Summary Basis of Decision for Zepatier

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:

Drug

Contact: Bureau of Gastroenterology Infection and Viral Diseases

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

Recent Activity for Zepatier

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Zepatier

Updated:

2022-11-14

The following table describes post-authorization activity for Zepatier, a product which contains the medicinal ingredients elbasvir and grazoprevir. 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 that are found in PAATs.

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

Drug Identification Number (DIN):

DIN 02451131 - 50 mg elbasvir and 100 mg grazoprevir, tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number	Date submitted	Decision and date	Summary of activities
DIN 02451131 cancelled (post-market)	Not applicable	Discontinuation date: 2022-08-16	The manufacturer notified Health Canada that sale of the drug has been discontinued post market. Health Canada cancelled the DIN pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.
SNDS # 245140	2020-12-04	Issued NOC 2021-03-18	Submission filed as a Level II – Supplement (Safety) to update the PM. The changes were in response to an Advisement Letter issued by Health Canada, dated 2020-10-26, requesting revisions related to the risk of hepatic decompensation and hepatic failure. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
Summary Safety Review	Not applicable	Posted 2020-12-02	Summary Safety Review posted for direct-acting antiviral products containing a protease inhibitor (Assessing the potential risks of hepatic decompensation and hepatic failure).
NC # 237321	2020-03-19	Issued NOL 2020-05-11	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 Warnings and Precautions, and Drug Interactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
Summary Safety Review	Not applicable	Posted 2020-04-02	Summary Safety Review posted for direct-acting antivirals (Assessing the potential risk of new or returning liver cancer named hepatocellular carcinoma).
Summary Safety Review	Not applicable	Posted 2020-02-17	Summary Safety Review posted for direct-acting antivirals (Assessing the potential risk of abnormal blood sugar levels [dysglycemia]).
New safety review	Not applicable	Started between 2019-12-01	Health Canada started a safety review for Zepatier related to hepatic failure (liver failure) and hepatic decompensation (worsening of liver function).
SNDS # 223174	2018-12-20	Issued NOC 2019-06-28	Submission filed as a Level I – Supplement Level I – Supplement to add an alternate site for manufacturing and testing of the drug substance. The data were reviewed and considered acceptable, and an NOC was issued.
New safety review	Not applicable	Started between 2019-02-01	Health Canada started a safety review for Zepatier related to dysglycaemia (abnormality in blood sugar stability – can include low blood sugar or high blood sugar).
New safety review started by Health Canada	Not applicable	Started between 2018-12-01	Health Canada started a safety review for Zepatier related to hepatocellular carcinoma (liver cancer).
NC # 204225	2017-03-29	Issued NOL 2017-06-29	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 Drug Interactions 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. As a result of the NC, modifications were made to the Drug Interactions 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.
SNDS # 202393	2017-03-01	Issued NOC 2017-05-26	Submission filed as a Level I - Supplement to update the PM with respect to Hepatitis B reactivation in Hepatitis C / Hepatitis B virus co-infected patients following a Health Canada Class-Labelling request to the sponsor, dated February 02, 2017. As a result of the SNDS, modifications were made to the Serious Warnings and Precautions Box, and Warnings and Precautions sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOC was issued. The benefit/risk profile for Zepatier remains positive when used for its approved indication.
NC # 201181	2016-12-14	Issued No Objection Letter 2017-03-21	Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to clarify the Contraindications section of the Product Monograph. As a result of the NC, modifications were made to the Contraindications, Warnings and Precautions, and Drug Interactions sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
Information Update posted	Not applicable	Posted 2016-12-01	Information Update posted (Direct-acting antivirals, used for hepatitis C, may reactivate hepatitis B), containing important safety information for the general public, healthcare professionals and hospitals.
Summary Safety Review posted	Not applicable	Posted 2016-12-01	Summary Safety Review posted for direct-acting antivirals, assessing the potential risk of hepatitis B virus reactivation.
New safety review started by Health Canada	Not applicable	Started between 2016-07-01	Health Canada started two safety reviews for direct-acting antivirals indicated for the treatment of hepatitis C related to early recurrence of hepatocellular carcinoma (liver cancer) and hepatitis B reactivation.
NC # 193658	2016-03-22	Issued No Objection Letter 2016-07-22	Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Product Monograph. As a result of the NC, modifications were made to the Contraindications (editorial), Adverse Reactions, Drug Interactions, and other sections of the Product Monograph. Corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
Drug product (DIN 02451131) market notification	Not applicable	Date of first sale: 2016-01-25	The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 185866	2015-06-30	Issued NOC 2016-01-19	Notice of Compliance issued for New Drug Submission.

Summary Basis of Decision (SBD) for Zepatier

Date SBD issued: 2016-03-15

The following information relates to the new drug submission for Zepatier.

Elbasvir and grazoprevir
50 mg elbasvir and 100 mg grazoprevir, tablet, oral

Drug Identification Number (DIN):

02451131

Merck Canada Inc.

New Drug Submission Control Number: 185866

On January 19, 2016, Health Canada issued a Notice of Compliance to Merck Canada Inc. for the drug product Zepatier.

