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1 한국임상약학회지제 29 권제 2 호 Korean J Clin Pharm, Vol. 29, No. 2, 2019 Case Report Korean Journal of Clinical Pharmacy Official Journal of Korean College of Clinical Pharmacy pissn eissn X Korean journal of clinical pharmacy (Online) URL: Atorvastatin/ezetimibe 복합제복용후발생한시야결손부작용사례보고 김지윤 1 이경규 1 김준영 1 이정민 2 김나영 2 이모세 2 지은희 1 * 1 가천대학교약학대학, 2 대한약사회지역의약품안전센터 (2019년 5월 20일접수 2019년 5월 31일수정 2019년 6월 8일승인 ) Visual Field Defect after Taking Atorvastatin/Ezetimibe, a Case Study Jiyoon Kim 1, Kyunggyu Lee 1, Junyoung Kim 1, Jung-Min Lee 2, Na-Young Kim 2, Mo-Se Lee 2, and Eunhee Ji 1 * 1 College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea 2 Regional Pharmacovigilance Center, Korean Pharmaceutical Association, Seoul 06708, Republic of Korea (Received May 20, 2019 Revised May 31, 2019 Accepted June 8, 2019) ABSTRACT Atorvastatin is one of the most widely prescribed medications for dyslipidemia treatment. In Korea, post combined therapy with ezetimibe, a 73-year-old woman was reported by a community pharmacy to have experienced visual field defect, which recovered after drug discontinuation. She had never experienced this symptom before, and several studies have reported an association between use of statins and visual disorders such as blurred vision, diplopia, and cataract. Blockage of cholesterol accumulation, oxidative stress, or myopathy is expected to be a cause of this symptom. Naranjo scale, Korean causality assessment algorithm (Ver.2), and World Health Organization-Uppsala Monitoring Center (WHO-UMC) criteria were the three tools used to determine causality between the visual disorder and atorvastatin. The results represent probable, certain, and probable/likely causality, respectively. Our results, in combination with a review of literature, indicate that ocular adverse effects are highly likely related to atorvastatin. KEY WORDS: Atorvastatin, visual field defect, adverse drug reaction, causality assessment Atorvastatin은혈중의콜레스테롤생성을억제하여고지혈증을치료하는데쓰이는 HMG-CoA 환원효소억제제계열의지질저하제이다. 미국에서의처방전발행순위가 2013년 7위, 2014년 5위, 2015년 3위, 2016년 3위로 1) 전세계적으로사용량이많은약물이다. 우리나라와미국 Food and Drug Administration (FDA) 의승인적응증에는관상동맥심질환의다중위험요소가있는성인환자의심혈관계질환의예방, 원발성고콜레스테롤혈증 ( 이형접합가족형및비가족형 ), 복합형이상지질혈증 (Fredrickson Type IIa 및 IIb) 등과같은다양한질환들이있다. 2) 최근에는 atorvastatin과 ezetimibe의복합제가시판되고있다. Atorvastatin/ezetimibe 복합제는 atorvastatin을단독으로사용할때보다중성지방과총콜레스테롤감소효과가빠르고, 3) 저밀도콜레스테롤, 고밀도콜레스테롤, high-sensitivity C-reactive protein (hs-crp) 수치를보다개선시킬수있다고한다. 4) Atorvastatin의임상시험및시판후조사에기초한이상반응으로감염 (infection), 소화불량 (indigestion), 설사 (diarrhea), 인후두통증 (laryngopharynx pain), 두통 (headache), 근골격계통증 (musculoskeletal pain), 알레르기반응 (allergic reaction) 등이 자주 ( 1/1,00, <1/10) 발생하고, 무력감 (helplessness), 피로 (fatigue), 저혈당증 (hypoglycemia), 복통 (stomachache), 구토 (vomit), 불면증 (insomnia), 어지러움 (giddiness), 횡문근융해 (rhabdomyolysis), 시야흐림 (blurred vision), 이명 (ear noise) 등이 때때로 ( 1/1,000, <1/100) 발생하며, 그외에혈소판감소증 (thrombocytopenia), 아나필락시스 (anaphylaxis), 시각장애 (visual impairment), 혈관신경성부종 (angioneurotic edema) 등이 드물게 ( 1/10,000, <1/1,000) 발생하는것으로보고되었다. 2) 본연구에서는 atorvastatin과 ezetimibe 복합제를복용한이후발생한시야흐림사례를보고하고, 그인과관계를 Naranjo 지표, 한국형인과성평가알고리즘 (Ver.2), 그리 *Correspondence to: Eunhee Ji, College of Pharmacy, Gachon University, 191 Hambakmoe-ro, Yeonsu-gu, Incheon 21936, Republic of Korea Tel: , Fax: ehji@gachon.ac.kr 133

