인터페론제제 Pharmacy Newsletter Aug 2009 해독제 () = 목차 = 해독제 () Journal Review 의약품안전성정보 약제과소식 1. 독성물질에따른해독제분류 독극물 / 약제 / 독소 해독제 Acetaminophen Acetylcysteine Anthracycline 계항암제 (epirubicin, doxorubicin) 의심장독성 Dexrazoxane Benzodiazepine 계약물의중추진정작용 Flumazenil Cisplatin 유발신독성 Mannitol, sodium thiosulfate Digoxin Atropine sulfate, phenytoin, lidocaine, Mg.sulfate Heparin 및 LMWH Protamine sulfate Isoniazid, cycloserine, hydralazine 등에의한 pyridoxine 결핍증상 Pyridoxine (vitamin B6) 항암제및 Opioids ( 마약성진통제등 ) Naloxone 기타약물 Oxazaphosphorine 계항암제 (ifosfamide, cyclophosphamide) 에의한출혈성방광염 Mesna Warfarin Phytonadione (vitamin K) 410-769 경기도고양시일산동구정발산로 111 번지국립암센터약제과 Tel. (031) 920-0217 Fax.(031) 920-0219 E-mail : nccph@ hanmail.net http://www.ncc.re.kr 비탈분극성근이완제 (atracurium, rocuronium, vecuronium 등 ) 엽산길항제 (methotrexate, trimethoprim, pyrimethamine, trimetrexate 등 ) 약인성추체외로증상약물및화학물질의경구중독약물에의한 acidosis, aciduria Ba (barium) Cu, Hg, Pb 금속및전해질 Fe, Al Fe ( 수혈의존성헤모시데린침착증 ) K ( 급 만성신부전동반 ) 유기인계 (parathion, fenitrothion 등 ) 살충제 Carbamate 계 (carbaryl, methomyl 등 ) Cyanide (CN) Ciguatera 식중독 ( 독어의유독성분 ) Hydrofluoric acid (HF) Neostigmine methylsulfate, pyridostigmine sulfate Folinate calcium Benztropine mesylate Activated charcoal Sodium bicarbonate Mg.sulfate, potassium chloride Penicillamine(-D) Deferoxamine mesylate Deferasirox Polystyrene sulfonate calcium Atropine sulfate Sodium thiosulfate Mannitol(-D) Ca.gluconate, Mg.sulfate Pharmacy Newsletter Vol. 8. No.8.
2. 원내해독제 해독제코드 / 제형및함량해독작용비고 Acetylcysteine ACSI : 1g/10ml amp Acetaminophen 해독 1 회요법으로충분함 Glutathione 을대신하여 acetaminophen 대사체를무독화시키거나고갈된 glutathione store 을보충 약물및화학물질의경구중독시응급처치 독성물질을비특이적으로흡착하여 Activated charcoal AC : 1kg/btl ( 원내제제 ) (acetaminophen, aspirin, atropine, barbiturates, digoxin, phenol, phenytoin, 위장관흡수를억제시킴 침식성물질, 유기용매, mineral acids TCAs, strychnine 등 ) 철, CN 중독시에는사용하지말것 Atropine sulfate ATI : 0.5mg/1ml amp 유기인계살충제 (parathion, fenitrothion), carbamate 계살충제 (carbaryl) 중독해독 Digoxin 중독치료 Acetylcholine antagonist Digoxin 중독에의한서맥역전 Anticholinergic antiparkinsonian Benztropine mesylate BZT1 : 1mg tab 약인성추체외로증상치료 ( 항정신병약투여로인한파킨슨증, 급성근긴장이상, 좌불안증치료 ) agent 로 acetylcholine 과 dopamine 활성의불균형감소 항정신병약투여로인한지연성운동 이상증에는효과없음 Calcium gluconate CAGI : 2g/20ml amp 중증고마그네슘혈증치료, Hydrofluoric acid (HF) 에의한전신독성치료 혈중 Mg 2+ 와 Ca 2+ 농도가반비례적으로변동하는것을이용, Mg 배설을증가시킴 HF 에의한 hypocalcemia 치료 Deferasirox (Exjade ) DFSX1 : 125mg tab DFSX2 : 250mg tab DFSX5 : 500mg tab 수혈의존성헤모시데린침착증치료 - 초기 : 1 일 1 회 20mg/kg 유지 : 3~6 개월마다 5~10mg/kg 씩단계적증량 (max. 30mg/kg) 확산정 ( 물또는오렌지주스 100-200 ml 에녹여현탁액으로만든후복용 ) Fe-selective chelating agent 로복합체를형성하여대변으로배설시킴 Deferoxamine mesylate DFR : 500mg vial 급 만성철분축적시 철분또는알루미늄축적여부진단 말기신부전환자의만성알루미늄축적시 Fe 3+, Al 3+ 와결합하여복합체를형성, 신장으로배설시킴 (chelating agent) Dexrazoxane (Cardioxane ) DXRA : 500mg vial Anthracycline 계항암제 (epirubicin, doxorubicin=adrs) 의심장독성방지 - Doxorubicin 의 20 배, epirubicin 의 10 배에해당하는양을항암제투여 30 분전에 15min inf (max. 1000mg/m 2 ) 철과결합함으로써 anthracycline 계항암제가 Fe 2+ 에자유라디칼을생성시키는것을억제하여심독성방지 ADRS 축적용량 300mg/m 2 일때시작 Flumazenil FMZ : 0.5mg/5ml amp FMZ03 : 0.3mg/3ml amp Benzodiazepine 계약물 (BZDs) 에의한중추진정작용역전 BZDs 중독확진및해독 BZDs 수용체에대한경쟁적길항작용 BZDs 이외의 GABA 효현제 (alcohol, barbiturate, 전신마취제 ) 의중추신경계효과는길항하지못함 Pharmacy Newsletter Vol. 8. No 8. 2/7
해독제코드 / 제형및함량해독작용비고 Folinate calcium LVR15I : 15mg/1ml amp LVR30I : 30mg/2ml amp LVR50I : 50mg/5ml amp LVR100I :100mg/10ml amp LVR : 15mg tab 엽산길항제 (methotrexate, trimethoprim, pyrimethamine, trimetrexate 등 ) 과량투여시해독 Methanol 중독시 cofactor therapy 엽산의활성형대사체 (dihydrofolate reductase 에의한환원과정필요없음 ) Methanol 의독성대사체인 formic acid 제거를촉진함 Lidocaine HCl LDC1I : 1% 20ml vial LDC2I : 2% 20ml vial LDC4I : 4% 20ml vial Digoxin, digitalis 에의한심실성부정맥치료 Class I b 항부정맥제 심실의확장기탈분극과자동성억제 Magnesium sulfate MGSI : 2g/20ml amp Barium (Ba), digoxin 중독시해독 Hydrofluoric acid (HF) 에의한전신독성치료 Ba 중독시경구투여하면침전형성하여장흡수감소시킴 (IV 투여는안됨 ) Digoxin 중독시심실전위, 부정맥치료 HF 에의한 hypomagnesemia 교정 Mannitol (-D) M11V : 15% 100ml bag M21V : 20% 100ml bag Ciguatera ( 독어의유독성분 ) 식중독 Cisplatin, amphotericin 신독성예방 신배설약물중독시배설증가 사구체여과삼투압을증가시켜수분과전해질이세뇨관에서재흡수되는것을막고뇨배설량을증가시킴 Mesna MSN4I : 400mg/4ml amp Oxazaphosphorine 계항암제 (ifosfamide, cyclophosphamide) 의출혈성방광염예방 - 항암제용량의 20% 에해당하는양을동시투여및 4hr, 8hr 후동량투여 신장에서유리형 thiol 화합물로환원되어항암제의독성대사체및 acrolein 과결합하여무독화시킴 Acute opioid toxicity 의 1 차선택약 기도확보및호흡조절장치, 순환기계 Naloxone HCl NLX4 : 0.4mg/1ml amp NLX2 : 2mg/2ml amp Opioid 과량투여시호흡억제및중추신경계억제의역전 기능유지장치함께사용 Opioid 수용체에대한경쟁적길항제 마약성효현작용은없음 심질환자의경우저혈압, 심실빈맥, 폐부종등을일으킬수있으므로주의 Neostigmine methylsulfate NSG : 0.5mg/1ml amp 비탈분극성근이완제의효과역전 (vecuronium, rocuronium, atracurium 등 ) 혈장 cholinesterase 활성을억제시킴으로써신경근접합부에서의 acetylcholine 농도를증가시킴 Penicillamine (-D) PNC : 250mg cap Pb, Hg, Cu 등중금속해독 - 1 회 250mg, 1 일 3~4 회, 1 주일복용 중금속과결합, 수용성복합체를형성하여신장으로배설시킴 (chelating agent) Phenytoin DPHI : 250mg/5ml Digoxin, digitalis 에의한심실성부정맥치료 강알칼리성이므로 SC, IM 추천안됨 심실의자발적인탈분극을억제함 Vitamin K dependent 혈액응고인자 Phytonadione KI : 10mg/1ml amp K : 5mg tab Warfarin 의항응고작용중화 활성화 (factor II, VII, IX, X) SC, IV 투여가능하나, 경구투여우선 추천됨 (safety & efficacy) Pharmacy Newsletter Vol. 8. No 8. 3/7
