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PrSOVALDI

Contact: Bureau of Gastroenterology Infection and Viral Diseases

Summary Basis of Decision (SBD)

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

Recent Activity for Sovaldi

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 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 Sovaldi

Updated: 2015/09/21

The following table describes post-authorization activity for Sovaldi, a product which contains the medicinal ingredient sofosbuvir. 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 02418355 - 400 mg, sofosbuvir, tablet, oral

Post-Authorization Activity Table (PAAT)
Activity/Submission Type, Control Number Date Submitted Decision and Date Summary of Activities
(the most recent activities are listed first)
NC # 183516 2015/04/07 Issued No Objection Letter 2015/07/21 Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Toxicology section of the Product Monograph (PM). Editorial changes were also made to the Warnings and Precautions and Adverse Reactions sections of the PM. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 183396 2015/03/31 Issued No Objection Letter 2015/07/10 Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Product Monograph (PM) with the increased risk of symptomatic bradycardia when Sovaldi is coadministered with amiodarone. As a result of the Notifiable Change (NC), revisions were made to the Warnings and Precautions, Adverse Reactions, and Drug Interactions sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
Dear Healthcare Professional Letter posted Not applicable Posted 2015/04/02 Dear Healthcare Professional Letter posted for Sovaldi and Harvoni, containing important safety information for healthcare professionals and the general public.
SNDS # 175080 2014/05/23 Issued NOC 2014/12/05 Submission filed as a Level I - Supplement to introduce data on the interaction of Sovaldi with hormonal contraceptives, and to provide a re-analysis of population pharmacokinetic (PK) data. As a result of the submission, changes were made to the Product Monograph (PM) to provide information about additional contraceptive options for patients undergoing treatment. In addition, the PM was revised to provide more accurate PK data. The data were reviewed and considered acceptable, and a Notice of Compliance was issued for safety updates to the Product Monograph.
SNDS # 172576 2014/02/26 Issued NOC 2014/09/30 Submission filed as a Level I - Supplement; as a result of the submission, information from three ongoing clinical studies was included in the Product Monograph (PM) for appropriate clinical use of Sovaldi for different patient populations. The three studies focus on evaluation of an interferon-free regimen of sofosbuvir + ribavirin in three treatment settings. Study 2025 (a Phase II non-comparative study) studied hepatitis C virus (HCV) patients awaiting liver transplantation. The Phase III PHOTON-1 Study assessed chronic hepatitis C virus (CHC) patients co-infected with HIV-1. The Phase III VALENCE study examined CHC patients with HCV genotype 2 or 3. The Supplemental New Drug Submission was reviewed in accordance with the Priority Review Policy. The submission was originally filed to expand the indications for Sovaldi, however the efficacy data were for special CHC patient populations already covered by the current indication for Sovaldi. Instead, the Notice of Compliance was issued for the addition of the data to the PM as described above.
Drug product (DIN) 02418355) market notification Not applicable Date of first sale: 2014/01/06 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Next link will take you to another Web site Food and Drug Regulations.
NDS # 165043 2013/04/15 Issued NOC 2013/12/13 Notice of Compliance issued for New Drug Submission.

Summary Basis of Decision (SBD) for Sovaldi

Date SBD Issued: 2014/02/18

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

  • Sofosbuvir
  • 400 mg, tablet, oral
  • Drug Identification Number (DIN): 02418355
  • Gilead Sciences Canada Inc.
  • New Drug Submission Control Number: 165043

On December 13, 2013, Health Canada issued a Notice of Compliance to Gilead Sciences Canada, Inc. for the drug product Sovaldi.

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 Sovaldi is favourable for the treatment chronic hepatitis C virus (CHC) infection in adult patients with compensated liver disease, including cirrhosis, for (a) the treatment of genotype 1 and genotype 4 CHC infection in combination with pegylated interferon (PEG) and ribavirin (RBV); and for (b) the treatment of genotype 2 and genotype 3 CHC infection in combination with ribavirin (RBV).