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 Zepatier is favourable for the treatment of chronic hepatitis C genotypes 1, 3, or 4 infection in adults as follows:

Without ribavirin:

in genotype (GT) 1 or 4 treatment-naïve (TN) and peginterferon alfa + ribavirin (PR) treatment-experienced (TE) relapsers (12 weeks)
in GT1 protease inhibitor (PI)/PR-TE relapsers (12 weeks)
in GT1b TN, non-cirrhotic patients (8 weeks)
in GT1b PR- or PI/PR-TE on-treatment virologic failures (12 weeks)

With ribavirin:

in GT1a PR- or PI/PR-TE on-treatment virologic failures (16 weeks)
in GT4 PR-TE on-treatment virologic failures (16 weeks)

With sofosbuvir:

in GT3 TN patients (12 weeks)

1 What was approved?

Zepatier, an antiviral agent, was authorized for the treatment of chronic hepatitis C genotypes 1, 3, or 4 infection in adults as follows:

Without ribavirin:

in genotype (GT) 1 or 4 treatment-naïve (TN) and peginterferon alfa + ribavirin (PR) treatment-experienced (TE) relapsers (12 weeks)
in GT1 protease inhibitor (PI)/PR-TE relapsers (12 weeks)
in GT1b TN, non-cirrhotic patients (8 weeks)
in GT1b PR- or PI/PR-TE on-treatment virologic failures (12 weeks)

With ribavirin:

in GT1a PR- or PI/PR-TE on-treatment virologic failures (16 weeks)
in GT4 PR-TE on-treatment virologic failures (16 weeks)

With sofosbuvir:

in GT3 TN patients (12 weeks)

There were a limited number of geriatrics patients (number of patients = 187) included in the clinical studies. There was no overall difference in safety or efficacy observed in these patients.

The safety and efficacy of Zepatier have not been established in pediatric patients less than 18 years of age Zepatier is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. If Zepatier is administered with ribavirin or sofosbuvir, the contraindications to ribavirin or sofosbuvir also apply to this combination regimen.

Zepatier is contraindicated in patients with moderate or severe hepatic impairment. Zepatier is contraindicated with organic anion transporting polypeptide 1B (OATP1B) inhibitors, strong inducers of cytochrome P450 3A (CYP3A), or efavirenz.

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

Zepatier (50 mg elbasvir/100 mg grazoprevir) is presented as a tablet. In addition to the two medicinal ingredients, the tablet contains colloidal silicon dioxide, copovidone, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, sodium chloride, sodium lauryl sulfate, and vitamin E polyethylene glycol succinate. The tablets are film-coated with a coating material containing the following inactive ingredients: carnauba wax, ferrosoferric oxide, hypromellose, iron oxide red, iron oxide yellow, lactose monohydrate, titanium dioxide and triacetin.

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

2 Why was Zepatier approved?

Health Canada considers that the benefit/risk profile of Zepatier is favourable for the treatment of chronic hepatitis C (CHC) genotypes 1, 3, or 4 infection in adults as follows:

Without ribavirin:

in genotype (GT) 1 or 4 treatment-naïve (TN) and peginterferon alfa + ribavirin (PR) treatment-experienced (TE) relapsers (12 weeks)
in GT1 protease inhibitor (PI)/PR-TE relapsers (12 weeks)
in GT1b TN, non-cirrhotic patients (8 weeks)
in GT1b PR- or PI/PR-TE on-treatment virologic failures (12 weeks)

With ribavirin:

in GT1a PR- or PI/PR-TE on-treatment virologic failures (16 weeks)
in GT4 PR-TE on-treatment virologic failures (16 weeks)

With sofosbuvir:

in GT3 TN patients (12 weeks)

Hepatitis C virus (HCV) infection is a global health challenge with over 150 million people infected globally. Six different genotypes of HCV have been identified so far. The most prevalent genotype of HCV infection is genotype (GT) 1, followed by GT3, and GT2. In Canada, GT4, GT5, and GT6 account for less than 5% of cases. Chronic HCV infection does not generally self-resolve and most cases advance to fibrosis, cirrhosis, and end-stage liver diseases including decompensated cirrhosis, as well as hepatocellular carcinoma if not treated.

Current treatment options for CHC infection are mainly based on Direct Acting Antiviral (DAA) based regimens which are usually highly efficacious and result in less adverse drug reactions than earlier treatment options. There are a few treatment options for GT1 and GT3. For GT3, the combined use of two DAAs or a DAA with ribavirin is needed to achieve a desirable Sustained Virologic Response 12 weeks after therapy (SVR12). Although the prevalence with GT4 infection in Canada is low, there is a clinical need for a treatment option for this genotype especially in treatment-experienced patients with cirrhosis. Some special difficult-to-treat populations such as patients with advanced chronic kidney disease or end-stage renal disease undergoing hemodialysis or those that received kidney transplantation need to be explored with CHC treatment with DAAs. Study results using Zepatier have provided a new treatment option for CHC infections especially for the previously mentioned difficult-to-treat populations.

The safety and efficacy of Zepatier were evaluated in eight clinical studies in approximately 1,800 patients with GT1, GT3, or GT4 CHC infection with compensated liver disease (with and without cirrhosis). The efficacy was demonstrated through the primary efficacy endpoint of the sustained viral response at follow-up week-12 (SVR12) defined as HCV ribonucleic acid (RNA) less than lower limit of quantification (LLOQ) at 12 weeks after the completion of 12-week treatment.

Treatment with Zepatier for 12 weeks showed an overall SVR12 of 95% among treatment-naive GT1 or GT4 CHC patients. An SVR12 of 100% was achieved in CHC GT1 or 4 patients who had relapsed in a prior treatment with peginterferon alfa and ribavirin. Treatment with Zepatier without ribavirin for 8 weeks was efficacious with a 94% SVR12 in G1b treatment-naïve non-cirrhotic patients whereas a 12-week regimen was required in GT1b patients who previously failed treatment with peginterferon alfa and ribavirin or with a protease inhibitor, peginterferon alfa and ribavirin (98% SVR). The SVR12 of 93% was achieved with a treatment regimen of Zepatier with ribavirin for 12 weeks in GT1a patients who had previously failed a regimen that included a protease inhibitor, peginterferon alfa and ribavirin. However, due to a 4% relapse rate with the regimen (compared to 0% relapse in the 16-week regimen), a 16-week regimen is recommended for this GT1a prior on-treatment failure population.