해독제코드 / 제형및함량해독작용비고 Polystyrene sulfonate calcium PSSC : 5g/pkg pow ARGAMATE ( 원외 ) : 5g/25g/ea jelly 급만성신부전을수반한고칼륨혈증치료 - 15~30g/day, 2~3 회분복 - PSSC : 물에현탁시켜복용 ARGAMATE : 물없이복용가능 양이온교환수지 ( 칼슘이온과장관내의 칼륨이온이교환되어대변으로배설 ) 1g 당 K 교환능 (in vivo) : 1mEq Potassium chloride K40PI : 40mEq/20ml amp Ba 중독해독 Ba 중독에의한 hypokalemia 교정 Protamine sulfate PTM : 50mg/5ml amp Heparin 및 LMWH 작용의중화 Heparine 과결합하여항응고작용 없는안정한복합체형성 Pyridostigmine bromides PRDI : 5mg/1ml amp 비탈분극성근이완제의효과역전 (vecuronium, rocuronium, atracurium 등 ) Cholinesterase inhibitor 로써신경근접합부에서 acetylcholine 농도증가 Isoniazid, cycloserine, hydralazine 등에 Isoniazid-induced convulsion : Pyridoxine B6 : 50mg tab 의한 pyridoxine 결핍증상 ( 말초신경병증 ) - 예방 : 25~50mg qd Isoniazid 와동량의 pyridoxine 을 IV push ( 원내주사제형은없음 ), BZDs 치료 : 50~300mg qd 병용시 synergic effect (eg. diazepam) Sodium bicarbonate HCO3I : 8.4% 20ml amp HCO3 : 500mg tab HCO3P : g pow 약물에의한 acidosis, aciduria 중화 위산중화 Bicarbonate 로해리되어혈장의수소이온을중화시키고, 뇨 ph 증가 HCO3I : Ca 이온포함제제와혼합사용금지 ( 침전생성 ) Sodium thiosulfate (Ametox ) NATS : 12.5g/50ml vial Cisplatin 신독성예방 CN 중독해독 : 단독사용또는 amyl nitrite/sodium nitrite 와병용투여 Cisplatin 신독성예방 CN 중독해독 : thiocyanate 생성을촉진하여신배설증가시킴 3. Nicotine / Alcohol 중독의약물치료 (1) Alcohol 중독 1 Methanol 중독 Alcohol dehydrogenase (ADH) 억제요법 : methanol 이독성대사체 (formic acid) 로대사되는것을억제함 - Ethanol : methanol 보다 ADH 에대한결합력이크므로독성대사체생성억제 - Fomepizole : ADH 억제제 Cofactor therapy (folic acid) : formic acid 제거촉진 2 음주로인한알코올의존증 음주로인한알코올중독에대한직접적인 antidote 는없으며금단증상 ( 불안, 불면, 발한, 심계항진, 경련, 섬망등 ) 을완화시켜주는약물이나알코올로인한신체적질환을치료하는약물을투여한다. 알코올중독환자의경우영양상태가불량하고알코올에의한비타민결핍상태인경우가많으므로 thiamine 을비롯한비타민및기타영양소를투여할수있다. 금단증상이소실되고치료가안정기에접어들면금주를계속유지하기위한약물요법을시행할수있다. - Naltrexone (opioid antagonist, 알코올에의한 opioid 분비증가로인한효과억제 ) - Disulfiram (acetaldehyde 의분해를억제하여음주후증상을극대화시킴으로써음주에대한혐오감유발 ) - Acamprosate Pharmacy Newsletter Vol. 8. No 8. 4/7
