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Dantrium® Intravenous (dantrolene sodium for injection) DESCRIPTION: Dantrium Intravenous is a sterile, non-pyrogenic, lyophilized formulation of dantrolene sodium for injection. Dantrium Intravenous is VXSSOLHGLQP/YLDOVFRQWDLQLQJPJGDQWUROHQHVRGLXPPJPDQQLWRODQGVXI¿FLHQWVRGLXPK\GUR[LGHWR\LHOGDS+RIDSSUR[LPDWHO\ZKHQ UHFRQVWLWXWHGZLWKP/VWHULOHZDWHUIRULQMHFWLRQ863ZLWKRXWDEDFWHULRVWDWLFDJHQW DantriumLVFODVVL¿HGDVDGLUHFWDFWLQJVNHOHWDOPXVFOHUHOD[DQW&KHPLFDOO\ DantriumLVK\GUDWHG>>>QLWURSKHQ\OIXUDQ\O@PHWK\OHQH@DPLQR@ imidazolidinedione sodium salt. The structural formula for the hydrated salt is: 7KHK\GUDWHGVDOWFRQWDLQVDSSUR[LPDWHO\ZDWHUPROHVDQGKDVDPROHFXODUZHLJKWRI7KHDQK\GURXVVDOWGDQWUROHQHKDVDPROHFXODUZHLJKWRI CLINICAL PHARMACOLOGY: In isolated nerve-muscle preparation, DantriumKDVEHHQVKRZQWRSURGXFHUHOD[DWLRQE\DIIHFWLQJWKHFRQWUDFWLOHUHVSRQVHRI WKHPXVFOHDWDVLWHEH\RQGWKHP\RQHXUDOMXQFWLRQ,QVNHOHWDOPXVFOHDantriumGLVVRFLDWHVWKHH[FLWDWLRQFRQWUDFWLRQFRXSOLQJSUREDEO\E\LQWHUIHULQJZLWK WKHUHOHDVHRI&DIURPWKHVDUFRSODVPLFUHWLFXOXP7KHDGPLQLVWUDWLRQRILQWUDYHQRXVDantriumWRKXPDQYROXQWHHUVLVDVVRFLDWHGZLWKORVVRIJULSVWUHQJWK DQGZHDNQHVVLQWKHOHJVDVZHOODVVXEMHFWLYH&16FRPSODLQWVVHHDOVR35(&$87,216,QIRUPDWLRQIRU3DWLHQWV,QIRUPDWLRQFRQFHUQLQJWKHSDVVDJHRI DantriumDFURVVWKHEORRGEUDLQEDUULHULVQRWDYDLODEOH ,QWKHDQHVWKHWLFLQGXFHGPDOLJQDQWK\SHUWKHUPLDV\QGURPHHYLGHQFHSRLQWVWRDQLQWULQVLFDEQRUPDOLW\RIVNHOHWDOPXVFOHWLVVXH,QDIIHFWHGKXPDQVLWKDV EHHQSRVWXODWHGWKDW³WULJJHULQJDJHQWV´HJJHQHUDODQHVWKHWLFVDQGGHSRODUL]LQJQHXURPXVFXODUEORFNLQJDJHQWVSURGXFHDFKDQJHZLWKLQWKHFHOOZKLFK UHVXOWVLQDQHOHYDWHGP\RSODVPLFFDOFLXP7KLVHOHYDWHGP\RSODVPLFFDOFLXPDFWLYDWHVDFXWHFHOOXODUFDWDEROLFSURFHVVHVWKDWFDVFDGHWRWKHPDOLJQDQW hyperthermia crisis. It is hypothesized that addition of DantriumWRWKH³WULJJHUHG´PDOLJQDQWK\SHUWKHUPLFPXVFOHFHOOUHHVWDEOLVKHVDQRUPDOOHYHORILRQL]HGFDOFLXPLQWKHP\RSODVP ,QKLELWLRQRIFDOFLXPUHOHDVHIURPWKHVDUFRSODVPLFUHWLFXOXPE\ DantriumUHHVWDEOLVKHVWKHP\RSODVPLFFDOFLXPHTXLOLEULXPLQFUHDVLQJWKHSHUFHQWDJHRI