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

1. What was approved?

Sovaldi, an antiviral agent, was authorized for the treatment chronic hepatitis C virus (CHC) infection in adult patients with compensated liver disease, including cirrhosis, for (a) the treatment of genotype 1 and genotype 4 CHC infection in combination with pegylated interferon (PEG) and ribavirin (RBV); and for (b) the treatment of genotype 2 and genotype 3 CHC infection in combination with ribavirin (RBV).

The following points should be considered when initiating treatment with Sovaldi:

  • Sovaldi must not be administered as monotherapy.
  • Treatment regimen and duration are dependent on both viral genotype and patient population.
  • Treatment response varies on baseline host and viral factors.

Sovaldi is contraindicated in patients with known hypersensitivity to any of the components of the product. When Sovaldi is used in combination with PEG+RBV or RBV only, the contraindications applicable to those agents are applicable to combination therapies. Sovaldi combination treatment with PEG+RBV or RBV is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant or may become pregnant because of the risks for birth defects and fetal death associated with ribavirin. Sovaldi was approved for use under the conditions stated in the Sovaldi Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Sovaldi (400 mg sofosbuvir) is presented as a tablet. In addition to the medicinal ingredient, the tablets contain mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. The tablets are film-coated with a coating material containing polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol, talc, 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 Sovaldi Product Monograph, approved by Health Canada and available through the Drug Product Database.

2. Why was Sovaldi approved?

Health Canada considers that the benefit/risk profile of Sovaldi is favourable for the treatment chronic hepatitis C virus (CHC) infection in adult patients with compensated liver disease, including cirrhosis, for (a) the treatment of genotype 1 and genotype 4 CHC infection in combination with pegylated interferon (PEG) and ribavirin (RBV); and for (b) the treatment of genotype 2 and genotype 3 CHC infection in combination with ribavirin (RBV).

Chronic hepatitis C (CHC) is a serious, progressive, and often life-threatening disease of major public health concern. The infection, if untreated, can result in progressive liver fibrosis, cirrhosis, and ultimately, hepatocellular carcinoma (HCC), the most common type of liver cancer. Although asymptomatic liver disease progression can occur over several decades, a number of patients with CHC will develop cirrhosis of the liver and will be at risk for developing HCC. Chronic hepatitis C virus (HCV) infection is the leading cause of cirrhosis and hepatic failure.

Sovaldi has been shown to be efficacious in adult patients with genotype 1 and genotype 4 chronic HCV infection in combination with PEG+RBV and in adult patients with genotype 2 and genotype 3 chronic HCV infection in combination with RBV. Sovaldi is not indicated for administration as monotherapy. The treatment regimen and duration are dependent on both viral genotype and patient population and the treatment response varies based on baseline host and viral factors.

The market authorization was primarily based on four Phase III clinical studies (NEUTRINO, FISSION, POSITRON and FUSION) conducted in a total of 1,296 patients with genotypes 1 to 6 CHC. All patients had compensated liver disease, including cirrhosis. Plasma HCV ribonucleic acid (RNA) values were measured to obtain the sustained virologic response (SVR), the primary endpoint to determine the HCV cure rate for these studies. The SVR was defined as HCV RNA less than the lower limit of quantification (LLOQ) of 25 international unit (IU)/mL at 12 weeks after the end of treatment.

The efficacy of Sovaldi for the proposed indication against genotypes 1 and 4 was based on the results of the Phase III clinical study NEUTRINO, conducted in treatment-na´ve patients with genotype 1, 4, 5 or 6 CHC in combination with PEG and RBV. The results showed that after 12 weeks of treatment with Sovaldi [sofosbuvir (SOF)]+PEG+RBV, the sustained virologic response (SVR12) rate was 90.2% amongst treatment-na´ve patients with chronic genotype 1, 4, 5, or 6 HCV infection. However, due to the limited number of patients with genotype 5 and 6 CHC enrolled in the NEUTRINO study [number of patients (n) = 1 and n = 6, respectively], the indication for chronic HCV infection for patients with genotype 5 and 6 CHC was not authorized considering the limited data available regarding the use of Sovaldi in those patients.