2 134 / Korean J Clin Pharm, Vol. 29, No. 2, 2019 고 World Health Organization-Uppsala Monitoring Center (WHO-UMC) 기준을통하여분석해보고자한다. 증례보고 73세여성이이상지질혈증치료를위하여 2016년 6월부터 pitavastatin 2 mg을하루에한번씩복용하였다. 2018년 12월 31일 pitavastatin 대신 atorvastatin/ezetimibe 10/10 mg으로처방을변경하였는데, 변경된약을복용한이틀뒤시야가보이지않는징후가나타났다. 이로인하여다시 pitavastatin으로처방을변경하였으며, 이후시야는정상적으로회복되었다. 이전에어떠한이유로든시야가흐려진경우는없었다고한다. 환자의시야관련징후는담당의사가신체검사를통해확인하였다. 이환자는 2016년 6월에고혈압을동시에진단받았으며, 그치료를위하여 amlodipine 5 mg을하루에한번씩복용하고있다. 고혈압과이상지질혈증을제외하면다른질병없이건강한편이며, statin과 amlodipine 이외에복용하는약물이나건강기능식품은없다고한다. 인과성평가의약품부작용용어국제표준분류체계인 World Health Organization-Adverse Reaction Terminology (WHO-ART) 기준에따르면환자에게발생한이상반응은시야결손 (visual field defect) 으로분류된다. Atorvastatin/ezetimibe과 amlodipine 의각각의부작용과약물상호작용을확인해보면 atorvastatin 의경우때때로시야흐림과드물게시각장애가나타나고, amlodipine은시각이상부작용이있으며 ezetimibe는시야관련부작용에대해보고된바가없었다. 세성분간약물상호작용은보고된바없었다. Amlodipine도시각이상부작용을발생시킬수는있지만증례보고에의하면환자가오랫동안 amlodipine을복용하였으며그동안에시야가흐려진경우가없다고하였으므로, 위보고에서나타난시야결손은 atorvastatin 에의한것으로추측된다. 따라서 Naranjo 지표, 한국형인과성평가알고리즘 (Ver.2), 그리고 WHO-UMC 기준에따라상기환자의시야결손과 atorvastatin 간의인과성평가를수행하였다. 먼저 Naranjo 알고리즘에따르면, 의심되는약제가해당이상반응을나타냈다고보고된바있고 (+1) 의심되는약제를투여한후이상반응이나타났으며 (+2), 복용을중단한후다시이상반응이사라졌고 (+1) 이이상반응에다른원인이있다고보기힘들기때문에 (+2) 총 6점으로 확실함 (probable) 으로평가되었다 (Table 1). 한국형인과성평가알고리즘 (Ver.2) 에따르면, 약물투여와이상사례사이에선후관계가합당하고 (+3), 투여를중단한후증상이사라지며호전되었고 (+3), 의심약물과상호작용으로설명이가능하며 (+2), 비약물요인으로는이상사례가설명되지않고 (+1) 해당이상사례가의심약물의허가사항에반영되어있기때문에 (+3) 총 12점으로본이상사례와약물간의인과성은 확실함 (certain) 으로평가되었다 (Table 2). 마지막으로 WHO-UMC 기준에따르면의심약물과이상사례의발생간시간적관계가합당하고그외에다른원인이있다고보기어려우며복용을중단했을때증상이호전되었으므로 Table 3에서와같이본이상사례와약물간의인과성은 상당히확실함 (probable/likely) 으로평가된다. 고찰 이상의인과성평가에따르면본증례보고에서환자가겪은시야결손은 atorvastatin에의한약물이상반응으로판단되는데, FDA와 Adverse Drug Reaction Advisory Committee (ADRAC) 에따르면 atorvastatin 뿐만아니라 fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin과같은 statin Table 1. Causality assessment using Naranjo scale Question Answer Score Are there previous conclusive reports on this reaction? Yes +1 Did the adverse event appear after the suspected drug was administered? Yes +2 Did the adverse reaction improve when the drug was discontinued, or a specific antagonist was administered? Yes +1 Did the adverse reaction reappear when the drug was re-administered? Do not know 0 Are there alternative causes (other than the drug) that could on their own have caused the reaction? No +2 Did the reaction reappear when a placebo was given? Do not know 0 Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? Do not know 0 Was the reaction more severe when the dose was increased or less severe when the dose was decreased? Do not know 0 Did the patient have a similar reaction to the same or similar drugs in any previous exposure? No 0 Was the adverse event confirmed by any objective evidence? Do not know 0 Total score +6 Causality evaluation Probable Highly Probable: 9, Probable: 5-8, Possible: 1-4, Doubtful: 0