For GT1a or GT4 patients who previously failed peginterferon alfa plus ribavirin therapy, including patients with compensated cirrhosis, Zepatier was efficacious when combined with ribavirin for 16 weeks of treatment (overall SVR12 for GT1a 95% and 100% for GT4). Comparable SVR12 rates were achieved in GT1a or GT4 cirrhotic prior on-treatment failure patients. The clinical efficacy of Zepatier in GT3 treatment-naïve patients with or without cirrhosis was also demonstrated with a 12-week regimen in combination with sofosbuvir (92% SVR12).

Comparable clinical efficacy of Zepatier was also demonstrated among GT1 or GT4 CHC and HIV-1 co-infected patients with similar regimens. The clinical efficacy of a 12-week regimen of Zepatier was also demonstrated in GT1, treatment-experienced, patients with severe renal impairment and end-stage renal disease including those on regular hemodialysis.

In the Zepatier studies, relapse at follow-up was the most common reason among a limited number of treatment failures that were reported, regardless of patient treatment experience or cirrhosis status. These failures were mainly associated with baseline HCV viral non-structural 5A (NS5A) polymorphisms at positions 28, 30, 31, 58, and 93. In GT1a patients, the presence of baseline NS5A resistance-associated-variants (RAVs) that confer a greater than five-time elbasvir potency shift in vitro (7% [55/825] in pooled efficacy populations) was associated with a substantial reduction in clinical efficacy, particularly in patients with a high baseline HCV viral load (SVR12: 47% [23/49] in pooled efficacy populations). The SVR12 rates were not affected among GT1b or GT4 patients with baseline NS5A polymorphisms.

Zepatier was generally well-tolerated among the diverse patient populations and different treatment regimens with or without ribavirin. The most commonly reported adverse drug reactions of Zepatier when it was used alone were fatigue, headache, and nausea. When combined with ribavirin use, mostly in treatment-experienced patients, the most commonly reported adverse drug reactions were fatigue, headache, anemia, and nausea. Most of these adverse drug reactions were mild in severity. A low rate of serious adverse events or discontinuations in patients treated with Zepatier with or without ribavirin was reported.

Risks of elevations in the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST), especially late ALT/AST elevations after 4 weeks of dosing have been identified during early stages of the clinical studies. Patients with moderate or severe hepatic impairment were excluded from the Phase II and Phase III studies. With these hepatic risk mitigation measures in the clinical studies, on-treatment late ALT/AST elevations of greater than 5 times above the upper limit of normal as hepatic adverse drug reactions were observed in less than 1% of these patients. The Zepatier Product Monograph was revised to highlight the dosing-related hepatic risks in the Warnings and Precautions section and in the Adverse Drug Reactions section. Furthermore, Zepatier use in moderate or severe hepatic impairment patients is contraindicated and other precautionary wording was incorporated into the Zepatier Product Monograph to advise healthcare professionals to closely monitor liver function prior to and during Zepatier treatment.

Co-administration of Zepatier with some human immunodeficiency virus (HIV) drugs (such as HIV protease inhibitors: atazanavir, darunavir, lopinavir, saquinavir or tipranavir) that inhibit the organic anion-transporting polypeptide (OATP) transporter OATP1B may significantly increase Zepatier serum exposure and therefore these drugs are contraindicated with the use of Zepatier. In addition, the concomitant use of Zepatier with some potent or moderate cytochrome P450 (CYP) enzyme CYP3A inducers such as efavirenz and etravirine may significantly decrease grazoprevir and elbasvir plasma concentrations leading to a reduced effect of Zepatier. Therefore, the use of Zepatier is contraindicated with efavirenz and is not recommended with etravirine.

A Risk Management Plan (RMP) for Zepatier was submitted by Merck Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

Health Canada reviewed the Look-alike Sound-alike Report submitted by the sponsor and accepted the proprietary name for the drug product.

Overall, the therapeutic benefits seen in the pivotal studies are positive and the benefits of Zepatier therapy are considered to outweigh the potential risks. Zepatier has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling, and adequate monitoring. Appropriate warnings and precautions are in place in the Zepatier Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Zepatier?

The drug submission for Zepatier was reviewed under the Priority Review Policy. Zepatier demonstrated a significant increase in effectiveness with an improved benefit/risk profile compared to existing therapies for chronic hepatitis C genotype 4 infection, a condition that is not adequately managed by a drug marketed in Canada. It was concluded that this disease is a serious, life-threatening condition and that there was also a lack of therapy options for chronic hepatitis C patients with chronic kidney disease.

Submission Milestones: Zepatier

Submission Milestone	Date
Pre-submission meeting:	2014-07-17
Request for priority status
Filed:	2015-05-20
Approval issued by Director, Bureau of Gastroenterology Infection and Viral Diseases	2015-06-22
Submission filed:	2015-06-30
Screening
Screening Acceptance Letter issued:	2015-07-23
Review
Quality Evaluation complete:	2016-01-16
Clinical Evaluation complete:	2016-01-19
Labelling Review complete:	2016-01-18
Notice of Compliance issued by Director General:	2016-01-19

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?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

5 What post-authorization activity has taken place for Zepatier?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization 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 Zepatier 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, Part III: Patient Medication Information, 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

Zepatier (elbasvir/grazoprevir) combines two direct-acting antiviral agents with distinct mechanisms of action to target hepatitis C virus (HCV) at multiple steps in the viral lifecycle.

Elbasvir is an inhibitor of HCV non-structural protein 5A (NS5A), which is essential for viral ribonucleic acid (RNA) replication and virion assembly. The mechanism of action of elbasvir has been characterized based on cell culture antiviral activity and drug resistance mapping studies.

