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Safety and Efficacy of Fimasartan with Essential Hypertension Patients In 2018;26(3):118-127 TCP Transl Clin Pharmacol https://doi.org/10.12793/tcp.2018.26.3.118 Safety and efficacy of fimasartan with essential hypertension patients in real world clinical practice: data from a post marketing surveillance in Korea Su-Eun Han, Seung Hee Jeong, Hye Jeong Kang, Myung Sook Hong, Eunah Paek, Hijung Cho and Seong Choon Choe* Seoul Research Institute, Boryung Pharmaceutical Co., Ltd., Seoul 03127, Republic of Korea *Correspondence: S. C. Choe; Tel: +82-2-708-8020, Fax: +82-2-740-4160, E-mail: [email protected] The safety and efficacy of fimasartan have been evaluated through post-marketing surveillance P Received 29 Jun 2018 in real world clinical practice. The multi-center, prospective, open-label and non-interventional M Revised 13 Aug 2018 S R study. A total of 3,945 patients (3,729 patients for safety assessment and 3,473 patients for efficacy Accepted 14 Aug 2018 EP assessment) were screened in patients with essential hypertension in 89 study centers from 9 Sep- ORT Keywords tember 2010 through 8 September 2016. Among the total patients, 2,893 patients (77.6%) were Fimasartan, administered fimasartan for 24 weeks or longer and were classified as 'patients with long-term Post marketing surveillance, Safety, follow-up', and the additional safety and efficacy analysis were performed. The improvement was defined as systolic blood pressure (SBP) controlled to ≤ 140 mmHg or decreased SBP differences ≥ pISSN: 2289-0882 eISSN: 2383-5427 20 mmHg after treatment or diastolic blood pressure (DBP) controlled to ≤ 90 mmHg or decreased DBP differences ≥ 10 mmHg after treatment. Adverse drug reactions (ADRs) were reported in 3.8% patients; dizziness, and hypotension were the most frequently reported ADRs in total patients. The results of patients with long-term follow-up were comparable with total patients. The overall improvement rate in all efficacy assessment at the last visit was 87.1% (3,025/3,473 patients). The overall improvement rate of the patients with long-term follow-up was 88.9%. Fimasartan was well tolerated, with no new safety concerns identified and an effective treatment in the real world clinical practice for Korean patients with hypertension. Introduction people out of the world population and the loss of 92 million Hypertension is a risk factor of cardiovascular diseases af- disability-adjusted life years were affected by hypertension, and fecting a population of more than 1 billion throughout the 54% of stroke and 47% of ischemic heart diseases were caused world and is a serious disease directly and indirectly causing by hypertension.[1] It was confirmed in Korean studies that the death of young adults and the middle-aged who are ac- hypertension is a factor related to stroke and transient ischemic tive in economic activities as well as the elderly. According to attack or a risk factor of death from cardiovascular diseases.[2- the study of Lawes, et al., the ‘premature death’ in 7.6 million 4] Also, WHO predicted that the cardiovascular diseases caused by hypertension or other risk factors would become the world's Copyright © 2018 Translational and Clinical Pharmacology It is identical to the Creative Commons Attribution Non-Commercial License number 1 cause of death by 2020.[5] Therefore, the purpose of (http://creativecommons.org/licenses/by-nc/3.0/). hypertension treatment is to reduce the morbidity and mortal- This paper meets the requirement of KS X ISO 9706, ISO 9706-1994 and ity rates of cardiovascular diseases. ANSI/NISO Z.39.48-1992 (Permanence of Paper). Typical antihypertensive agents include beta-blockers, renin Reviewer inhibitors, angiotensin converting enzyme inhibitor (ACEI), This article reviewed by peer experts who are not TCP editors. angiotensin II receptor blocker (ARB), calcium channel blocker 118 Vol. 26, No.3, Sep 15, 2018 Su-Eun Han, et al. TranslTCP Clin Pharmacol (CCB), diuretics, etc. These therapeutic agents are all employing istration (patients who have hypersensitivity to fimasartan or the principle of blocking the physiological mechanism causing any of the ingredients contained in fimasartan, pregnant or hypertension, and demonstrate antihypertensive effect. ACEIs breast-feeding women, patients on renal dialysis, patients with have played an important role in the treatment of hypertension moderate to severe hepatic impairment, patients with biliary and heart failure for the past 10 years or so, but their use has atresia, patients with a genetic condition such as galactose intol- been limited due to well-known side effects such as dry cough erance or glucose-galactose malabsorption, patients with dia- and angioedema. These side effects are believed to be caused by betes or moderate to severe renal impairment (GFR < 60 mL/ the inhibition of the metabolism of bradykinin and substance P min/1.73m2), or patients with diabetic nephropathy who are in addition to the inhibition of the generation of angiotensin II taking angiotensin-converting enzyme (ACE) inhibitors) were by ACE inhibitors.