3 Atorvastatin/Ezetimibe 복합제복용후발생한시야결손부작용사례보고 / 135 Table 2. Causality assessment using Korean causality assessment algorithm (Ver.2) Chronological relationship Dose reduction or discontinuation Past ADR history Question Answer Score Is there any information on chronological relationship Appropriate chronological relationship +3 of the suspected drug and ADR? Is there any information on dose reduction or discontinuation? Have you ever experienced ADR with the same or similar drug? Clinical improvement after dose reduction or discontinuation No information 0 Concomitant medication Is there any information on drugs being taken concomitantly? Explain with interaction with suspicious drug +2 Non-drug cause Is there any information on non-drug cause? Cannot explain ADR with non-drug cause +1 Any known information on the suspected drug Is there any information on the suspected drug? Indicated in approved materials by MFDS +3 Re-administration Is there any information on re-administration? No re-administration 0 Specific tests Certain: 12, Probable: 6-11, Possible: 2-5, Unlikely: 1 Specific tests such as plasma drug concentration monitoring? No information 0 Total score +12 Causality evaluation Certain +3 Table 3. Causality assessment using WHO-UMC criteria Causality term Certain Probable/likely Possible Unlikely Conditional/ Unclassified Unassessable/ Unclassifiable Assessment criteria Event or laboratory test abnormality, with plausible time relationship to drug intake Cannot be explained by disease or other drugs Response to withdrawal plausible (pharmacologically, pathologically) Event definitive pharmacologically or phenomenologically Rechallenge satisfactory, if necessary Event or laboratory test abnormality, with reasonable time relationship to drug intake Unlikely to be attributed to disease or other drugs Response to withdrawal clinically reasonable Rechallenge not required Event or laboratory test abnormality, with reasonable time relationship to drug intake Could also be explained by disease or other drugs Information on drug withdrawal may be lacking or unclear Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) Disease or other drugs provide plausible explanations Event or laboratory test abnormality More data for proper assessment needed, or Additional data under examination Report suggesting an adverse reaction Cannot be judged because information is insufficient or contradictory Data cannot be supplemented or verified World Health Organization-Uppsala Monitoring Center, WHO-UMC 계열약물들은공통적으로시야흐림, 시각장애, 시각적예민도감소 (reduced visual acuity), 안구출혈 (hemophthalmia), 시야결손 (visual field defect) 등과같은다양한눈관련부작용을유발할수있다고한다. 그러나각 statin을상호비교하였을때다른 statin 계열약물들의 odds ratio (OR) 는 atorvastatin의 0.6~0.7으로더낮았고, statin 계열약물을복용한군의전체평균 (1.8%) 에비해 atorvastatin을복용한군 (2.1%) 에서눈의 이상반응이더많이나타났기때문에 atorvastatin이다른 statin 계열약물보다눈관련부작용을일으킬가능성이더높다는것을알수있었다. 5) 호주의 Therapeutic Goods Administration (TGA), 영국의 Medicines and Healthcare products Regulatory Agency (MHRA), WHO-UMC에등록된 statin 계열약물과관련된안구부작용사례보고에서도 452명의환자중 147명이 atorvastatin 복용에의한부작용을경험하여다른 statin 계