< 원내알코올의존증치료제 > 약품명코드 / 함량및제형용법및용량비고 60kg 이상 : 2-2-2 정 (6 정 / 일 ) 억제성신경전달물질 GABA 전달을 Acamprosate ACPS ( 원외 ) : 333mg tab 60kg 미만 : 1-1-2 정 (4 정 / 일 ) 자극하고, 흥분성아미노산 (glutamate) 6 개월이상복용 전달을억제 (2) Nicotine 중독 급성과량투여시 antidote로써 acetylcholinergic antagonist를사용하는경우는드물고니코틴에의한 cholinergic effect 가심하게나타날경우 atropine sulfate 사용을고려해볼수도있다. 금연요법 - 니코틴의혈중농도를어느정도유지시켜줌으로써금단증상을줄여주는니코틴대체요법이주로사용되고, 불안, 긴장, 식욕증가등금단증상이나타났을때이를완화시켜주는약물을사용할수있다. - 금연요법에사용되는약물은금단증상을줄여주는보조제로사용될뿐금연을위한절대적인수단이아님을환자에게설명한다. < 원내금연치료보조제 > 약품명코드 / 함량및제형용법및용량비고 Bupropion (Wellbutrin ) BPP : 150mg SR tab 목표금연일을투약후첫 2 주내로설정 (2 주째에설정하는것이권장됨 ) - 초기 : 1 일 1 회 150mg 6 일간투여 - 유지 : 1 회 150mg, 1 일 2 회최소 7 주간투여 (max. 150mg/dose, 300mg/day) 니코틴패치와병용시용량 / 용법변경필요없음 ( 병용투여시작일을목표금연일로설정 ) 발작에대한역치를낮추므로발작위험있는환자에서주의 서방형 : 씹거나갈아서복용하지말것 Nicotine (Nicostop patch) NCTT1 ( 원외 ) :19mg/ea patch NCTT2 ( 원외 ) :38mg/ea patch NCTT3 ( 원외 ) :57mg/ea patch 1 일 1 회 1 매부착 - 심한흡연가 (1 일 20 개비이상 ) : NCTT3 으로시작하여 NCTT2, NCTT1 순서로각각 4 주동안적용 - 보통흡연가 (1 일 20 개비까지 ) : NCTT2 8 주적용후, NCTT1 4 주적용 - 치료기간은 3 개월을초과하지말것 털없는신체부위에부착하되, 매일부착부위변경하도록함 패치를사용하는기간에는반드시금연해야함 ( 담배를피울경우니코틴에의한이상반응이심하게나타날수있음 ) Varenicline tartrate (Champix ) VRNC05 : 0.5mg tab VRNC1 : 1mg tab 목표금연일로부터 1~2 주전에시작 - 1~3 일 : 0.5mg 1 일 1 회 4~7 일 : 0.5mg 1 일 2 회 8 일 ~12 주 : 1mg 1 일 2 회 (12 주추가투여가능 ) α 4 ß 2 신경세포의니코틴성아세틸콜린수용체에결합하여작용제로써활성을나타내면서, 동시에니코틴이동수용체에결합하는것을차단함 [Reference] 1. Medical toxicology 3th 2. Micromedex 3. 제품설명서, DC 자료집 4. 알코올중독정보센터 (http://www.neuropsychiatry.co.kr) 5. 한국중독정신학회 (http://www.addictionacademy.org) < 조제계김혜원약사 > Pharmacy Newsletter Vol. 8. No 8. 5/7
Journal Review Hearing improvement after Bevacizumab in patients with Neurofibromatosis Type 2 양측성전정신경초증과관련된유전적질환인신경섬유종증 2 형은심각한청력손실의합병증이나타난다. 10 명의환자에 anti-vegf 단일클론항체인 Bevacizumab 을투여하여면역조직화학적검사를통해분석하였을때 BVCZ 투여전의매년평균종양크기의성장율은 62% 였으나투여후 10 명중 9 명에서종양크기가감소하였고 26% 의평균감소율을나타내어 BVCZ 는어느정도청력증진에효과가있음을입증하였다. Background Profound hearing loss is a serious complication of neurofibromatosis type 2, a genetic condition associated with bilateral vestibular schwannomas, benign tumors that arise from the eighth cranial nerve. There is no medical treatment for such tumors. Methods We determined the expression pattern of vascular endothelial growth factor (VEGF) and three of its receptors, VEGFR-2, neuropilin-1, and neuropilin-2, in paraffinembedded samples from 21 vestibular schwannomas associated with neurofibromatosis type 2 and from 22 sporadic schwannomas. Ten consecutive patients with neurofibromatosis type 2 and progressive vestibular schwannomas who were not candidates for standard treatment were treated with bevacizumab, an anti-vegf