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Report on the Deliberation Results December 10, 2013 Evaluation And Report on the Deliberation Results December 10, 2013 Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau Ministry of Health, Labour and Welfare [Brand name] Adempas Tablets 0.5 mg, 1.0 mg, 2.5 mg [Non-proprietary name] Riociguat (JAN*) [Applicant] Bayer Yakuhin, Ltd. [Date of application] May 17, 2013 [Results of deliberation] In the meeting held on November 29, 2013, the First 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 of the product is 10 years. Both the drug substance and the drug product are classified as powerful drugs, and the drug product is not classified as a biological product or a specified biological product. [Conditions for approval] The applicant is required to conduct a drug use-results survey involving all treated patients after the market launch until data from a certain number of patients have been accumulated in order to grasp the characteristics of patients treated with this product, since the product has been studied only in a limited number of patients in Japan; and at the same time, safety and efficacy data on the product should be collected without delay and necessary measures should be taken to facilitate the proper use of the 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 November 19, 2013 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] Adempas Tablets 0.5 mg, 1.0 mg, 2.5 mg [Non-proprietary name] Riociguat [Applicant] Bayer Yakuhin, Ltd. [Date of application] May 17, 2013 [Dosage form/Strength] A film-coated tablet containing 0.5, 1.0, or 2.5 mg of Riociguat [Application classification] Prescription drug (1) Drug with a new active ingredient [Chemical structure] Molecular formula: C20H19FN8O2 Molecular weight: 422.42 Chemical name: Methyl N-(4,6-diamino-2-{1-[(2-fluorophenyl)methyl]-1H- pyrazolo[3,4-b]pyridin-3-yl}pyrimidin-5-yl)-N-methylcarbamate [Items warranting special mention] Orphan drug (Notification No. 0908-6 from the Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, MHLW, dated September 8, 2011) [Reviewing office] Office of New Drug II 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 November 19, 2013 [Brand name] Adempas Tablets 0.5 mg, 1.0 mg, 2.5 mg [Non-proprietary name] Riociguat [Applicant] Bayer Yakuhin, Ltd. [Date of application] May 17, 2013 [Results of review] Based on the submitted data, it is concluded that the efficacy of the product in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or those with postoperative persistent or recurrent CTEPH has been demonstrated and its safety is acceptable in view of its observed benefits. The safety in patients with systolic blood pressure of <95 mmHg, in patients with renal impairment, and in patients with hepatic impairment should be investigated via post-marketing surveillance etc. As a result of its regulatory review, the Pharmaceuticals and Medical Devices Agency has concluded that the product may be approved for the indication and the dosage and administration as shown below, with the following conditions. [Indication] Inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or postoperative persistent or recurrent CTEPH [Dosage and administration] Dose titration period The usual initial dosage for adults is 1.0 mg of Riociguat administered orally 3 times daily. If the systolic blood pressure remains at ≥95 mmHg for 2 weeks and the patient shows no signs or symptoms of hypotension, the dose should be increased by 0.5 mg at 2-week intervals up to the maximum daily dose of 2.5 mg 3 times daily. If the systolic blood pressure is <95 mmHg but the patient shows no signs or symptoms of hypotension, the current dose should be maintained. If the patient shows any signs or symptoms of hypotension, the dose should be reduced by 0.5 mg 3 times daily. Dose maintenance period The dose determined during the dose titration period should be maintained. The maximum daily dose is 2.5 mg 3 times daily during the dose maintenance period as well. If not tolerated (e.g., occurrence of signs or symptoms of hypotension), the dose should be reduced by 0.5 mg 3 times daily. [Conditions for approval] The applicant is required to conduct a drug use-results survey involving all treated patients after the market launch until data from a certain number of patients have been accumulated in order to grasp the characteristics of patients treated with this product, since the product has been studied only in a limited number of patients in Japan; and at the same time, safety and efficacy data on the product should be collected without delay and necessary measures should be taken to facilitate the proper use of the product. 3 Review Report (1) October 11, 2013 I. Product Submitted for Registration [Brand name] Adempas Tablets 0.5 mg, 1.0 mg, 2.5 mg [Non-proprietary name] Riociguat [Name of applicant] Bayer Yakuhin, Ltd. [Date of application] May 17, 2013 [Dosage form/Strength] A film-coated tablet containing 0.5, 1.0, or 2.5 mg of Riociguat [Proposed indication] Inoperable or postoperative persistent or recurrent chronic thromboembolic pulmonary hypertension [Proposed dosage and administration] Dose titration period The usual initial dosage in adults is 1.0 mg of Riociguat administered orally 3 times daily (with a dosing interval of approximately 6-8 hours) for 2 consecutive weeks. If the systolic blood pressure remains at ≥95 mmHg and the patient shows no signs or symptoms of hypotension, the dose should be increased by 0.5 mg at 2-week intervals up to the maximum daily dose of 2.5 mg 3 times daily. If the systolic blood pressure is <95 mmHg but the patient shows no signs or symptoms of hypotension, the current dosage should be maintained. If the patient shows any signs or symptoms of hypotension, the dose should be reduced by 0.5 mg 3 times daily. Dose maintenance period The dose determined during the dose titration period should be maintained. The maximum daily dose is 2.5 mg 3 times daily during the dose maintenance period as well. If the dose is not tolerated (e.g., occurrence of signs or symptoms of hypotension), the dose should be reduced. In the case that a dose is missed, the patient should continue with the next dose as scheduled. After dose interruption If the treatment is interrupted for 3 days or longer, the oral dose of riociguat should be resumed at 1.0 mg 3 times daily and the dose level should be continued for 2 weeks. Thereafter, the dose should be adjusted according to the procedure as described above. II. Summary of the Submitted Data and Outline of Review by Pharmaceuticals and Medical Devices Agency The data submitted in this application and the outline of 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. Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by chronic stenosis/obstruction of the pulmonary arterial lumen due to the organized thrombus and resultant increase in pulmonary vascular resistance, presenting with clinical symptoms such as exertional breathlessness. It is reported that, in CTEPH, the nitric oxide (NO)-soluble guanylate cyclase 4 (sGC)-cyclic guanosine monophosphate (cGMP) signal transduction pathway is blocked by chronic pulmonary vascular disorder, resulting in a decreased cGMP concentration. sGC is activated by NO, resulting in an increase in cGMP concentration within vascular smooth muscle cells and platelets. Riociguat increases cGMP concentration by directly stimulating and activating sGC, and is therefore expected to be effective in CTEPH. Development of riociguat as a therapeutic agent for CTEPH and for pulmonary arterial hypertension (PAH), a disease with clinical characteristics similar to those of CTEPH, was initiated by Bayer HealthCare (Germany) in 1997, and the application was submitted for approval in February 2013 in Europe and the US with the proposed indications for inoperable or post- operative persistent or recurrent CTEPH and PAH. As of September 2013, riociguat is approved in Canada with the indication for CTEPH. In Japan, development of riociguat tablets (the drug product) was initiated by Bayer Yakuhin, Ltd. in 2006. Based on the results from global clinical studies in which Japanese patients also participated, a marketing application of riociguat with the proposed indication of “inoperable or postoperative persistent or recurrent chronic thromboembolic pulmonary hypertension” has now been filed. An application for the indication of PAH is scheduled to be submitted. 2. Data relating to quality 2.A Summary of the submitted data 2.A.(1) Drug substance 2.A.(1).1) Characterization The drug substance is a white to yellowish crystalline powder. The determined general properties include description, specific rotation, pH, dissociation constant (pKa), partition coefficient, hygroscopicity, density, solubility, melting point, particle size, and crystalline polymorphism.
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