Grazoprevir is an inhibitor of the HCV NS3/4A protease which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. In a biochemical assay, grazoprevir inhibited the proteolytic activity of the recombinant NS3/4A protease enzymes from HCV genotype (GT) 1a, 1b, 3, and 4.

The clinical pharmacology included reports on the pharmacodynamics and pharmacokinetics of elbasvir and grazoprevir. The clinical pharmacological data support the use of Zepatier for the specified indication.

Thorough QT studies were conducted for elbasvir and grazoprevir. Using a single supra-therapeutic dose of grazoprevir (1600 mg) and elbasvir (700 mg), no clinically relevant prolongations in QTc interval were observed.

The clinical doses of elbasvir 50 mg once daily and grazoprevir 100 mg once daily were based on data from Phase I and II dose-ranging studies and further supported by exposure-response analyses from pooled Phase I, II, and III data.

Zepatier is contraindicated in HCV-infected patients with moderate and severe hepatic impairment, due to significant increase in grazoprevir exposure. In Phase II and Phase III studies, late elevations of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed and considered to be related to grazoprevir.

Both elbasvir and grazoprevir are substrates of cytochrome P450 (CYP) enzyme CYP3A and P-glycoprotein (P-gp). Drug interaction studies demonstrated significant decreases in elbasvir and grazoprevir exposure with moderate and strong CYP3A/P-gp inducers. Grazoprevir is an organic anion transporting polypeptide 1B (OATP1B) substrate. Concomitant administration of OATP1B inhibitors (such as rifampin and cyclosporine) with the Zepatier increases grazoprevir exposure and is contraindicated. The Zepatier Product Monograph includes a comprehensive list of drugs that are either contraindicated or not recommended for concomitant use.

Clinical Efficacy

The clinical efficacy of Zepatier was demonstrated in three pivotal Phase III studies (C-EDGE TN, C-EDGE CO-INFECTION, and C-EDGE TE) and five supportive Phase II or Phase II/III studies (C-SALVAGE, C-WORTHY, C-SWIFT, C-SURFER, and C-SCAPE).

The primary efficacy endpoint in all of the studies was the proportion of chronic hepatitis C (CHC) patients that achieved a Sustained Virologic Response 12 weeks after the end of all study therapy (SVR12), defined as hepatitis C virus ribonucleic acid (HCV RNA) less than the lower limit of quantification (LLOQ) 12 weeks after the end of all study therapy. The designs of the Phase II and III studies were well accepted in terms of primary and secondary endpoints. In terms of the genotypes involved in the studies, most CHC patients had genotype (GT) 1a or GT1b infection. An acceptable number of GT3 and GT4 infected patients were enrolled in these studies.

C-EDGE TN was a pivotal Phase III randomized, double-blind, placebo-controlled clinical study to evaluate the efficacy of Zepatier once daily for 12 weeks in treatment-naïve GT1, GT4, and GT6 CHC patients. Patients were randomized to receive Zepatier for 12 weeks (the immediate treatment group) or placebo for 12 weeks followed by open-label treatment with Zepatier for 12 weeks (the delayed treatment group). Of the enrolled patients, approximately 94% had GT1, 6% had GT4, and 3% had GT6. The majority of the patients had a baseline HCV RNA viral load >800,000 IU/mL and did not have advanced hepatic fibrosis. Approximately 23% of the patients were cirrhotic (Child-Pugh A). The median baseline values for alanine aminotransferase (ALT) and aspartate aminotransferase (AST) for patients in both groups were comparable (a little higher than the upper limit of normal). The SVR12 for the immediate treatment group was 95% (299/316; confidence interval [CI]: 91.5, 96.8) in the full analysis set (FAS) population which was similar to the per protocol (PP) population (patients who adhered perfectly to the clinical study instructions as stipulated in the protocol); SVR12 of 96% (299/313). Subgroup analyses revealed that the SVR12 among GT1a patients was comparable but lower (92%, FAS) than that of GT1b (99%, FAS). The SVR12 of 100% was achieved among a limited number of GT4 patients (number of patients [n] = 18). Due to very limited enrollment of GT6 patients in the study, the virologic analysis of GT6 patients was not evaluated. The number of patients who did not achieve SVR12 were low and mainly due to relapse (n = 12) and mostly in patients with GT1a (n = 9). On-treatment virologic failures were very rare (n = 1, GT1a). A high proportion of cirrhotic patients (97%) and non-cirrhotic patients (94%) achieved SVR12 regardless of genotype.

C-EDGE CO-INFECTION was a pivotal single-arm, open-label, multicentre Phase III study enrolling cirrhotic or non-cirrhotic treatment-naïve patients with HCV GT1, GT4, or GT6 infection and were also co-infected with human immunodeficiency virus type one (HIV-1). All patients in the single-treatment group received Zepatier for 12 weeks, with 24 weeks of follow-up after dosing was completed. Antiretroviral regimens allowed in this protocol included a dual nucleoside reverse transcriptase inhibitor (NRTI) backbone of either tenofovir or abacavir, emtricitabine or lamivudine, and a third antiretroviral drug of either raltegravir, dolutegravir or rilpivirine. The efficacy of SVR12 was measured against historic data which set SVR12 at 70%. Strong or moderate CYP3A inducers or inhibitors used by HIV patients were excluded from the study. Enrolled patients were mostly male (84%), <65 years of age (97%), White or African American (94%), with non-CC genotypes for the interleukin-28B (IL28B) gene (65%), and GT1 patients (86%) (GT1a [n = 144] or GT1b [n = 44]). There were also some GT4 (n = 28) and GT6 (n = 1) patients. A total of 16% of the patients had compensated cirrhosis. All the patients had HIV treatment compliance and had suppressed HIV viral load with recommended HIV regimens. The SVR12 for the HIV co-infected patients was 95% (207/218, FAS) which is superior to the historic efficacy reference of 70%. The per protocol SVR12 was higher but comparable (97%, 207/214). The SVR12s were comparable among different genotypes, cirrhosis status, sex, age, race, IL28B genotypes, baseline HCV RNA viral load or concomitant HIV treatment regimens. The analysis of GT6 patients was not reliable due to very limited number of GT6 patients.