monoclonal antibody. An imaging response was defined as a decrease of at least 20% in tumor volume, as compared with baseline. A hearing response was defined as a significant increase in the word-recognition score, as compared with baseline. Results VEGF was expressed in 100% of vestibular schwannomas and VEGFR-2 in 32% of tumor vessels on immunohistochemical analysis. Before treatment, the median annual volumetric growth rate for 10 index tumors was 62%. After bevacizumab treatment in the 10 patients, tumors shrank in 9 patients, and 6 patients had an imaging response, which was maintained in 4 patients during 11 to 16 months of follow-up. The median best response to treatment was a volumetric reduction of 26%. Three patients were not eligible for a hearing response; of the remaining seven patients, four had a hearing response, two had stable hearing, and one had progressive hearing loss. There were 21 adverse events of grade 1 or 2. Conclusions VEGF blockade with bevacizumab improved hearing in some, but not all, patients with neurofibromatosis type 2 and was associated with a reduction in the volume of most growing vestibular schwannomas. NEJM 2009;361(4):358-367 Overall Survival and Updated Results for Sunitinib Compared With Interferon Alfa in Patients With Metastatic Renal Cell Carcinoma IFN- 와비교하여전이성 RCC 1 차요법제로 sunitinib 우월성은 3 상임상시험의 PFS 결과로입증되었다. 최종생존분석결과, 전체생존율의중간값 (sunitinib vs. IFN- ) 이 26.4 vs. 21.8 mos(hr=0.821;p=.051), 반응율이 47% vs. 12% 로 sunitinib 에서더긴생존율및반응율을나타내었다. Background A randomized, phase III trial demonstrated superiority of sunitinib over interferon alfa (IFN- ) in progression-free survival (primary end point) as first-line treatment for metastatic renal cell carcinoma (RCC). Final survival analyses and updated results are reported. Methods Seven hundred fifty treatment-naïve patients with metastatic clear cell RCC were randomly assigned to sunitinib 50 mg orally once daily on a 4 weeks on, 2 weeks off dosing schedule or to IFN- 9 MU subcutaneously thrice weekly. Overall survival was compared by two-sided log-rank and Wilcoxon tests. Progression-free survival, response, and safety end points were assessed with updated follow-up. Results Median overall survival was greater in the sunitinib group than in the IFN- group (26.4 v 21.8 months, respectively; hazard ratio [HR] = 0.821; 95% CI, 0.673 to 