ࡱ> ~}_ bjbj ubb+&1 22222$VVVP$V.:  M.O.O.O.O.O.O.03`O.E2"O.22.rrr22M.rM.rr'h(ŤA(9..0.Q(4L4 ((42,hrO.O.j.4 : KHOA DC N V DLS - TTT BN TIN THNG TIN THUC THNG 9/2019 NI DUNG:  TOC \o "1-3" \h \z \u  HYPERLINK \l "_Toc25736600" 1. Tp cht nitrosamin: tng hp mt s vn  cn lu t thng tin ca cc thuc b thu hi  PAGEREF _Toc25736600 \h 1  1. TP CHT NITROSAMIN: Tng hp mt s vn  cn lu t thng tin ca cc thuc b thu hi N-nitrosodimethylamine (NDMA) v N-nitrosodiethylamine (NDEA) l nhng dn cht nitrosamin c phn loi vo nhm cc cht c th gy ung th trn ngi. Tp cht ny c pht hin ln u tin trong cc thuc thnh phm cha valsartan c nguyn liu c sn xut bi Cng ty Zhejiang Huahai Pharmaceuticals (ZHP), Linhai, Trung Quc. T , hng lot l thuc valsartan c nguyn liu c sn xut ti y  b thu hi ti nhiu quc gia trn th gii v ti Vit Nam. Vic xut hin NDMA v NDEA trong thuc thnh phm valsartan c cho rng c lin quan n mt s giai on nht nh trong quy trnh sn xut nguyn liu ca ZHP. Nm 2012, ZHP tin hnh mt s thay i trong quy trnh tng hp vng tetrazole trong cng thc ca valsartan  tng hiu sut sn xut nhng li dn n hnh thnh tp cht NDMA. Tng t, trong mt s iu kin cc phn ng nht nh, tp cht NDEA cing c th c hnh thnh. Tetrazole l cu trc ph bin trong cng thc ha hc ca cc hot cht thuc c ch th th AT1. V vy, khng ch ring valsartan, cc thuc khc trong nhm ny nh candesartan, irbesartan, losartan v olmesartan c cu trc vng tetrazole cing c a vo r sot. Sau , mt s l thuc valsartan, losartan v irbesartan t cc nh sn xut khc nhau b pht hin nhim tp cht  b thu hi. Khng ch NDMA v NDEA, vic r sot losartan ti Hoa K cn pht hin thm mt tp cht mi l N-Nitroso-N-methyl-4-aminobutyric acid (NMBA). Tp cht ny cing l mt dn cht nitrosamin c nguy c gy ung th tng t NDMA. C Quan Qun l Dc phm Chu u  c tnh nguy c mc ung th lin quan n cc tp cht NDMA v NDEA da trn d liu ngoi suy t ng vt. Nu 100.000 bnh nhn s dng valsartan c sn xut bi ZHP hng ngy trong vng 6 nm  liu cao nht (320 mg/ngy) th pht sinh thm 22 trng hp ung th do NDMA. Cn NDEA c th dn n c thm 8 trng hp ung th cing  liu cao nht thuc ny khi s dng trong 4 nm. C quan Qun l Thuc v Thc phm Hoa K (FDA) cing c tnh,  mc liu 320 mg/ngy valsartan trong vng 4 nm, nguy c pht sinh thm ca ung th mi l 1/8000 bnh nhn phi nhim.  gim thiu nguy c cho bnh nhn, cc C quan Qun l Dc phm trn th gii khuyn co cc nh sn xut nn t nguyn thu hi thuc nu pht hin thuc thnh phm nhim tp cht nitrosamin. Tuy nhin,  trnh tnh trng thiu thuc, Cc C quan Qun l  a ra ng thun v gii hn tm thi ti a cho php vi cc cht