C-EDGE TE was a pivotal Phase III, randomized, parallel-group, multicentre, open-label study using Zepatier once daily with or without ribavirin for 12 or 16 weeks in patients with CHC GT1, GT4, or GT6 infection with or without cirrhosis who failed prior peginterferon alfa + ribavirin based treatment. Patients were randomized into four treatment groups (Zepatier 12 weeks, Zepatier + ribavirin 12 weeks, Zepatier 16 weeks, Zepatier + ribavirin 16 weeks). Randomization was also stratified according to cirrhosis status and prior peginterferon alfa + ribavirin treatment response (relapse, partial responder or null responder). The majority of the enrolled patients were male (65%), <65 years of age (86%), White or African American (85%), with non-CC genotypes for IL28B (79%). Most patients were GT1 (89%) (GT1a [n = 227] or GT1b [n = 147]). There were also some GT4 (n = 37) and GT6 (n = 6) patients. A total of 35% of the patients had compensated cirrhosis. All of the HIV co-infected patients were HIV treatment compliant and had suppressed HIV viral load with recommended HIV regimens. The majority of the patients were non-responders to the prior peginterferon alfa + ribavirin treatment (64%: null responders 43% and partial responders 21%) and relapsers (36%). Only 5% of the patients were co-infected with HIV-1. In terms of the primary efficacy endpoint, the group treated with Zepatier + ribavirin for 16 weeks achieved the highest SVR12 of 97% (103/106, FAS) versus 92% in the other two groups treated with Zepatier without ribavirin, and 94% in the group treated with Zepatier + ribavirin for 12 weeks. All these highly efficacious treatment regimens were superior to the historic SVR12 of 58%. There were 25 treatment failures in this study, 19 of which were due to virologic failures (relapse n = 16). Among them, the Zepatier + ribavirin 16-week group did not have any virologic failures (SVR12: 100%, PP). There were three prior relapsers (one each of GT1a, GT1b, and GT6) in the Zepatier 16-week group that failed the treatment. The SVR12 was achieved at a slightly lower rate among GT1a patients (95% in the Zepatier + ribavirin 16-week group) while all other genotypes reported 100% in the same treatment group. Therefore, prior relapsers (peginterferon alfa + ribavirin treatment-experienced patients who were a GT1a/b relapser or GT4 relapser, or GT1b non-responder) had high efficacy with the Zepatier 12-week regimen (without ribavirin). The GT1a or GT4 patients who were prior non-responders achieved very high efficacy results with the 16-week Zepatier + ribavirin regimen in this study. The indication for GT6 peginterferon alfa + ribavirin treatment-experienced patients was not supported by the study data.

Apart from the three pivotal Phase III studies, there were five core Phase II studies to support Zepatier use with or without ribavirin in protease inhibitor/ peginterferon alfa + ribavirin based treatment-experienced GT1 patients (C-SALVAGE); in GT1 patients with advanced renal disease (C-SURFER); in GT3 treatment-naïve patients (C-SWIFT); with a shorter treatment duration for GT1b non-cirrhotic treatment-naïve patients (C-WORTHY); and an exploratory Phase II study for different genotypes (C-SCAPE).

The Phase II study C-SALVAGE and the pivotal Phase III study C-EDGE TE both included HCV treatment-experienced patients. Although the primary endpoint of SVR12 for C-SALVAGE showed comparable high efficacy in a 12-week regimen with ribavirin to a 16-week regimen with Zepatier + ribavirin in the C-EDGE TE study, there were 2 treatment failures in the C-SALVAGE study compared to no failures in the 16 weeks of treatment with Zepatier + ribavirin in the C-EDGE TE group. Therefore, it is recommended in the Zepatier Product Monograph to treat all GT1a treatment-experienced non responding patients who have previously failed peginterferon alfa + ribavirin therapy or protease inhibitor/ peginterferon alfa + ribavirin therapy, as well as GT4 peginterferon alfa + ribavirin treatment-experienced non-responding patients with a 16-week Zepatier + ribavirin regimen. Patients with GT4 CHC infection who failed prior protease inhibitor/ peginterferon alfa + ribavirin treatment were not studied in the C-SALVAGE study and therefore this population was excluded from the indication in the Zepatier Product Monograph. For GT1b treatment-experienced patients (peginterferon alfa + ribavirin treatment-experienced or protease inhibitor/ peginterferon alfa + ribavirin treatment-experienced) relapsers or non-responders, a 12-week regimen without ribavirin was proven effective in the C-EDGE TE study and C-SALVAGE study, and therefore recommended in the Zepatier Product Monograph.

In the C-SURFER study, the efficacy of Zepatier was evaluated in a randomized parallel-group, placebo-controlled study involving GT1 treatment-naïve or peginterferon alfa + ribavirin treatment-experienced CHC patients (with or without cirrhosis) who had advanced chronic kidney disease and who were on hemodialysis. Many of the patients had diabetes, hypertension, cardiovascular disease or other co-morbidities. Among this difficult to treat special population, treatment with Zepatier for 12 weeks without ribavirin achieved very high SVR12 (94%, FAS).

Zepatier in combination with sofosbuvir (400 mg once daily) for 12 weeks in the C-SWIFT study achieved high SVR12 for GT3 treatment-naïve patients with or without cirrhosis. The SVR12 for GT3 patients without cirrhosis with the 12-week regimen was 100% (14/14, PP) and the SVR12 for GT3 cirrhotic patients with the12-week regimen was 91% (10/11, PP). This regimen of Zepatier + sofosbuvir provides an additional option to daclatasvir/sofobuvir for patients who cannot tolerate ribavirin or prolonged HCV treatment with other regimens.