[6-8] Out of two types of typical receptors of excluded. angiotensin II, ARB drugs selectively block AT1 receptor which Patients were to receive once daily fimasartan 30 mg to 60 was confirmed to mediate most of the actions by angiotensin mg at the same time each day if possible (e.g., in the morning) II such as vasoconstriction and secretion of aldosterone and with or without having a meal and if the blood pressure was not have less side effects of ACE inhibitors, so they are being widely regulated well at this dose, fimasartan was increased up to once used recently. It has proved to be clinically effective not only on daily 120 mg. Considering that "MFDS Notification No. 2010- hypertension but also on kidney diseases and heart failure of 94" specifies the total number of patients as 3,000, this study has patients with type 2 diabetes. set a goal to make assessment on more patients than the speci- Fimasartan, the ninth and latest ARB, was approved for the fied number. Although, antihypertensive agents are normally treatment of hypertension by the Ministry of Food and Drug administered for an extended period of time of 24 weeks or lon- Safety (MFDS) on September 9, 2010. Fimasartan, a pyrimidin- ger, investigation on long-term use was performed in approxi- 4(3H)-one derivative of losartan with the imidazole ring re- mately 15% or more of the total patients. Patients who received placed, which enables higher potency and longer duration than the fimasartan for 24 weeks or longer were classified as patients losartan.[9] with long-term follow-up. A total of 5 clinical studies have performed for fimasartan in patients with hypertension - phase IIa and phase IIb study,[10] Measurements ambulatory blood pressure monitoring (ABPM) study,[11] This study had following items to be evaluated regarding de- phase III active-controlled study,[12] and phase IIIb study[13] - mographic characteristics, drug administration status, safety, and demonstrated the clinical efficacy of fimasartan. This post- and efficacy. marketing surveillance data was reported to MFDS on Decem- The demographic data were collected for study center, sex, ber 7, 2016 and updated to product information on August 18, age, and BMI of patients. The date of diagnosis and duration 2017. The objective of this article is to provide an evaluation of of disease regarding medical history of hypertension and other the clinical utility of fimasartan in the treatment of patients with diseases, and presence of hepatic or renal impairment were hypertension from the results of this post-marketing surveil- investigated. For administration conditions of fimasartan, num- lance. ber of daily administrations, duration of administration, treat- ment compliance, change in dose and reason for dose change, Methods etc. were investigated. Efficacy assessment was conducted based on the blood pressure measured at each visit and by classifying Study design efficacy by 'clinical symptoms' and 'overall improvement rate' This was multi-center, prospective, open-label and non- at the last visit. Clinical symptoms were categorized as either interventional study. The study was approved by the respective 'Improved', 'Worsened', or 'Unchanged'. Clinical symptom was Institutional Review Boards. The data was collected across 89 assessed as 'Improved' if any of the followings was met: 1) post- centers in Korea from September 9, 2010 to September 8, 2016. dose DBP decreased ≥ 10 mmHg from pre-dose: 2) post-dose The objective of the study was to evaluate the safety and efficacy DBP regulated to a normal blood pressure of ≤ 90 mmHg: 3) of fimasartan (Kanarb®, Boryung pharmaceutical Co., Ltd) as post-dose SBP decreased by ≥ 20 mmHg from pre-dose: or 4) an antihypertensive therapy during a planned treatment and post-dose SBP regulated to a normal blood pressure of ≤ 140 observation period for at least 8 weeks. mmHg. In addition, if the blood pressure was increased after administration of fimasartan, it was defined as 'Worsened' while Study patients any case that fell under neither 'Improved' nor 'Worsened' was This study enrolled all patients sequentially and thoroughly defined as 'Unchanged'. who received fimasartan and provided consent to participation For the decision on the overall improvement rate at the last in this study in outpatients or hospitalized patients who had visit of each patient, it was assessed as 'Improved' if blood pres- the indication (essential hypertension) of fimasartan. However, sure lowering effect was observed after treatment, as 'Unim- those patients who were prohibited from fimasartan admin- proved' if not included in the improved range or worsened, or as 119 Vol. 26, No.3, Sep 15, 2018 Post marketing surveillance of fimasartan in Korea TCPTransl Clin Pharmacol 'Unassessible' if cannot be evaluated compared to pre-treatment the safety analysis set was defined as the patients who received status. at least one dose of fimasartan and had safety follow-up (phone The safety assessment including the incidence of any adverse call, letter, e-mail, request for additional visit, etc.) completed.
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