The efficacy of Sovaldi for the treatment of genotype 2 and 3 HCV infections was based on the results of three Phase III studies: FISSION, POSITRON and FUSION. The results of FISSION study showed that the difference in the overall SVR rates between SOF+RBV and PEG+RBV treatment groups was 0.3% [95% confidence interval (CI): -7.5% to 8.0%] and that the study met the predefined non-inferiority criterion.

The SOF-containing regimens had favourable safety profiles compared to historical and/or current standard-of-care regimens. The majority of adverse events (AEs) with Sovaldi were mild or moderate in intensity. The most common AE observed during the clinical studies was fatigue. No adverse drug reactions specific to Sovaldi have been identified.

The proposed SOF+RBV treatment regimens for the treatment of genotype 2 and genotype 3 CHC infections provide a significantly shorter, simple, well-tolerated oral regimen without the need for subcutaneous injections of PEG, which is associated with numerous side effects. These regimens eliminate the need for response guided treatment algorithms with up to 48 weeks of current standard-of-care treatment. The SOF+RBV regimen also provide an option for treatment-experienced patients who currently do not have any recommended or approved treatment options and shows promise for those awaiting liver transplantation and those with HCV/HIV co-infection.

A Risk Management Plan (RMP) for Sovaldi was submitted by Gilead Sciences 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.

Overall, the therapeutic benefits seen in the pivotal studies are positive and the benefits of Sovaldi therapy seem to outweigh the potential risks. Sovaldi has demonstrated a favourable safety profile that did not appear to contribute any additional significant toxicity not already associated with background therapy of RBV. In addition, the shorter duration of SOF+PEG+RBV treatment resulted in a lower rate of discontinuation compared with typical standard-of-care treatment. The proposed SOF+RBV treatment regimens for the treatment of genotype 2 and genotype 3 HCV infection represent important new therapeutic options for the treatment of patients with chronic HCV infection.

In conclusion, based on the review of the data, the overall risk/benefit ratio is considered positive for market authorization when Sovaldi is prescribed under the conditions of use recommended in the Sovaldi Product Monograph.

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 Next link will take you to another Web site 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 Sovaldi?

The drug submission for Sovaldi was reviewed under the Priority Review Policy. Sovaldi, in combination with pegylated interferon (PEG) and ribavirin (RBV) for the treatment of adult patients with genotype 1 and 4 chronic hepatitis C virus (HCV) infection, and Sovaldi in combination with RBV for the treatment of adult patients with genotype 2 and 3 chronic HCV infection, demonstrated a significant increase in effectiveness with an improved benefit/risk profile compared to existing therapies for chronic HCV infection, a condition that is not adequately managed by a drug marketed in Canada.

Submission Milestones: Sovaldi
Submission Milestone Date
Pre-submission meeting: 2013/03/20
Request for priority status
Filed: 2013/04/15
Approval issued by Director: 2013/05/17
Screening
Screening Acceptance Letter issued: 2013/06/14
Review
Biopharmaceutics Evaluation complete: 2013/11/13
Quality Evaluation complete: 2013/11/27
Clinical Evaluation complete: 2013/12/12
Labelling Review complete: 2013/12/12
Notice of Compliance issued by Director General: 2013/12/13

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 Next link will take you to another Web site Food and Drugs Act and Next link will take you to another Web site Regulations.

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

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 Sovaldi 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:

7. What was the scientific rationale for Health Canada's decision?

Clinical Basis for Decision

Clinical Pharmacology

The medicinal ingredient of Sovaldi, sofosbuvir (SOF), is a nucleotide analog NS5B polymerase inhibitor that has a direct antiviral action against the hepatitis C virus (HCV). It blocks a specific step in the replication of the HCV virus. The stopping of viral replication leads to a rapid decline of HCV viral load and clearing of HCV levels in the body.