ERXQGFDOFLXP,QWKLVZD\SK\VLRORJLFPHWDEROLFDQGELRFKHPLFDOFKDQJHVDVVRFLDWHGZLWKWKHPDOLJQDQWK\SHUWKHUPLDFULVLVPD\EHUHYHUVHGRUDWWHQXDWHG ([SHULPHQWDOUHVXOWVLQPDOLJQDQWK\SHUWKHUPLDVXVFHSWLEOHVZLQHVKRZWKDWSURSK\ODFWLFDGPLQLVWUDWLRQRILQWUDYHQRXVRURUDOGDQWUROHQHSUHYHQWVRUDWWHQXDWHV WKHGHYHORSPHQWRIYLWDOVLJQDQGEORRGJDVFKDQJHVFKDUDFWHULVWLFRIPDOLJQDQWK\SHUWKHUPLDLQDGRVHUHODWHGPDQQHU7KHHI¿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¿FDQWFDUGLRUHVSLUDWRU\FKDQJHV 6SHFL¿FPHWDEROLFSDWKZD\VIRUWKHGHJUDGDWLRQDQGHOLPLQDWLRQRI DantriumLQKXPDQVKDYHEHHQHVWDEOLVKHG'DQWUROHQHLVIRXQGLQPHDVXUDEOHDPRXQWVLQ EORRGDQGXULQH,WVPDMRUPHWDEROLWHVLQERG\ÀXLGVDUHK\GUR[\GDQWUROHQHDQGDQDFHW\ODPLQRPHWDEROLWHRIGDQWUROHQH$QRWKHUPHWDEROLWHZLWKDQXQNQRZQ structure appears related to the latter. DantriumPD\DOVRXQGHUJRK\GURO\VLVDQGVXEVHTXHQWR[LGDWLRQIRUPLQJQLWURSKHQ\OIXURLFDFLG 7KHPHDQELRORJLFKDOIOLIHRIDantriumDIWHULQWUDYHQRXVDGPLQLVWUDWLRQLVYDULDEOHEHWZHHQWRKRXUVXQGHUPRVWH[SHULPHQWDOFRQGLWLRQV%DVHGRQDVVD\V RIZKROHEORRGDQGSODVPDVOLJKWO\JUHDWHUDPRXQWVRIGDQWUROHQHDUHDVVRFLDWHGZLWKUHGEORRGFHOOVWKDQZLWKWKHSODVPDIUDFWLRQRIEORRG6LJQL¿FDQWDPRXQWV RIGDQWUROHQHDUHERXQGWRSODVPDSURWHLQVPRVWO\DOEXPLQDQGWKLVELQGLQJLVUHDGLO\UHYHUVLEOH &DUGLRSXOPRQDU\GHSUHVVLRQKDVQRWEHHQREVHUYHGLQPDOLJQDQWK\SHUWKHUPLDVXVFHSWLEOHVZLQHIROORZLQJWKHDGPLQLVWUDWLRQRIXSWRPJNJLYGDQWUROHQH 7KLVLVWZLFHWKHDPRXQWQHHGHGWRPD[LPDOO\GLPLQLVKWZLWFKUHVSRQVHWRVLQJOHVXSUDPD[LPDOSHULSKHUDOQHUYHVWLPXODWLRQLQKLELWLRQ$WUDQVLHQW LQFRQVLVWHQWGHSUHVVDQWHIIHFWRQJDVWURLQWHVWLQDOVPRRWKPXVFOHVKDVEHHQREVHUYHGDWKLJKGRVHV INDICATIONS AND USAGE: Dantrium IntravenousLVLQGLFDWHGDORQJZLWKDSSURSULDWHVXSSRUWLYHPHDVXUHVIRUWKHPDQDJHPHQWRIWKHIXOPLQDQW K\SHUPHWDEROLVPRIVNHOHWDOPXVFOHFKDUDFWHULVWLFRIPDOLJQDQWK\SHUWKHUPLDFULVHVLQSDWLHQWVRIDOODJHVDantrium,QWUDYHQRXVVKRXOGEHDGPLQLVWHUHGE\ continuous rapid intravenous push as soon as the malignant hyperthermia reaction is recognized (i.e., tachycardia, tachypnea, central venous