and IPF-related mortality remains inconclusive.

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

Clinical Safety

Clinical safety data for Esbriet (pirfenidone 2,403 mg/day) included two randomized, double-blind, placebo-controlled Phase III studies (PIPF-004 and PIPF-006) in patients with idiopathic pulmonary fibrosis (IPF). The design of these two studies was very similar and this enabled the data to be pooled to increase the power to detect potential safety trends.

A total of 345 patients received Esbriet and 347 received placebo. The majority of patients remained on treatment for more than 66 weeks. The most frequently reported adverse drug reactions included skin disorders (rash and photosensitivity reaction) and gastro-intestinal disorders (nausea, vomiting, dyspepsia, gastroesophageal reflux disease, stomach discomfort, and abdominal pain) as well as weight loss, fatigue, dizziness, anorexia, pharyngolaryngeal pain, insomnia, urinary tract infection, and hot flush. In general, these events were not serious. Dose reductions, treatment interruptions, and premature discontinuations were also more common in patients treated with Esbriet compared to placebo. Esbriet is associated with a dose-response effect regarding gastro-intestinal side-effects including nausea, vomiting, diarrhoea, dyspepsia, and stomach discomfort, and photosensitivity/rash and liver laboratory abnormalities.

The percentages of patients with serious adverse events (SAEs) were generally similar among study groups, with IPF being the most common SAE reported. There were no notable effects on cardiac QTc or other cardiac associated adverse events. Overall less than 10% of patents died in these clinical studies. The majority of the deaths in the study were respiratory in nature and were considered related to IPF.

In comparison with placebo, treatment with Esbriet was associated with elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the upper limit of normal (ULN). Abnormal hepatic function and liver disorders were also reported in post-market surveillance. It is recommended in the Esbriet Product Monograph that liver chemistry tests should be conducted prior to the initiation of treatment with Esbriet, and subsequently at monthly intervals for the first 6 months of treatment and then every 3 months.

Pharmacology studies demonstrated that there was a mean increase of 60% in Esbriet exposure after a single dose of 801 mg Esbriet (3 × 267 mg capsule) in patients with moderate hepatic impairment. Esbriet is therefore contraindicated for patients with severe hepatic impairment or end-stage liver disease. A contraindication was also added for patients with severe renal impairment or end-stage renal disease, as a precautionary measure against increased exposure to Esbriet.

In vitro studies with hepatic microsomes indicate that Esbriet is primarily metabolized via the cytochrome P450 (CYP) isoenzyme CYP1A2 with minor contribution from other CYP isoenzymes. Co-administration of Esbriet and fluvoxamine [a strong inhibitor of the cytochrome P450 (CYP) isoenzyme CYP1A2] resulted in a significant increase in the exposure of Esbriet. Co-administration of strong inhibitors of CYP1A2 is therefore contraindicated. Due to potential drug-drug interactions between Esbriet and other medications, a boxed warning for drug-interaction with inhibitors of CYP1A2 and other CYP isoenzymes was added to the Product Monograph.

Health Canada considers that the safety profile of Esbriet was adequately assessed in patients with IPF. It appears that Esbriet was generally well-tolerated in the two pivotal studies. A dose reduction and management plan for certain adverse events (such as skin and gastrointestinal disorders) likely contributed to the overall tolerability.

Non-Clinical Basis for Decision

The non-clinical studies submitted for review are adequate to support the market authorization of Esbriet (pirfenidone) for mild to moderate idiopathic pulmonary disease (IPF). The primary pharmacodynamic efficacy was demonstrated in a variety of in vitro systems and animal models suggesting that pirfenidone has both antifibrotic and anti-inflammatory activities.

The toxicology program was comprehensive and pirfenidone was generally administered orally, the clinical route of administration. Transient central nervous system effects were observed at high doses in single-dose toxicity studies. In repeat-dose studies in mice, rats, and dogs, decreased body weight was observed. The target organ in all species was the liver with increased organ weights, hepatic centrilobular hypertrophy and increased metabolic enzyme content.

Pirfenidone was phototoxic in guinea pigs and mice inducing transient erythema at doses 4-fold higher than the clinical dose. The effects were mitigated by sunscreen in guinea pigs. Photosensitivity reactions and rash were also observed in the clinical studies. With the exception of phototoxicity, weight loss, and liver toxicity, the non-clinical data revealed no other special hazards for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenicity, and reproductive toxicity.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph. Appropriate warnings and precautionary measures are in place in the Product Monograph to address the identified safety concerns.

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

Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Esbriet 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. The proposed limits of drug-related impurities are considered adequately qualified from toxicological studies.

Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable. The commercial manufacturing process does not differ significantly from the manufacturing process used to manufacture the drug product used in supporting clinical studies. The commercial drug product formulation is identical to that used in the pivotal clinical studies.

Based on the stability data submitted, the proposed shelf-life is acceptable. The container closure system met all validation test acceptance criteria.

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

The hard gelatin capsules are the only component used in the manufacture of Esbriet capsules that contain material derived from animal origin. The gelatin material used in the manufacture of the hard gelatin capsules meets current European guidelines on bovine spongiform encephalopathy and transmissible spongiform encephalopathy (BSE/TSE) requirements. A declaration from the supplier confirming TSE compliance and copies of Certificates of Suitability for this material were provided. All other compendial excipient suppliers have provided a certification indicating that no BSE/TSE components are used in the manufacturing or processing of the specified compendial excipients.