4 136 / Korean J Clin Pharm, Vol. 29, No. 2, 2019 열약물보다높은부작용수치를보였다. 6) 이상에서와같이 atorvastatin은다른 statin 계열약물보다유의미하게높은비율로안구관련부작용을일으키는데, 이러한부작용의종류와발생빈도에관해서도다수의보고가있다. 국내에서는때때로 ( 1/1000, <1/100) 시야흐림이, 드물게 ( 1/10000, <1/1000) 시각장애가발생한다고보고된바있는데, 2) 이때시각장애에는안구출혈, 복시 (diplopia), 안검하수 (ptosis), 안근마비 (ophthalmoplegia), 그리고백내장 (cataract) 등이포함된다. 1988년에서 2013년사이 atorvastatin에의해발생한안구관련부작용을나타낸미국 FDA자료에서도흐린시야 (42.1%) 와시각장애 (26.6%) 가가장많이보고되었는데, 이러한이상반응은주로단독으로나타났으며 (1.5%), 근육의이상반응과동시에나타난경우 (0.6%) 도있었다. 5) 또한 Fraunfelder와 Richards의보고에따르면 statin 계열약물을복용한 256명의환자중 atorvastatin을복용한 68명에서 55명, 5명, 3명이각각복시, 안검하수, 안근마비를경험하였다고한다. 7) 이외에 atorvastatin을포함한 statin 계열약물복용환자가가령성백내장 (age related cataract), 핵경화성백내장 (nuclear sclerotic cataract), 후낭하백내장 (posterior subcapsular cataract) 에이환될확률이그렇지않을확률보다높다는것을보인연구도있었다. 8) Statin 계열약물이시각계에문제를일으키는사례가여러연구에서보고되고있지만정확한기전은아직알려져있지않다. 기전을설명하기위한여러가설중하나는혈중콜레스테롤수치를낮추는약물이눈의렌즈에영향을미쳐백내장을유발할수있다는것이다. 일반적으로정상적인사람의렌즈막은투명성을유지하기위해콜레스테롤함유량이매우높아야하는데 statin 계열약물은콜레스테롤수치를낮추기때문에정상적으로렌즈에축적되어야하는콜레스테롤의양을감소시켜백내장으로진행될가능성을높일수있다고한다. 9-11) 콜레스테롤의감소외에도 statin 계열약물이유발한산화적스트레스에의해서도백내장이발생할수있다는보고가있다. 12) 여러동물실험에서 statin 계열약물이조직의 coenzyme Q 농도를감소시키는것을확인하였고, 16,17) 가족성고콜레스테롤혈증환자를대상으로한임상연구에서는 statin 계열약물중에서 atorvastatin을복용했을때혈장의 coenzyme Q 농도가유의미하게감소한결과가도출되었다. 18) coenzyme Q가결핍되면산화적스트레스가발생하는데, 이산화적스트레스가렌즈에손상을줄것으로추측되고있다. Statin 계열약물은눈자체에영향을주어시각이상을발생시킬수도있지만, 골격근에미치는부작용을통해눈주위근육에작용하여안검하수, 안근마비등의시각이상을야기할수도있다. 먼저, Statin 계열약물은 prelamin A를 lamin A로바꾸는프레닐레이션 (prenylation) 과정을저해한다고예상되는데핵막을구성하는단백질인 lamin A를암호화하는유전자 에변이가생기면근육질환이발생한다. 즉, Stain 계열약물에의한 prelamin A의 lamin A로의전환저해는핵을구조적으로취약하게하고, 근수축이일어나는동안핵이기계적인힘을견디기힘들게할것이라예상된다. 19) 또다른주장은 stain 계열약물이미토콘드리아의투과성을증가시켜 cytochrome c 가 ATP와복합체를형성하고 caspases을활성화하여세포자멸사를촉진한다는것이며, statin 계열약물을복용하면서운동을병행했을때근육세포에서유비퀴틴프로테아좀 (ubiquitin proteasome) 경로의발현이증가하여근위축 (muscle atrophy) 을유도한다는연구도있다 ) 또한 statin 계열약물에의해증가된세포내 Ca 2+ 은근소포체 (sarcoplasmic reticulum) 에서의 Ca 2+ 방출을유지하여근수축을지속시킴으로써근육에통증과경련을일으키며세포질의높은 Ca 2+ 농도는근육세포의세포자멸을일으킬수도있다. 13,15) 이처럼 statin 계열약물이시각에관한부작용을일으킨다는것은여러통계와사례를통해알려져있지만부작용을일으키는명확한기전에대해서는일치된의견이없다. 이것은제품설명서에도명시되어있듯이시야관련부작용이매우낮은확률로발생하여많은연구가이루어지지않았기때문이라고할수있다. 따라서지역의약품안전센터를통해꾸준히부작용사례보고가이루어져야하고, 이를바탕으로하는연구가필요해보인다. 결 Atorvastatin은 HMG-CoA 환원효소억제제계열에속하는약으로혈중콜레스테롤생성을억제하여고지혈증을치료하는데사용된다. 본사례보고에서는 atorvastatin 복용과시야흐림발생간의인과성평가를수행하였고 Naranjo 지표, 한국형인과성평가알고리즘 (Ver.2), 그리고 WHO-UMC 기준 3가지로비교한결과, 각각 probable, certain, 그리고 probable/ likely 이라는결과가도출되어인과성이있다고판단된다. Atorvastatin이시야흐림을유발하는기전은아직명확하게밝혀지지않았으나실제발생사례들과그관련성이기술된연구들이존재하므로 atorvastatin을사용할때보다주의하여야하며이후적극적인약물모니터링이필요하다. 론 참고문헌 1. ClinCalc.com DrugStats Database. Atorvastatin, Drug Usage Statistics, United States, Available from com/drugstats/drugs/atorvastatin. Accessed March 10, Korean Index of Medical Specialties (KIMS). Atorvastatin. Available from geninfo/gatr0. Accessed March 10, Lee SH, Park S, Kang SM, et al. Effect of atorvastatin monotherapy and low-dose atorvastatin/ezetimibe combination on fasting and

