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Daklinza Tablets 60 Mg [Non-Proprietary Name] Daclatasvir Hydrochloride (JAN*) [Name of Applicant] Bristol-Myers K.K

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Daklinza Tablets 60 Mg [Non-Proprietary Name] Daclatasvir Hydrochloride (JAN*) [Name of Applicant] Bristol-Myers K.K Report on the Deliberation Results June 26, 2014 Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau Ministry of Health, Labour and Welfare [Brand name] Daklinza Tablets 60 mg [Non-proprietary name] Daclatasvir Hydrochloride (JAN*) [Name of applicant] Bristol-Myers K.K. [Date of application] October 29, 2013 [Results of deliberation] In the meeting held on June 26, 2014, the Second Committee on New Drugs concluded that the product may be approved and that this result should be reported to the Pharmaceutical Affairs Department of the Pharmaceutical Affairs and Food Sanitation Council. The re-examination period is 8 years, the drug substance and the drug product are both classified as powerful drugs, and the product is not classified as a biological product or a specified biological product. *Japanese Accepted Name (modified INN) This English version of the Japanese review report is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA will not be responsible for any consequence resulting from the use of this English version. Review Report June 6, 2014 Pharmaceuticals and Medical Devices Agency The results of a regulatory review conducted by the Pharmaceuticals and Medical Devices Agency on the following pharmaceutical products submitted for registration are as follows. [Brand name] (a) Daklinza Tablets 60 mg (b) Sunvepra Capsules 100 mg [Non-proprietary name] (a) Daclatasvir Hydrochloride (b) Asunaprevir [Applicant] Bristol-Myers K.K. [Date of application] October 29, 2013 [Dosage form/Strength] (a) Each tablet contains 66 mg of Daclatasvir Hydrochloride (60 mg as Daclatasvir) (b) Each capsule contains 100 mg of Asunaprevir [Application classification] (1) Drug with a new active ingredient [Chemical structure] This English version of the Japanese review report is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA will not be responsible for any consequence resulting from the use of this English version. (a) Daclatasvir Hydrochloride Molecular formula: C40H50N8O6·2HCl Molecular weight: 811.80 Chemical name: DimethylN,N’-([1,1’-biphenyl]-4,4’-diylbis{1H-imidazole-5,2-diyl-[(2S)-pyrrolidine-2,1- diyl][(1S)-3-methyl-1-oxobutane-1,2-diyl]})dicarbamate dihydrochloride (b) Asunaprevir Molecular formula: C35H46ClN5O9S Molecular weight: 748.29 Chemical name: 1,1-Dimethylethyl{(2S)-1-[(2S,4R)-4-({7-chloro-4-methoxyisoquinolin-1-yl}oxy)-2- ({(1R,2S)-1-[(cyclopropanesulfonyl)carbamoyl]-2-ethenylcyclopropyl}carbamoyl) pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl}carbamate 3 [Items warranting special mention] Priority Review (Notification No. 1225-1 of Director of Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, MHLW, dated December 25, 2013) [Reviewing office] Office of New Drug IV 4 Review Results June 6, 2014 [Brand name] (a) Daklinza Tablets 60 mg (b) Sunvepra Capsules 100 mg [Non-proprietary name] (a) Daclatasvir Hydrochloride (b) Asunaprevir [Applicant] Bristol-Myers K.K. [Date of application] October 29, 2013 [Results of review] Based on the submitted data, the efficacy of the products in patients with chronic hepatitis C, or chronic hepatitis C with compensated cirrhosis has been demonstrated and their safety is acceptable in view of their observed benefits. As a result of its review, the Pharmaceuticals and Medical Devices Agency concluded that the products may be approved for the following indications and dosage and administration. [Indications] Improvement of viraemia in either of the following patients with chronic hepatitis C serogroup 1 (genotype 1), or chronic hepatitis C serogroup 1 with compensated cirrhosis: (1) patients who are treatment-naïve and ineligible for or who are intolerant of interferon-based therapy, or (2) patients who have failed to respond to interferon-based therapy. [Dosage and administration] [Daklinza Tablets 60 mg] The usual adult dosage is 60 mg of Daclatasvir orally administered once daily. Daklinza should be used in combination with Asunaprevir for a duration of 24 weeks. [Sunvepra Capsules 100 mg] The usual adult dosage is 100 mg of Asunaprevir orally administered twice daily. Sunvepra should be used in combination with Daclatasvir Hydrochloride for a duration of 24 weeks. 