The clinical pharmacology included reports on the human pharmacodynamic and the pharmacokinetic studies. Results from these studies showed that no dosage adjustment is recommended for patients with mild or moderate renal impairment or mild, moderate or severe hepatic impairment. Overall, the clinical pharmacological data support the use of Sovaldi for the specified indication.

One patient developed the primary treatment-emergent Sovaldi resistance mutation (S282T) in a Phase II study, in which the patient received Sovaldi in monotherapy. Therefore, Sovaldi must not be administered as monotherapy and must only be used in combination with either peginterferon alfa (PEG)+ribavirin (RBV) or RBV for the treatment of HCV.

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

Clinical Efficacy

The efficacy of Sovaldi [sofosbuvir (SOF)] was evaluated in four Phase III clinical studies: NEUTRINO, FISSION, POSITRON and FUSION.

The study NEUTRINO was a Phase III, multicentre, open-label, single-arm study that investigated the efficacy and safety of Sovaldi with peginterferon alfa 2a (PEG) and ribavirin (RBV) for 12 weeks in treatment-na´ve patients with chronic genotype 1, 4, 5, or 6 HCV infection. A total of 327 patients were treated for 12 weeks with SOF (400 mg once daily)+PEG (180 μg/week)+RBV (1,000 or 1,200 mg/day). The primary efficacy endpoint was the proportion of patients with sustained virologic response at 12 weeks (SVR12), defined as HCV ribonucleic acid (RNA) less than the lower limit of quantification (LLOQ) 12 weeks after discontinuation of treatment in the full analysis set population.

The overall treatment response 12 weeks post-treatment (SVR12) rate was 90.2% amongst treatment-na´ve patients with chronic genotype 1, 4, 5, or 6 HCV infection. By comparison, the SVR12 rate for chronic HCV genotype 1 in combination with the NS3/4A protease inhibitors (telaprevir and boceprevir) was approximately 70%, with SVR rates slightly lower for genotype 4 and 6. No patients had the on-treatment virologic failure (breakthrough, rebound or non-response). HCV RNA levels declined rapidly, with a decline of approximately 5 log10 after 1 week of treatment, which was maintained throughout the remainder of treatment. These results demonstrated that the combination of SOF+interferon (INF)+RBV suppresses HCV RNA quickly and in a very potent manner. None of the patients developed the primary treatment-emergent Sovaldi resistance mutation (S282T). Specified subgroups that have classically been considered to be harder to treat were analysed. These subgroups all had SVR rates of ~80% or higher, with the exception of patients with cirrhosis, who had an SVR rate of 79.6%. Blacks/African Americans had an SVR rate of 87%, while those with either a cytosine-thymine (CT) or thymine-thymine (TT) IL28B genotype had an SVR rate of 87.1% (compared to 97.9% for the CC genotype). Classically, genotype 1a has normally been harder to treat than genotype 1b. However, the SVR12 rate for Sovaldi against genotype 1a was 92%, compared to 82% for genotype 1b. For those with genotypes 4, 5, and 6, the SVR12 rate was 97.1% (34/35 patients, with only 1 patient with genotype 5, and 6 patients with genotype 6, all of whom achieved SVR12).

Due to the limited number of patients with genotype 5 and 6 CHC enrolled in the NEUTRINO study [number of patients (n) = 1 and n = 6, respectively], the indication for chronic HCV infection for patients with genotype 5 and 6 CHC was not authorized considering the limited data available regarding the use of Sovaldi in those patients.

Three Phase III studies (FISSION, POSITRON and FUSION) were conducted to support the indication and dosing recommendation for the treatment of genotypes 2 and 3 chronic HCV infection.