NDMA v NDEA. Ring FDA c thm gii hn cho NMBA. Cc gii hn ny c tnh ton da trn lng cht ti a hp thu hng ngy c th chp nhn c vi mi tp cht: 96 nanogam vi NDMA, 26,5 nanogam vi NDEA v 96 nanogam vi NMBA. S liu ny sau  c chia cho liu ti a hng ngy ca mi hot cht thuc  a ra mc gii hn theo n v ppm (1 ppm = 1/ 1.000.000). Gii hn tm thi cho cc tp cht nitrosamin cho cc sn phm thuc c ch th th AT1 c trnh by trong bng 1. Cc sn phm c nng  tp cht vt qu gii hn trn s tip tc b thu hi. Cn lu , y ch l cc mc gii hn tm thi trong thi gian cho php cc cng ty sn xut tin hnh thay i quy trnh sn xut v c cc bin php kim nghim nhm pht hin hm lng tp cht thp nht, tin ti mc tiu loi b hon ton cc tp cht nitrosamin trong sn phm thuc. Bng 1.Gii hn tm thi ca tp cht nitrosamin trong cc thuc c ch th th AT1 Hot cht (liu ti a hng ngy)NMDANDEANMBALng cht hp thu hng ngy ti a c th chp nhn c (ng)Gii hn (ppm)Lng cht hp thu hng ngy ti a c th chp nhn c (ng)Gii hn (ppm)Lng cht hp thu hng ngy ti a c th chp nhn c (ng)Gii hn (ppm)Azilsartan (80 mg)96,01,20026,50,33396,01,200Candesartan (32 mg)96,03,00026,50,82096,03,000Eprosartan (800 mg)96,00,12026,50,33396,00,120Irbesartan (300 mg)96,00,32026,50,08896,00,320Losartan (150 mg) (theo EMA)96,00,64026,50,17796,0Losartan (100 mg) (theo FDA)96,00,96026,50,27096,00,960Olmesartan (40 mg)96,02,40026,50,66396,02,400Telmisartan (80 mg)96,01,20026,50,33396,01,200Valsartan (320 mg)96,00,30026,50,08296,00,300 Hin nay, cc C quan Qun l Dc phm trn th gii vn ang tip tc m rng r sot n c cc thuc khc sau bi hc v tp nhim NDMA v NDEA t cc thuc chn th th AT1 vt qu gii hn cho php. Gn y, mt s l thuc cha ranitidin  b thu hi do nguyn nhn ny t nhiu C quan Qun l Dc phm trn th gii nh Singapore, c, Hoa K& Gii h@~     򽯽v\M;"hGhGCJaJmHnHuhG0JCJaJmHnHu2jYhGhG0JCJUaJmHnHuhGhGCJaJmHnHu#hGhG0JCJaJmHnHu,jhGhG0JCJUaJmHnHuhGh=5CJ\aJ#jhGh=5CJU\aJhE7m5CJ\aJ.jh$sJhxJ5CJU\aJmHnHuh$sJhxJ5CJ\aJ8:<>@ vvvnfddhgd$sJd gd$sJ $d a$gd$sJ_kd$$Ifl0% t644 lapytxJ$d $Ifa$gd$sJ$d $Ifa$gdh          ׾阄n\QF6'hGh5kfCJOJQJaJhGh5kfCJOJQJ\aJhGh\mCJaJhGhGCJaJ"h$sJh=1]5CJOJQJ\aJ+jhGh=5CJOJQJU\aJ'h;hGCJOJQJaJmHnHu,jhGhG0JCJUaJmHnHuhC0qCJaJmHnHu1jhGhGCJUaJmHnHu"hGhGCJaJmHnHu+jhGhGCJUaJmHnHu   %%2%%"&,&m$$If[$\$a$gd5kf$If[$\$gd5kf$dh[$\$a$gdTXdh[$\$gd5kf$dh[$\$a$gdC0q$dh[$\$`a$gdC0q$dh[$\$a$gd5kfdhgd\m dhgd$sJ %0%4%%% &"&*&,&4&6&>&D&&&&&\'^'z'|'''(J(T(`(j(v(((((((("),)8)B)N)X)))))))* ***A*F*L*Q*W*\*v*{*****************.hC0qhTX0JCJaJhC0qh5kf0JCJaJhC0qh;CJaJhC0qh5kfCJaJQ,&6&@&B&D&&&B9 $Ifgd5kfkdO$$If4\aD%FF F F t0%62x2K24Bayt5kf$$If[$\$a$gd5kf&^'|''($$If[$\$a$gd5kf((kd$$If4֞a f!D%BFUFGFFFF t0%62x2K24Bayt5kf(@(J(V(`(l(v(($$If[$\$a$gd5kf$If[$\$gd5kf((kd$$If֞a f!D%FFUFGFFFF t0%62x2K24Bayt5kf(((((((($$If[$\$a$gd5kf$If[$\$gd5kf((kd$$If֞a f!D%FFUFGFFFF t0%62x2K24Bayt5kf()").)8)D)N)Z)$$If[$\$a$gd5kf$If[$\$gd5kfZ)\)kd $$If֞a f!D%FFUFGFFFF t0%62x2K24Bayt5kf\))))))))$$If[$\$a$gd5kf$If[$\$gd5kf))kd$$If֞a f!D%FFUFGFFFF t0%62x2K24Bayt5kf))** *****$$If[$\$a$gd5kf$If[$\$gd5kf**kd$$If֞a f!D%FFUFGFFFF t0%62x2K24Bayt5kf*1*<*A*G*L*R*W*]*$$If[$\$a$gd5kf$If[$\$gd5kf]*^*kd$$If֞a f!D%FFUFGFFFF t0%62x2K24Bayt5kf^*q*v*|*****$$If[$\$a$gd5kf$If[$\$gd5kf**kd$$If֞a f!D%FFUFGFFFF t0%62x2K24Bayt5kf********$$If[$\$a$gd5kf$If[$\$gd5kf**kd $$If֞a f!D%FFUFGFFFF t0%62x2K24Bayt5kf********$$If[$\$a$gd5kf$If[$\$gd5kf**kd $$If֞a f!D%FFUFGFFFF t0%62x2K24Bayt5kf*+klll$noJrutxvxxVZx$dh[$\$a$gdC0qdh[$\$`gdC0qdh[$\$gdC0q$dh[$\$`a$gdC0q$dh[$\$a$gd5kfn cho php ca tp cht NDMA theo gii hn chp nhn quy nh ti ICH M7; c th: Gii hn tm thi chp nhn khng qu 0,32 ppm (tnh trn liu chp nhn ti a ca NDMA l 96 nanogam/ngy v liu s dng ti a ca ranitidin l 300 mg/ngy). Ti Vit Nam, Cc Qun l Dc cing  c cng vn 16814/QLD-CL thng bo thu hi mt s thuc cha ranitidin nhim tp cht. Cc C quan Qun l Dc phm trn th gii v ti Vit Nam ang rt n lc, vi nhng bin php tch cc r sot, pht hin cc thuc cha tp cht NDMA v NDEA  cung cp thng tin n cng ng. Tuy nhin, cing cn lu , khng phi ton b cc thuc cha ranitidin hay cc thuc  sartan trn th trng u nhim tp cht ny. Tng hp khuyn co dnh cho cn b y t v cho ngi bnh t cc c quan qun l Dc phm trn th gii n thi im hin ti nh sau: Thng tin dnh cho ngi bnh - Bnh nhn ang s dng thuc thuc nhm "sartan" hoc ranitidin nn kim tra thuc ca mnh c nm trong danh sch cc sn phm cha ranitidin b thu hi hay khng. - Nguy c gy hi tim tng ca tp cht nhm nitrosamin lin quan n s dng thuc trong thi gian di, do  bnh nhn c k n dng ngn hn cc thuc b nh hng c th tip tc s dng thuc - Cc bnh nhn s dng cc thuc nhm "sartan" hoc thuc ranitidin theo n, bao gm c sn phm b thu hi, khng nn t ngng s dng thuc. Bnh nhn cn trao i vi bc s iu tr v thng nht c phng n iu tr thay th, v nguy c do dng iu tr t ngt c th ln hn ri ro lin quan n phi nhim NDMA. - Bnh nhn dng ch phm cha cc thuc nhm "sartan" hoc ranitidin theo n thuc nhng mun ngng thuc nn trao i vi cn b y t v dng la chn iu tr thay th. Nhiu loi thuc c ph duyt vi ch nhtng t nh cc thuc ny v c th thay th c cc thuc ny. Ngi bnh dng ch phm cha ranitidin khng k n c