A shorter duration of treatment (8-weeks) for GT1b non-cirrhotic treatment-naïve patients was demonstrated in the C-WORTHY study. The SVR12 was 94% (29/31, PP) for the GT1b non-cirrhotic treatment-naïve patients who were given Zepatier for 8 weeks. The FAS SVR12 for this group was similar to the PP population. An 8-week regimen for GT1b non-cirrhotic treatment-naïve patients is therefore acceptable, as indicated in the Zepatier Product Monograph.

The C-SCAPE study included non-cirrhotic, treatment-naïve patients with GT2, GT4, GT5 or GT6 CHC infection. Patients received Zepatier for 12 weeks or Zepatier + ribavirin for 12 weeks. Patients with GT2, GT5, and GT6 infection were not relevant to this drug submission. However, results showed that the GT4 patients with or without ribavirin had the same treatment outcome with both treatment groups achieving 100% SVR12 (9/9 with ribavirin and 7/7 without ribavirin).

Resistance Associated Variants to NS3/4A or NS5A

The antiviral activity of Zepatier (elbasvir/grazoprevir) against HCV is due to the inhibition of HCV nonstructural protein 5A (NS5A) by elbasvir, and the inhibition of HCV NS3/4A protease by grazoprevir.

Although the prevalence of baseline NS3 resistance associated variants (RAVs) was high (for example [e.g.] 46% in C-SALVAGE), their presence at baseline had no evident impact on the efficacy of Zepatier dosing regimens. A small number of patients had baseline NS3 RAVs conferring measurable potency shifts to grazoprevir (that is [i.e.] >5-fold reduction in potency), but the presence of these RAVs at baseline also had no evident impact on SVR12.

On the contrary, the combination of baseline NS5A RAVs conferring a >5-fold elbasvir potency shift and high viral load (defined as >800,000 IU/mL) in vitro and GT1a treatment-experienced patients demonstrated an evident impact on the efficacy of Zepatier (i.e. SVR12).

In the Zepatier studies, relapse at follow-up was the most common reason among a limited number of treatment failures that were reported, regardless of patient treatment experience or cirrhosis status. These failures were mainly associated with baseline HCV viral NS5A RAVs in these patients; a greater than five-time elbasvir potency shift in antiviral activity in vitro was found. The prevalence of baseline NS5A RAVs that caused a greater than 5-fold decrease in elbasvir potency was detected in 7% (55/825) of the GT1a pooled efficacy population and the clinical efficacy seemed impacted in GT1a patients with RAVs at amino acid position 28, 30, 31, 58 and 93 who were with a higher HCV RNA viral load (SVR12 47% [23/49] in these patients). The overall SVR12 impact on GT1a treatment-naïve /treatment experienced patients was limited. The GT1a patients who did not achieve SVR12 due to NS5A RAVs (>5 fold decrease in elbasvir potency) + high HCV RNA viral load among all studies combined was 3% (26/825). The SVR12 rates were not affected among GT1b or GT4 patients with NS5A polymorphisms.

Treatment-emergent RAVs in the NS3 and/or NS5A genes were observed in patients experiencing virologic failure. In 50 patients who failed treatment and had sequence data available (6 with on-treatment virologic failure and 44 with post-treatment relapse), treatment-emergent substitutions were detected in both NS3 and NS5A in 62% (23/37) of GT1a patients, 13% (1/8) of GT1b patients, and 40% (2/5) of GT4 patients. In GT3 patients treated with Zepatier + sofosbuvir for 12 weeks in the C-SWIFT study, one patient experienced relapse associated with treatment-emergent NS5A substitution (Y93H) as well as a persistent NS3 RAV (Q168R). Concerns regarding resistance-associated substitutions are included in the Zepatier Product Monograph.

Indication

The proposed indication by the sponsor for Zepatier for this New Drug Submission (NDS) was:

"Zepatier (elbasvir/grazoprevir) is indicated for the treatment of chronic hepatitis C (CHC) genotypes 1, 3, 4, or 6 infection in adults."

Following the review of the NDS, Health Canada recommended the following indication: "Zepatier (elbasvir/grazoprevir) is indicated for the treatment of chronic hepatitis C (CHC) genotypes 1, 3, or 4 infection in adults" as follows:

Without ribavirin:

in genotype (GT) 1 or 4 treatment-naïve (TN) and peginterferon alfa + ribavirin (PR) treatment-experienced (TE) relapsers (12 weeks)
in GT1 protease inhibitor (PI)/PR-TE relapsers (12 weeks)
in GT1b TN, non-cirrhotic patients (8 weeks)
in GT1b PR- or PI/PR-TE on-treatment virologic failures (12 weeks)

With ribavirin:

in GT1a PR- or PI/PR-TE on-treatment virologic failures (16 weeks)
in GT4 PR-TE on-treatment virologic failures (16 weeks)

With sofosbuvir:

in GT3 TN patients (12 weeks)

Zepatier was originally proposed as treatment for CHC infected GT1, GT3, GT4 or GT6 patients. Due to very limited GT6 enrollment in the clinical studies, an indication for GT6 patient dosing was not approved.