FISSION was a Phase III, randomized, open-label, active-controlled study that evaluated the efficacy and safety of SOF+RBV administered for 12 weeks, in comparison with the current standard of care treatment with PEG+RBV administered for 24 weeks for the treatment of genotype 2 and 3 CHC infection. A total of 499 patients were treated with SOF (400 mg)+RBV (1,000-2,000 mg) daily for 12 weeks or PEG-INF (180 µg/week)+RBV (800 mg/day) for 24 weeks. The primary efficacy endpoint of SVR12 was comparable between treatment groups. In the SOF+RBV group, the SVR12 rate was 67.2% compared to the SVR12 rate of 66.7% in the PEG+RBV group. The results of the protocol defined statistical analysis showed a difference of 0.3% between the two treatment groups, with a 95% confidence interval (CI) of -7.5 to 8.0%. The lower bound of the two-sided 95% CI for the difference between groups (SOF+RBV or PEG+RBV) was -7.5, demonstrating the non-inferiority of SOF+RBV versus (vs.) PEG+RBV. In the SOF+RBV group, HCV genotype 2 patients had higher SVR12 rates compared to HCV genotype 3 patients (95% vs. 56%, respectively). Within each genotype, relapse accounted for most treatment failures with HCV genotype 3 (relapse rate of 40%) compared to HCV genotype 2 (relapse rate of 5%).

POSITRON was a Phase III, randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of 12 weeks of SOF+RBV in patients with chronic genotype 2 or 3 HCV infection who were IFN intolerant, IFN ineligible, or unwilling to take IFN. A total of 278 patients were treated with SOF (400 mg)+RBV (1,000-2,000 mg) daily for 12 weeks or placebo for 12 weeks. The results showed that a significantly higher proportion of patients in the SOF+RBV group achieved SVR12 (77.8%; 95% CI: 71.5−83.2%) compared to placebo (0%; 95% CI: 0.0−5.1%) (p < 0.001). Although this population cannot take interferon and therefore had no available treatment options, this SVR can favorably be compared to historic treatment success rates for genotype 2 and 3 HCV infections. In this study HCV genotype 2 patients had higher SVR12 rates (93%) compared to HCV genotype 3 patients (61%).

FUSION was a Phase III, randomized, double-blind study that evaluated the efficacy and safety of 12 versus 16 weeks of SOF+RBV in treatment-experienced patients with chronic genotype 2 or 3 HCV infection and who had failed prior treatment with an IFN-based regimen. A total of 201 patients were treated with SOF (400 mg)+RBV (1,000-2,000 mg) daily for 12 weeks or SOF (400 mg)+RBV (1,000 or 2,000 mg) daily for 16 weeks. The SVR12 rates in the SOF+RBV 12 week group and the SOF+RBV 16 week group were 50% and 72.6%, respectively, compared to the historical rate of 25% (p<0.001). None of the patients in either treatment group had on-treatment virologic failure. Genotype 2 HCV-infected patients had similar SVR12 rates in the SOF+RBV 12 week and SOF+RBV 16 week groups (86.1% and 93.8%, respectively), whereas genotype 3 HCV-infected patients had higher SVR12 rates in the SOF+RBV 16 week group (61.9%) compared to the SOF+RBV 12 week group (29.7%). Within each treatment group, analyses of SVR12 by subgroup revealed similar SVR12 rates for the age, ethnicity, baseline body mass index, IL28B genotype, and response to prior HCV treatment subgroups. In both the SOF+RBV 12 week and SOF+RBV 16 week treatment groups, higher SVR12 rates were observed in genotype 2 HCV-infected patients compared to genotype 3 HCV-infected patients. Higher SVR12 rates were observed in female patients compared to male patients. In the SOF+RBV 12 week group, a higher SVR12 rate was observed in non-cirrhotic patients (60.9%) compared to cirrhotic patients (30.6%); this difference was less pronounced in the SOF+RBV 16 week group (76.2% vs. 65.6%).

Overall, the data obtained from the clinical studies demonstrated that the Sovaldi-containing regimens met their primary efficacy endpoints and had a favourable safety profile compared with historical and/or current standard-of-care regimens.