1.001; P =.051) per the primary analysis of unstratified log-rank test (P =.013 per unstratified Wilcoxon test). By stratified log-rank test, the HR was 0.818 (95% CI, 0.669 to 0.999; P =.049). Within the IFN- group, 33% of patients received sunitinib, and 32% received other vascular endothelial growth factor signaling inhibitors after discontinuation from the trial. Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN- (P <.001). Objective response rate was 47% for sunitinib compared with 12% for IFN- (P <.001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%). Conclusions Sunitinib demonstrates longer overall survival compared with IFN- plus improvement in response and progressionfree survival in the first-line treatment of patients with metastatic RCC. The overall survival highlights an improved prognosis in patients with RCC in the era of targeted therapy. JCO 2009;27(22):3584-3590 Pharmacy Newsletter Vol. 8. No 8. 6/7
의약품안전성정보 TNF blockers increased risk of cancer 미국 FDA 는 08 년 6 월안전성관련발표이후 TNF blocker 에대한분석을종료하고어린이와 청소년에서 TNF blocker 의사용이림프종및또다른암의위험을증가시킨다고발표하였다. 이러한 정보는 TNF blocker 제품의 BOX Warning 으로추가되었다. 또한 TNF blocker 치료를받은환자에서 백혈병의발생과새롭게발병한건선과도관련이있음을입증하였다 (TNF blocker 의현재처방정보는 앙성종양에대한경고를포함하나특별히백혈병에대한언급은없다 ). TNF blocker 안전성정보관련내용 - FDA Med Watch(09.8) 2008 년 10 월 : Fungal infection (TNF blocker 로인한 Histoplasma 위험성경고 ) 2008 년 6 월 : 소아, 청소년에서림프종등발생으로처방시주의 Colchicine - FDA Med Watch (09. 8) - drug interaction 미국 FDA 는가족성지중해열과급성통풍발적의치료를위한최초의단일성분경구 colchicine 제품인 Colcrys 를승인하면서 colchicine 의기관에보고된부작용사례, 출판된문헌, 제약회사에서후원된약동학, 약물상호작용연구에서의안전성자료를분석하였다. 이를통해표준치료용량의 colchicine 과 clarithromycin 을동시사용한환자에서치명적인 colchicines 독성이나타났다. 이는 colchicine 의위장관흡수와간대사에영향을미치는상호작용이 colchicine 독성진전에중요한역할을하는것으로밝혀졌다. 의료진및 colchicine 투약환자권고내용 신장, 간장장애환자에게 P-gp inhibitor 또는강력한 CYP3A4 inhibitor 금지 콜키신은일반적인진통제로사용불가하며치료기간중자몽또는자몽쥬스섭취를피한다. 근육약화, 저린감, 심각한설사, 입술, 혀등창백해지는증상발현시즉시전문가와상담을한다. * P-glycoprotein inhibitor, CYP3A4 inhibitor : cyclosporin, clarithromycin, erythromycin, ketoconazole, itraconazole, nefazodone... - FDA Med Watch (09. 8) - 품절의약품안내 성분 ( 함량 ) 효능 내용 Nutriflex 40 (1L/bag) 영양수액제 9 월초까지일시품절 Hydromorphone (4mg/tab) 마약성진통제 하나제약생산중단 코드종료 (8/4) Labetalol (100mg/tab) 혈압강하제 장기품절 재고소진시코드종료 Colistimethate (150mg/vial) 항생제 9 월초까지일시품절 재고소진시희귀의약품센터에서구입 발행인 : 김영주편집인 : 정혜진, 전혜원, 한지은, 김미강, 김혜원발행일 : 2009 년 8 월 12 일 Pharmacy Newsletter Vol. 8. No 8. 7/7