Since protease inhibitor/peginterferon alfa + ribavirin treatment-experienced patients were only evaluated in the C-SALVAGE study among GT1 patients, treatment for those that failed prior therapy with protease inhibitor/peginterferon alfa + ribavirin treatment is restricted to GT1 protease inhibitor/peginterferon alfa + ribavirin treatment-experienced patients. However, due to higher SVR12 and zero virologic failures achieved for peginterferon alfa + ribavirin treatment-experienced patients in the study C-EDGE TE with a 16-week regimen of Zepatier + ribavirin and due to the fact that some virologic failures were observed in the C-SALVAGE study, a 16-week regimen of Zepatier + ribavirin regimen is recommended for all treatment-experienced patients (GT1 or GT4). GT1b treatment-naïve, non-cirrhotic patients are able to have a shortened Zepatier regimen (8 weeks). GT1b peginterferon alfa + ribavirin treatment-experienced patients as well as protease inhibitor/peginterferon alfa + ribavirin treatment-experienced patients will be recommended a 12-week Zepatier (ribavirin-free) regimen. Based on the C-SWIFT study, a Zepatier + sofosbuvir regimen for 12 weeks is recommended for GT3 treatment-naïve patients with or without cirrhosis. A special difficult-to-treat GT1 patient group who had severe renal impairment and who were on regular hemodialysis was evaluated and Zepatier treatment for 12 weeks without ribavirin was recommended; however, a caveat for GT3 or GT4 patients with similar conditions has been cautioned in the Zepatier Product Monograph.

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

Clinical Safety

The safety profile of Zepatier was based on data from two placebo-controlled studies and eight uncontrolled Phase II and III clinical studies in approximately 2,000 patients with CHC infection with compensated liver disease (with or without cirrhosis) who received Zepatier with or without ribavirin.For more information about the Phase II and Phase III studies, see Clinical Efficacy.

Zepatier once daily alone for 12 weeks in treatment-naïve patients or Zepatier once daily plus weight-based ribavirin (twice a day) for 16 weeks in treatment-experienced patients (GT1a peginterferon alfa + ribavirin treatment-experienced patients or protease inhibitor/ peginterferon alfa + ribavirin treatment-experienced patients; and GT4 peginterferon alfa + ribavirin treatment-experienced patients) were generally well-tolerated. The most common drug-related adverse drug reactions (ADRs) were fatigue, headache, and nausea in the drug regimen without ribavirin. Ribavirin-containing regimens were associated with an increase in frequency of drug-related adverse events (AEs) of asthenia, anemia, pruritus, rash, and dyspnea et cetera. Tolerability did not differ substantially according to baseline factors such as age, gender, race/ethnicity, presence of cirrhosis, presence of HCV/HIV co-infection, or the presence of advanced chronic kidney disease (Stage 4-5). Tolerability was comparable in regimens with 16 weeks versus 12 weeks of treatment.

In the Phase III placebo-controlled study C-EDGE TN where treatment-naïve patients received Zepatier alone or placebo for 12 weeks, the drug-related adverse drug reactions (ADRs) with an incidence rate of ≥2% for the on-treatment period showed comparable ADR results for both groups. The most commonly reported ADRs at ≥10% frequency in patients treated with Zepatier for 12 weeks were fatigue (11%) and headache (10%). In the placebo group, fatigue was reported at 10% and headache 9%. None of the patients had serious adverse reactions. Late alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations of >5 times the upper limit of normal (ULN) from 4 weeks after the start of treatment was identified in four patients (Grade 3 or 4) in the Zepatier group but none of these cases were associated with elevated levels of serum bilirubin. All these patients were asymptomatic. The frequency of discontinuation of study drug due to adverse events (AEs) was low and comparable between the two groups (approximately 1%) and 2 of the 4 patients who had late ALT/AST elevations in the Zepatier group discontinued. The ALT/AST elevations were resolved upon discontinuation.

The other placebo-controlled study was C-SURFER. This study evaluated the use of Zepatier in CHC GT1 patients with chronic kidney disease. The most commonly reported adverse reactions occurring at ≥10% frequency in patients treated with Zepatier alone for 12 weeks were nausea and headache. None of the patients experienced a serious adverse event (SAE) or discontinued treatment due to ADRs. Based on the results of this study, a recommendation of Zepatier 12 weeks without ribavirin can be made for the special population of CHC GT1 with chronic kidney disease.

In the C-EDGE CO-INFECTION pivotal study where HCV/HIV-1 co-infected patients with GT1 or GT4 infection received Zepatier alone for 12 weeks, the ADRs ≥5% were fatigue (16/218, 7.3%), and headache (15/218, 6.9%). No drug-related SAEs were identified and no deaths occurred during treatment. Elevations of ALT/AST were common in these patients (65%/50%) and the majority of them were Grade 1 or 2. Two patients had a late transaminase elevation >5 times the ULN (Grade 3) and remained in the study; SVR12 was achieved in these patients.

In the C-EDGE TE pivotal study where Zepatier was administered with or without ribavirin for 12 or 16 weeks, the dosing regimen was generally well-tolerated in the diverse population of patients studied. The most common AEs were fatigue (23.1%), headache (19.8%), and nausea (11.0%), and these occurred with a similar frequency across treatment groups. Generally, there were no notable differences in the AE profiles of the 12- and 16-week regimens. Anemia was reported only in ribavirin-treated patients, and fatigue, nausea, insomnia, dyspnea, rash and pruritis were observed more frequently among ribavirin-treated patients than among patients who were not treated with ribavirin. Patients who received ribavirin for 16 weeks had a modest increase in the incidence of ribavirin-related adverse experiences relative to those receiving ribavirin for 12 weeks. Most reported AEs were mild or moderate in severity. Only 1 patient had SAEs (abdominal pain and transient ischemic attack) that were considered to be related to Zepatier. Seven patients (1.7%) discontinued study medication due to AEs with more discontinuations in the 16-week Zepatier + ribavirin group (n = 5) compared with the other treatment groups. Ten patients (4.8%) in the ribavirin groups and no patients in the ribavirin-free groups had Grade 3 or 4 hemoglobin values on treatment. Altogether, 14 patients (6.7%) in the ribavirin-treated groups had a Grade 3 or 4 increased total bilirubin; the majority were associated with decreases in hemoglobin. Five patients in the study had either a late transaminase elevation >5 times the ULN or a hepatic event of clinical interest. The ALT/AST elevations in these patients were all reported as AEs that were not considered to be drug-related by the investigators.