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

Clinical Safety

The clinical safety of Sovaldi was based on data from the pooled Phase III clinical studies (NEUTRINO, FISSION, POSITRON and FUSION) described in the Clinical Efficacy section. These studies included 566 patients who received SOF+RBV combination therapy for 12 weeks, 98 patients who received SOF+RBV combination therapy for 16 weeks, 327 patients who received SOF+PEG+RBV combination therapy for 12 weeks, 243 patients who received PEG+RBV for 24 weeks and 71 patients who received placebo for 12 weeks.

Overall, Sovaldi (400 mg/day) in combination with PEG+RBV and Sovaldi (400 mg/day) in combination with RBV was well-tolerated and provided effective treatment for genotype 1 and 4 CHC infection (NEUTRINO) and genotype 2 and 3 CHC infection (FISSION, POSITRON, FUSION).

In the study NEUTRINO, 304 patients (93.0%) had at least 1 treatment-emergent adverse event (TEAE). The 3 most frequently reported adverse events (AEs) assessed as related to study treatment were fatigue (56.3%, 184 patients), nausea (31.2%, 102 patients), and headache (30.9%, 101 patients). Four serious AEs (SAEs) were assessed as related to a study drug: anemia and cryoglobulinemia (both in one patient) and leukopenia and pyrexia (both in one patient). All of the TEAEs, AEs and SAEs are consistent with the expected safety profile of PEG+RBV treatment. There were no deaths reported in this study. Overall, the proposed regimen of SOF+PEG+RBV was well-tolerated and the safety profile is comparable to what would be seen for PEG and RBV alone for 12 weeks, despite the addition of Sovaldi 400 mg.

Across the clinical studies FISSION, POSITRON and FUSION, SOF + RBV regimens were generally safe and well-tolerated. The incidence of AEs leading to permanent discontinuation of treatment regimen was low in all SOF-containing regimens (0.0−1.5%) and lower than the incidence of AEs leading to permanent discontinuation of treatment regimen in the placebo group in POSITRON (4.2%) and PEG+RBV group in FISSION (10.7%). In the SOF+RBV groups, there were no AEs leading to permanent discontinuation of SOF+RBV that occurred in more than 1 patient. The three most frequently occurring AEs across all groups in the primary safety population were fatigue, headache, and nausea. The incidence of these events was higher in the PEG-containing groups (PEG+RBV or SOF+PEG+RBV), which was consistent with the expected safety profile of PEG+RBV treatment. Other than the expected AEs and laboratory abnormalities associated with RBV, the SOF+RBV 12 week and SOF+RBV 16 week groups had a safety profile similar to the placebo group. No additional AEs to the expected safety profile for RBV or PEG+RBV were identified in the SOF+RBV or SOF+PEG+RBV groups, respectively.

Appropriate warnings and precautions are in place in the approved Sovaldi Product Monograph to address the identified safety concerns.

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

Non-Clinical Basis for Decision

The non-clinical pharmacology and toxicology studies support the use of Sovaldi for the specified indication.

The effects of Sovaldi on the central nervous, cardiovascular, and respiratory systems were examined in a core battery of safety pharmacology studies. The results showed no undesirable pharmacodynamic effect of Sovaldi on physiological function at the therapeutic dose level.

A series of single-dose toxicity, repeat-dose toxicity, genotoxicity, reproductive and developmental toxicity, and local tolerance studies, as well as other specific toxicity studies were conducted to evaluate Sovaldi's toxic potential. The primary target organs identified were the cardiovascular, hepatobiliary, gastrointestinal (GI) and hematopoietic (erythroid) systems.

There are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Sovaldi 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.

The proposed limits of drug-related impurities are considered now adequately qualified (that is 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 Next link will take you to another Web site Food and Drug Regulations.

None of the excipients used in the manufacture of Sovaldi tablets are of human or animal origin.