th cn nhc s dng cc sn phm khng k n khc thay th nu ph hp. - Trong khi cc c quan qun l ang iu tra nguyn nhn hm lng tp cht NDMA cao hn gii hn cho php v nguy c gy hi cho ngi bnh, ngi s dng v bnh nhn c th tip tc dng cc ch phm cha thuc nhm "sartan" v ranitidin khng b thu hi.Lu quan trng cn nh l khng phi tt c cc thuc cha "sartan" v ranitidin trn th trng u b thu hi. Thng tin dnh cho cn b y t Nng  chp nhn c ca nitrosamin c nh mc theo n v nanogram (ng). Gi tr ny c coi l an ton nu bnh nhn dng thuc hng ngy n 70 nm. Cho n nay, hm lng NDMA c pht hin trong cc thuc nhm "sartan" v ranitidin, nu dng trong nhiu thp k, c th lm tng nh nguy c ung th cho tng c th ngi bnh. Hm lng  mc  chp nhn c bt ngun t cc nghin cu gy ung th trn ng vt kt hp vi mc  an ton cao, tuy nhin khng th a ra mt con s chnh xc c tnh mc  ri ro gy ung th lin quan n tp cht NDMA da vo d liu an ton hin c. Mc d nguy c b sung do tp cht NDMA trong "sartan" v ranitidin  cc nng  xc nh cho n nay l thp, i vi cc bnh nhn ang s dng cc thuc cha tp cht NDMA nguy c trn c th vt tri li ch khi s dng thuc. V l do ny, cc bc s) ang iu tr cho bnh nhn nn cn nhc s dng cc thuc thay th ph hp. i vi ranitidin, cc thuc ny c th thay th bao gm khng receptor H2, c ch bm proton, v/hoc thay i li sng v ch  n. Cc dc s) ang t vn cho ngi bnh dng ranitidin khng k n nn trao i v cc la chn iu tr v xem xt liu phc  hin ti c ph hp hay khng. Ti liu tham kho: 1. Cc Qun l Dc, Cng vn s 13124/QLD-CL v 13125/QLD-CL ngy 10/7/2018, 16813/QLD-CL, 16814/QLD-CL ngy 02/10/2019. 2. EMA (2019),  Sartan medicines: companies to review manufacturing processes to avoid presence of nitrosamine impurities , truy cp ngy 8/10/2019. 3. FDA (2019),  FDA updates table of interim limits for nitrosamine impurities in ARBs , truy cp ngy 8/10/2019. 4. Charoo NA et al (2019),  Lesson Learnt from Recall of Valsartan and Other Angiotensin II Receptor Blocker Drugs Containing NDMA and NDEA Impurities , AAPS PharmSciTech. 2019 Apr 15;20(5):166. doi: 10.1208/s12249-019-1376-1. 5. FDA (2019),  FDA announces voluntary recall of Sandoz ranitidine capsules following detection of an impurity , ngy 24/9/2019. 6. Health Canada (2019),  Health Canada requests that companies stop distributing ranitidine drugs in Canada while it assesses NDMA; additional products being recalled , ngy 26/9/2019. 7. HSA (2019),  HSA Stops Supply of Eight Brands of Ranitidine Products in Singapore , truy cp ngy 08/10/2019 8. 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