5 Atorvastatin/Ezetimibe 복합제복용후발생한시야결손부작용사례보고 / 137 postprandial triglycerides in combined hyperlipedemia. J Cardiovasc Pharmacol Ther 2012;17(1): Ballantyne CM, Houri J, Notarbartolo A, et al. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation 2003;107(19): Mizranita V and Pratisto EH. Statin-associated ocular disorders: the FDA and ADRAC data. Int J Clin Pharm 2015;37(5): Bahrami B, Rajak S, Selva D. Orbital myositis secondary to statin therapy. Med J Aust 2015;203(9): Fraunfelder FW and Richards AB. Diplopia, blepharoptosis, and ophthalmoplegia and 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor use. Ophthalmology 2008;115(12): Machan CM, Hrynchak PK, Irving EL. Age-related cataract is associated with type 2 diabetes and statin use. Optom Vis Sci 2012;89(8): Cenedella RJ. Cholesterol and cataracts. Surv Ophthalmol 1996;40(4): Zelenka PS. Lens lipids. Curr Eye Res 1984;3(11): Spurgeon D. Antibiotic use with cholesterol lowering drugs may increase risk of cataracts. BMJ 2002;325(7374): Kanski JJ and Bowling B. Clinical Ophthalmology: A Sytematic Approach, 7th ed. Philadelphia, PA: Elsevier 2011: Beltowski J, Wojcicka G, Jamroz-Wisniewska A. Adverse effects of statins-mechanisms and consequences. Curr Drug Saf 2009;4(3): Satoh K and Ichihara K. Effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in ischemic rat hearts. Eur J Pharmacol 1995;292(3-4): Satoh K, Yamato A, Nakai T, et al. Effects of 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in ischaemic dog hearts. Br J Pharmacol 1995; 116(2): Willis RA, Folkers K, Tucker JL, et al. Lovastatin decreases coenzyme Q levels in rats. Proc Natl Acad Sci USA 1990;87(22): Littarru GP and Langsjoen P. Coenzyme Q10 and statins: biochemical and clinical implications. Mitochondrion 2007; 7(suppl):S Kawashiri MA, Nohara A, Tada H, et al. Comparison of effects of pitavastatin and atorvastatin on plasma coenzyme Q10 in heterozygous familial hypercholesterolemia: results from a crossover study. Clin Pharmacol Ther 2008;83(5): Baker SK. Molecular clues into the pathogenesis of statin-mediated muscle toxicity. Muscle Nerve 2005;31(5): Dirks AJ and Jones KM. Statin-induced apoptosis and skeletal myopathy. Am J Physiol Cell Physiol 2006;291(6):C Urso ML, Clarkson PM, Hittel D, et al. Changes in ubiquitin proteasome pathway gene expression in skeletal muscle with exercise and statins. Arterioscler Thromb Vasc Biol 2005;25(12): Liantonio A, Giannuzzi V, Cippone V, et al. Fluvastatin and atorvastatin affect calcium homeostasis of rat skeletal muscle fibers in vivo and in vitro by impairing the sarcoplasmic reticulum/ mitochondria Ca 2+ -release system. J Pharmacol Exp Ther 2007; 321(2):

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract