Report on the Deliberation Results March 4, 2014 Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau Ministry of Health, Labour and Welfare [Brand name] Avigan Tablet 200 mg [Non-proprietary name] Favipiravir (JAN*) [Applicant] Toyama Chemical Co., Ltd. [Date of application] March 30, 2011 [Results of deliberation] In the meeting held on February 3, 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, and the drug substance and the drug product are both classified as powerful drugs. The product is not classified as a biological product or a specified biological product. Some changes to the conditions for approval were decided in the course of the deliberation. The revised conditions for approval are as follows: [Conditions for approval] 1. The applicant is required to conduct a pharmacokinetic study in accordance with the approved dosage and administration in Japan, and submit the study data and analysis results immediately after the completion of the study and within 1 year after the date of the marketing approval. 2. The applicant is required to conduct a clinical study of the product in patients with seasonal influenza virus infection to verify the efficacy and confirm the safety, and to submit the study data and analysis results immediately after the completion of the study. 3. The applicant must not manufacture the product without the request of the Minister of Health, Labour and Welfare, unless the study data and analysis results specified in the above 1 and 2 are submitted and necessary actions are taken accordingly. 4. The applicant is required to establish a strict distribution management system, and take thorough safety measures in order to ensure that the product is not used in patients with seasonal influenza virus infection, even when the product is to be marketed. 5. The applicant is required to take strict and proper measures in order to ensure that the product is not administered to patients unless each individual patient, who is judged to be eligible for its use, or his/her family member is informed of the efficacy and risk of the product in writing and their written informed consent is obtained prior to the start of treatment. *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 January 23, 2014 Pharmaceuticals and Medical Devices Agency The results of a regulatory review conducted by the Pharmaceuticals and Medical Devices Agency on the following pharmaceutical product submitted for registration are as follows. [Brand name] Avigan Tablet 200 mg [Non-proprietary name] Favipiravir [Applicant] Toyama Chemical Co., Ltd. [Date of application] March 30, 2011 [Dosage form/Strength] Film-coated tablets: Each tablet contains 200 mg of favipiravir. [Application classification] Prescription drug, (1) Drug with a new active ingredient [Chemical structure] O F N NH2 N OH Molecular formula: C5H4FN3O2 Molecular weight: 157.10 Chemical name: 6-Fluoro-3-hydroxypyrazine-2-carboxamide [Items warranting special mention] Priority Review (Notification No. 0630-1 from the Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, MHLW, dated June 30, 2011) [Reviewing office] Office of New Drug IV 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 Results January 23, 2014 [Brand name] Avigan Tablet 200 mg [Non-proprietary name] Favipiravir [Applicant] Toyama Chemical Co., Ltd. [Date of application] March 30, 2011 [Results of review] Based on the submitted data, the Pharmaceuticals and Medical Devices Agency (PMDA) considers that the efficacy of Avigan (favipiravir) in patients with seasonal influenza A or B virus infection has not been confirmed, and only the clinical efficacy has been suggested in the US. Favipiravir, however, has a mechanism of action different from those of the approved influenza antiviral drugs, and is expected to have an antiviral activity against avian influenza A (H5N1) and A (H7N9) viruses, which has only been demonstrated by non-clinical data. In light of the recent outbreaks of influenza infection, therefore, it is of significance to make favipiravir available for patients with novel or re-emerging pandemic influenza virus infection in whom other influenza antiviral drugs are ineffective or not sufficiently effective, and in whom the efficacy of favipiravir can be expected. PMDA has concluded that it is meaningful to approve Avigan (favipiravir) for the indication of treatment of patients with novel or re-emerging pandemic influenza virus infection on the premise that post-marketing requirements are imposed on the approval as the risk control measures, which include the following conditions: (1) a clinical study should be conducted immediately after the approval in consideration that the efficacy of favipiravir against seasonal influenza virus infection has not been confirmed, that favipiravir has the risk of teratogenicity, etc., and that the proposed dosage and administration are set mainly based on the foreign clinical study data while the dosage regimen has not been studied in Japan; (2) favipiravir must not be administered to patients unless each individual patient, who is judged to be eligible for its use, or his/her family is informed of the efficacy and risk of favipiravir in writing and their written informed consent is obtained prior to treatment with favipiravir; and (3) a strict distribution management system and thorough safety measures should be in place to ensure that favipiravir is not used in patients with seasonal influenza virus infection. As a result of its regulatory review, PMDA has concluded that, at the current stage, it is meaningful to approve the product for the indication and the dosage and administration as shown below, with the following conditions. [Indication] Treatment of novel or re-emerging pandemic influenza virus infections (limited to cases in which other influenza antiviral drugs are ineffective or not sufficiently effective). [Dosage and administration] The usual adult dosage is 1600 mg of favipiravir administered orally twice daily on Day 1, followed by 600 mg orally twice daily from Day 2 to Day 5. The total treatment duration should be 5 days. [Conditions for approval] 1. The applicant is required to conduct a pharmacokinetic study in accordance with the approved dosage and administration in Japan, and submit the study data and analysis results immediately after the completion of the study. 3 2. The applicant is required to conduct a clinical study of the product in patients with seasonal influenza virus infection to verify the efficacy and confirm the safety, and to submit the study data and analysis results immediately after the completion of the study. 3. The applicant is required to establish a strict distribution management system, and take thorough safety measures in order to ensure that the product is not used in patients with seasonal influenza virus infection. 4. The applicant is required to take strict and proper measures in order to ensure that the product is not adminitered to patients unless each individual patient, who is judged to be eligible for its use, or his/her family member is informed of the efficacy and risk of the product in writing and their written informed consent is obtained prior to the start of treatment. 4 Review Report (1) October 6, 2011 I. Product Submitted for Registration [Brand name] Avigan Tablet 200 mg [Non-proprietary name] Favipiravir [Applicant] Toyama Chemical Co., Ltd. [Date of application] March 30, 2011 [Dosage form/Strength] Film-coated tablets: Each tablet contains 200 mg of favipiravir. [Proposed indication] Influenza A or B virus infection [Proposed dosage and administration] The usual adult dosage is 1200 mg of favipiravir administered orally as the initial dose and 400 mg as the second dose on Day 1, followed by 400 mg orally twice daily from Day 2 to Day 5. II. Summary of the Submitted Data and Outline of the Review by the Pharmaceuticals and Medical Devices Agency 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 history of discovery and usage conditions in foreign countries etc. Favipiravir is a new antiviral drug against influenza discovered by Toyama Chemical Co., Ltd. Favipiravir is metabolized into favipiravir ribosyl triphosphate (favipiravir RTP) by an intracellular enzyme, and favipiravir RTP selectively inhibits RNA polymerase (RNA-dependent RNA polymerase) of the influenza virus, preventing replication of the influenza virus. Influenza virus is classified into the 3 types A, B, and C, and of these, 2 strains of type A (H1N1, H3N2) and type B have epidemically spread in recent years. In addition, animal influenza viruses, especially, avian and swine viruses may become infectious to humans through gene mutation or recombination, leading to a rapid spread of infection from human to human. Such a mutated virus is called a pandemic influenza virus. Outbreaks of pandemic influenza virus infection occur once every decade to several decades. The circumstances surrounding influenza are changing every moment; in 2009, the outbreak of pandemic H1N1 influenza virus infection was confirmed in the American Continent, and human infection cases of highly pathogenic avian influenza A (H5N1) virus have been reported worldwide since 2003.