desaturation, K\SHUFDUELDPHWDEROLFDFLGRVLVVNHOHWDOPXVFOHULJLGLW\LQFUHDVHGXWLOL]DWLRQRIDQHVWKHVLDFLUFXLWFDUERQGLR[LGHDEVRUEHUF\DQRVLVDQGPRWWOLQJRIWKHVNLQ and, in many cases, fever). Dantrium,QWUDYHQRXVLVDOVRLQGLFDWHGSUHRSHUDWLYHO\DQGVRPHWLPHVSRVWRSHUDWLYHO\WRSUHYHQWRUDWWHQXDWHWKHGHYHORSPHQWRIFOLQLFDODQGODERUDWRU\VLJQV RIPDOLJQDQWK\SHUWKHUPLDLQLQGLYLGXDOVMXGJHGWREHPDOLJQDQWK\SHUWKHUPLDVXVFHSWLEOH CONTRAINDICATIONS:1RQH WARNINGS: The use of Dantrium IntravenousLQWKHPDQDJHPHQWRIPDOLJQDQWK\SHUWKHUPLDFULVLVLVQRWDVXEVWLWXWHIRUSUHYLRXVO\NQRZQVXSSRUWLYH PHDVXUHV7KHVHPHDVXUHVPXVWEHLQGLYLGXDOL]HGEXWLWZLOOXVXDOO\EHQHFHVVDU\WRGLVFRQWLQXHWKHVXVSHFWWULJJHULQJDJHQWVDWWHQGWRLQFUHDVHGR[\JHQ UHTXLUHPHQWVPDQDJHWKHPHWDEROLFDFLGRVLVLQVWLWXWHFRROLQJZKHQQHFHVVDU\PRQLWRUXULQDU\RXWSXWDQGPRQLWRUIRUHOHFWURO\WHLPEDODQFH 6LQFHWKHHIIHFWRIGLVHDVHVWDWHDQGRWKHUGUXJVRQDantriumUHODWHGVNHOHWDOPXVFOHZHDNQHVVLQFOXGLQJSRVVLEOHUHVSLUDWRU\GHSUHVVLRQFDQQRWEHSUHGLFWHG SDWLHQWVZKRUHFHLYHLYDantrium preoperatively should have vital signs monitored. ,ISDWLHQWVMXGJHGPDOLJQDQWK\SHUWKHUPLDVXVFHSWLEOHDUHDGPLQLVWHUHGLQWUDYHQRXVRURUDODantriumSUHRSHUDWLYHO\DQHVWKHWLFSUHSDUDWLRQPXVWVWLOOIROORZ DVWDQGDUGPDOLJQDQWK\SHUWKHUPLDVXVFHSWLEOHUHJLPHQLQFOXGLQJWKHDYRLGDQFHRINQRZQWULJJHULQJDJHQWV0RQLWRULQJIRUHDUO\FOLQLFDODQGPHWDEROLFVLJQV RIPDOLJQDQWK\SHUWKHUPLDLVLQGLFDWHGEHFDXVHDWWHQXDWLRQRIPDOLJQDQWK\SHUWKHUPLDUDWKHUWKDQSUHYHQWLRQLVSRVVLEOH7KHVHVLJQVXVXDOO\FDOOIRUWKH administration of additional i.v. dantrolene. PRECAUTIONS: General:&DUHPXVWEHWDNHQWRSUHYHQWH[WUDYDVDWLRQRIDantriumVROXWLRQLQWRWKHVXUURXQGLQJWLVVXHVGXHWRWKHKLJKS+RIWKHLQWUDYHQRXVIRUPXODWLRQDQG potential for tissue necrosis. :KHQPDQQLWROLVXVHGIRUSUHYHQWLRQRUWUHDWPHQWRIODWHUHQDOFRPSOLFDWLRQVRIPDOLJQDQWK\SHUWKHUPLDWKHJRIPDQQLWROQHHGHGWRGLVVROYHHDFKPJYLDO of i.v. DantriumVKRXOGEHWDNHQLQWRFRQVLGHUDWLRQ Information for Patients:%DVHGXSRQGDWDLQKXPDQYROXQWHHUVSHULRSHUDWLYHO\LWLVDSSURSULDWHWRWHOOSDWLHQWVZKRUHFHLYHDantrium Intravenous that V\PSWRPVRIPXVFOHZHDNQHVVVKRXOGEHH[SHFWHGSRVWRSHUDWLYHO\LHGHFUHDVHLQJULSVWUHQJWKDQGZHDNQHVVRIOHJPXVFOHVHVSHFLDOO\ZDONLQJGRZQVWDLUV ,QDGGLWLRQV\PSWRPVVXFKDV³OLJKWKHDGHGQHVV´PD\EHQRWHG6LQFHVRPHRIWKHVHV\PSWRPVPD\SHUVLVWIRUXSWRKRXUVSDWLHQWVPXVWQRWRSHUDWHDQ DXWRPRELOHRUHQJDJHLQRWKHUKD]DUGRXVDFWLYLW\GXULQJWKLVWLPH&DXWLRQLVDOVRLQGLFDWHGDWPHDOVRQWKHGD\RIDGPLQLVWUDWLRQEHFDXVHGLI¿FXOW\VZDOORZLQJ DQGFKRNLQJKDVEHHQUHSRUWHG&DXWLRQVKRXOGEHH[HUFLVHGLQWKHFRQFRPLWDQWDGPLQLVWUDWLRQRIWUDQTXLOL]LQJDJHQWV +HSDWRWR[LFLW\VHHQ with Dantrium Capsules: Dantrium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antriumIRUYDU\LQJSHULRGVRIWLPH2YHUWKHSDWLWLVKDVRFFXUUHGDWYDU\LQJLQWHUYDOVDIWHULQLWLDWLRQRI WKHUDS\EXWKDVEHHQPRVWIUHTXHQWO\REVHUYHGEHWZHHQWKHWKLUGDQGWZHOIWKPRQWKRIWKHUDS\7KHULVNRIKHSDWLFLQMXU\DSSHDUVWREHJUHDWHULQIHPDOHV LQSDWLHQWVRYHU\HDUVRIDJHDQGLQSDWLHQWVWDNLQJRWKHUPHGLFDWLRQVLQDGGLWLRQWRDantrium (dantrolene sodium). DantriumVKRXOGEHXVHGRQO\LQ FRQMXQFWLRQZLWKDSSURSULDWHPRQLWRULQJRIKHSDWLFIXQFWLRQLQFOXGLQJIUHTXHQWGHWHUPLQDWLRQRI6*27RU6*37 )DWDODQGQRQIDWDOOLYHUGLVRUGHUVRIDQLGLRV\QFUDWLFRUK\SHUVHQVLWLYLW\W\SHPD\RFFXUZLWKDantrium therapy. Drug Interactions: DantriumLVPHWDEROL]HGE\WKHOLYHUDQGLWLVWKHRUHWLFDOO\SRVVLEOHWKDWLWVPHWDEROLVPPD\EHHQKDQFHGE\GUXJVNQRZQWRLQGXFHKHSDWLF PLFURVRPDOHQ]\PHV+RZHYHUQHLWKHUSKHQREDUELWDOQRUGLD]HSDPDSSHDUVWRDIIHFW DantriumPHWDEROLVP%LQGLQJWRSODVPDSURWHLQLVQRWVLJQL¿FDQWO\ DOWHUHGE\GLD]HSDPGLSKHQ\OK\GDQWRLQRUSKHQ\OEXWD]RQH%LQGLQJWRSODVPDSURWHLQVLVUHGXFHGE\ZDUIDULQDQGFOR¿EUDWHDQGLQFUHDVHGE\WROEXWDPLGH &DUGLRYDVFXODUFROODSVHLQDVVRFLDWLRQZLWKPDUNHGK\SHUNDOHPLDKDVEHHQUHSRUWHGLQSDWLHQWVUHFHLYLQJGDQWUROHQHLQFRPELQDWLRQZLWKFDOFLXPFKDQQHO EORFNHUV,WLVUHFRPPHQGHGWKDWWKHFRPELQDWLRQRILQWUDYHQRXVGDQWUROHQHVRGLXPDQGFDOFLXPFKDQQHOEORFNHUVVXFKDVYHUDSDPLOQRWEHXVHGWRJHWKHU during the management of malignant hyperthermia crisis. $GPLQLVWUDWLRQRIGDQWUROHQHPD\SRWHQWLDWHYHFXURQLXPLQGXFHGQHXURPXVFXODUEORFN Carcinogenesis, Mutagenesis, and Impairment of Fertility:6SUDJXH'DZOH\IHPDOHUDWVIHG Dantrium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incidence of hepatic lymphangiomas and hepatic angiosarcomas. 