The Zepatier + ribavirin 12 week regimen was generally well tolerated in the C-SALVAGE study (n = 79). Most of the drug-related ADRs were fatigue, headache, nausea and asthenia. No drug-related SAEs, discontinuation or deaths were reported. Most clinical chemistry and hematology laboratory assessments remained within normal reference ranges. No patients had elevated transaminases that were considered events of clinical interest. No patients had a late transaminase elevation >2 times the ULN after normalization of values during study treatment. Six patients (7.6%) were reported to have drug-related anemia. Mild to moderate (Grade 1 or 2) transient increases in total bilirubin were common especially among those who developed anemia.

In the C-WORTHY study, regimens of Zepatier + ribavirin were generally well tolerated. The AEs that were reported as drug related in more than 5% of all GT1-infected patients were fatigue, headache, nausea, asthenia, insomnia, pruritus, myalgia, and rash. Drug-related AEs with a notably higher incidence in ribavirin-treated groups compared with ribavirin-free groups included fatigue, nausea, anemia, insomnia, cough, dyspnea, pruritus, and rash. Three GT1-infected patients reported AEs that led to discontinuation of one or more study drugs. One of the 3 AEs leading to discontinuation (tachycardia associated with anemia) was considered drug related. No treatment-related deaths were reported. Two patients (0.3%) experienced late Grade 3 ALT elevation events that developed approximately 8 weeks after the initiation of study medication and resolved within 4 weeks. Safety profiles of Zepatier with and without ribavirin treatment were similar in treatment-naïve, noncirrhotic mono-infected patients; treatment-naïve, non-cirrhotic patients co-infected with HCV/HIV; treatment-naïve cirrhotic patients; and prior null responders to peginterferon alfa/ribavirin therapy who were either cirrhotic or non-cirrhotic.

The safety of Zepatier with sofosbuvir in treatment-naïve patients with CHC GT3 infection was assessed in 143 patients (C-SWIFT safety population). No ADRs were reported at ≥5% frequency. The ADRs occurring at ≥1% to <5% frequency were diarrhea (1%), fatigue (1%), nausea (2%) and headache (3%). None of the patients had SAEs and no subjects discontinued treatment due to adverse reactions.

Overall, Zepatier was generally well tolerated among the divergent patient populations and different treatment regimens with or without ribavirin. The most commonly reported ADRs of Zepatier when used alone were fatigue, headache and nausea. When combined with ribavirin use (mostly in treatment-experienced patients), the most commonly reported ADRs were fatigue, headache, anemia and nausea. Most of these ADRs were mild in severity. The SAEs or discontinuations in patients treated with Zepatier with or without ribavirin were rare.

Zepatier use in patients with hepatic impairment has been very cautious based on some Phase II pharmacokinetic and safety studies where grazoprevir exposure increase was associated with late ALT/AST elevation and worsening of liver functions in Child-Pugh B cirrhotic patients (moderate or severe hepatic impairment). These conditions have been used as exclusion criteria in the later Phase II and Phase III studies. As such, Zepatier use in moderate or severe hepatic impairment patients has been contraindicated and other precautionary wording was included to recommend close monitoring of liver functions prior to and during Zepatier dosing. Appropriate warnings and precautions are in place in the approved Zepatier Product Monograph to address the identified safety concerns.

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

7.2 Non-Clinical Basis for Decision

Zepatier contains two medicinal ingredients elbasvir and grazoprevir. The non-clinical program for elbasvir and grazoprevir was appropriate with regard to the proposed indication for Zepatier and the regulatory requirements.

In efficacy studies, elbasvir and grazoprevir showed potency against HCV genotypes 1, 3 or 4. Variants with reduced susceptibility to either agent were appropriately identified and characterized.

Pharmacokinetic studies with elbasvir and grazoprevir demonstrated the potential for drug interactions via the cytochrome P450 (CYP) 3A4 enzyme and various drug transporters. These interactions were further characterized in humans and adequately addressed in the Zepatier Product Monograph.

In safety studies with elbasvir, phospholipidosis occurred in dogs but was reversible upon treatment cessation. The safety margin for this effect was approximately 1.6 times the clinical dose. The clinical relevance of phospholipidosis is unknown and therefore this information was added to the Zepatier Product Monograph.

In safety studies with grazoprevir, adverse effects occurred in the hepatobiliary and gastrointestinal systems. These effects seem to be mechanistically related to inhibition of bile acid transporters by grazoprevir and its biliary excretion. The safety margin was >80 times the clinical exposure. These non-clinical effects of grazoprevir are presented in the Zepatier Product Monograph.

Carcinogenicity studies with elbasvir and grazoprevir were not conducted. This is considered acceptable with respect to the intended clinical use of Zepatier (less than 6 months), the pharmacology of grazoprevir and elbasvir, the negative genotoxicity studies, and the absence of any neoplastic or other potentially tumorigenic findings in the non-clinical toxicology studies.

For more information, refer to the Zepatier 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 Zepatier has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf-life of 24 months is acceptable when stored at 15-30°C and protected from moisture.

Proposed limits of drug-related impurities are considered adequately qualified [that is within International Council for 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.

The lactose monohydrate used in the drug product is derived from milk certified to originate from healthy animals and is collected in the same manner as milk fit for human consumption.

The magnesium stearate in the drug product is derived from vegetable origin.

Date modified:: 2026-04-20

Language selection

WxT Language switcher

WxT Search form

Review decision

Clinical Pharmacology

Clinical Efficacy

Clinical Safety