5 Review Report (1) April 23, 2014 I. Products Submitted for Registration [Brand name] (a) Daklinza Tablets 60 mg (b) Sunvepra Capsules 100 mg [Non-proprietary name] (a) Daclatasvir Hydrochloride (b) Asunaprevir [Name of applicant] Bristol-Myers K.K. [Date of application] October 29, 2013 [Dosage form/Strength] (a) Each tablet contains 66 mg of Daclatasvir Hydrochloride (60 mg as Daclatasvir) per tablet (b) Each capsule contains 100 mg of Asunaprevir per capsule [Proposed indications] Improvement of viraemia in either of the following patients with chronic hepatitis C serogroup 1 (genotype 1), or chronic hepatitis C serogroup 1 with compensated cirrhosis: ● patients who are treatment-naïve and ineligible for, or who are intolerant of interferon therapy, or ● patients who have failed to respond to interferon therapy. [Proposed dosage and administration] (a) The usual adult dosage is 60 mg of Daclatasvir orally administered once daily. Daklinza should be used in combination with Asunaprevir for a duration of 24 weeks. (b) The usual adult dosage is 100 mg of Asunaprevir orally administered twice daily. Sunvepra should be used in combination with Daclatasvir Hydrochloride for a duration of 24 weeks. II. Summary of the Submitted Data and Outline of Review A summary of the submitted data and the outline of a review by the Pharmaceuticals and Medical Devices Agency (PMDA) are as shown below. 1. Origin or background of discovery and usage conditions in foreign countries etc. Daclatasvir Hydrochloride (DCV) and Asunaprevir (ASV) are a selective hepatitis C virus (HCV) NS5A replication complex inhibitor and a selective HCV NS3/4A serine protease inhibitor, respectively, developed as treatments for HCV infection by Bristol-Myers Squibb Company and Bristol-Myers K.K. 6 There are estimated to be approximately 150 million people infected with HCV globally1) and 1.5 to 2 million in Japan.2),3) After the initial infection, 70% to 80% will become chronically infected and if the HCV infection is left untreated, liver fibrosis will progress slowly and develop into liver cirrhosis. Liver cirrhosis causes liver failure and furthermore, patients with liver cirrhosis are at high risk for hepatocellular carcinoma and it has been reported that the hepatocellular carcinogenesis rate in patients with chronic hepatitis C was 12.4% at the end of the 10th year4) and that the hepatocellular carcinogenesis rate in patients with cirrhosis infected with HCV was 53.9% after a mean observation period of 9.2 years.5) In Japan, approximately 70% of about 30,000 people who die of hepatocellular carcinoma each year are those infected with HCV6),7) and many of patients with chronic hepatitis C are elderly patients, who are at an increased risk of developing hepatocellular carcinoma.8) Currently in Japan, interferon (IFN) preparations, pegylated IFN (PegIFN) preparations, ribavirin (RBV) preparations, and HCV NS3/4A serine protease inhibitors (telaprevir and simeprevir sodium) have been approved as drugs for chronic hepatitis C to achieve viral clearance and the Japanese guidelines recommend a triple therapy of an HCV NS3/4A serine protease inhibitor and PegIFN/RBV.2) PegIFN/RBV combination therapy has been approved for the treatment of patients with HCV with compensated cirrhosis. However, even these therapies are not adequately effective in patients with chronic hepatitis C with previous treatment failure or patients with HCV with compensated cirrhosis. In addition, there are problems with the triple therapy of an HCV NS3/4A serine protease inhibitor and PegIFN/RBV: patients have to visit their physician weekly to receive PegIFN; dose reduction or discontinuation of PegIFN or RBV may be needed depending on the patient’s condition; and there are many patients who have difficulty tolerating side effects associated with the therapy. Especially, elderly patients and patients with comorbidities (hypertension, heart disease, psychiatric disorder, cytopenia, etc.) are difficult to treat with PegIFN/RBV combination therapy. Based on the above, there is a high medical need for new treatments in patients with chronic hepatitis C who are either IFN-ineligible or -intolerant, patients with chronic hepatitis C with previous treatment failure, and patients with HCV with compensated cirrhosis. Anti-HCV activity of a combination of DCV and ASV was determined in a non-clinical study, which demonstrated their combined effects. Foreign clinical studies showed that resistance mutations may emerge in patients with chronic hepatitis C treated with DCV or ASV alone, but each drug produced reductions in HCV RNA and there were no particular safety issues. Therefore, it was considered that the combination of DCV and ASV, which have different mechanisms of action, has an enhanced anti-viral effect, can offer a new treatment option to HCV-infected patients with no or poor response to current therapies, and reduces patients’ burden 1) http://www.who.int/mediacentre/factsheets/fs164/en/ (April 2014) 2) Drafting Committee for Hepatitis Management Guidelines, the Japan
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