7KHRQO\GUXJUHODWHGHIIHFWVHHQLQDPRQWKVWXG\LQ)LVFKHUUDWVZDVDGRVHUHODWHGUHGXFWLRQLQWKHWLPHRIRQVHWRIPDPPDU\DQGWHVWLFXODUWXPRUV $PRQWKVWXG\LQ+D0,&5PLFHUHYHDOHGQRHYLGHQFHRIFDUFLQRJHQLFDFWLYLW\ 7KHVLJQL¿FDQFHRIFDUFLQRJHQLFLW\GDWDUHODWLYHWRXVHRIDantriumLQKXPDQVLVXQNQRZQ 'DQWUROHQHVRGLXPKDVSURGXFHGSRVLWLYHUHVXOWVLQWKH$PHV67\SKLPXULXPEDFWHULDOPXWDJHQHVLVDVVD\LQWKHSUHVHQFHDQGDEVHQFHRIDOLYHUDFWLYDWLQJV\VWHP 'DQWUROHQHVRGLXPDGPLQLVWHUHGWRPDOHDQGIHPDOHUDWVDWGRVHOHYHOVXSWRPJNJGD\DSSUR[LPDWHO\WLPHVWKHPD[LPXPUHFRPPHQGHGGDLO\GRVHRQ DPJP 2 EDVLVVKRZHGQRDGYHUVHHIIHFWVRQIHUWLOLW\RUJHQHUDOUHSURGXFWLYHSHUIRUPDQFH Pregnancy: 3UHJQDQF\&DWHJRU\&DantriumKDVEHHQVKRZQWREHHPEU\RFLGDOLQWKHUDEELWDQGKDVEHHQVKRZQWRGHFUHDVHSXSVXUYLYDOLQWKHUDWZKHQ JLYHQDWGRVHVVHYHQWLPHVWKHKXPDQRUDOGRVH7KHUHDUHQRDGHTXDWHDQGZHOOFRQWUROOHGVWXGLHVLQSUHJQDQWZRPHQDantrium IntravenousVKRXOGEH XVHGGXULQJSUHJQDQF\RQO\LIWKHSRWHQWLDOEHQH¿WMXVWL¿HVWKHSRWHQWLDOULVNWRWKHIHWXV Labor and Delivery: In one uncontrolled study, 100 mg per day of prophylactic oral DantriumZDVDGPLQLVWHUHGWRWHUPSUHJQDQWSDWLHQWVDZDLWLQJODERU DQGGHOLYHU\'DQWUROHQHUHDGLO\FURVVHGWKHSODFHQWDZLWKPDWHUQDODQGIHWDOZKROHEORRGOHYHOVDSSUR[LPDWHO\HTXDODWGHOLYHU\QHRQDWDOOHYHOVWKHQIHOO DSSUR[LPDWHO\SHUGD\IRUGD\VEHIRUHGHFOLQLQJVKDUSO\1RQHRQDWDOUHVSLUDWRU\DQGQHXURPXVFXODUVLGHHIIHFWVZHUHGHWHFWHGDWORZGRVH0RUHGDWD DWKLJKHUGRVHVDUHQHHGHGEHIRUHPRUHGH¿QLWLYHFRQFOXVLRQVFDQEHPDGH Nursing Mothers:'DQWUROHQHKDVEHHQGHWHFWHGLQKXPDQPLONDWORZFRQFHQWUDWLRQVOHVVWKDQPLFURJUDPVSHUP/GXULQJUHSHDWLQWUDYHQRXVDGPLQLVWUDWLRQ RYHUGD\V%HFDXVHRIWKHSRWHQWLDOIRUVHULRXVDGYHUVHUHDFWLRQVLQQXUVLQJLQIDQWVIURPGDQWUROHQHDGHFLVLRQVKRXOGEHPDGHZKHWKHUWRGLVFRQWLQXHQXUVLQJ RUWRGLVFRQWLQXHWKHGUXJWDNLQJLQWRDFFRXQWWKHLPSRUWDQFHRIWKHGUXJWRWKHPRWKHU Geriatric Use:&OLQLFDOVWXGLHVRIDantrium IntravenousGLGQRWLQFOXGHVXI¿FLHQWQXPEHUVRIVXEMHFWVDJHGDQGRYHUWRGHWHUPLQHZKHWKHUWKH\UHVSRQG GLIIHUHQWO\IURP\RXQJHUVXEMHFWV2WKHUUHSRUWHGFOLQLFDOH[SHULHQFHKDVQRWLGHQWL¿HGGLIIHUHQFHVLQUHVSRQVHVEHWZHHQWKHHOGHUO\DQG\RXQJHUSDWLHQWV ,QJHQHUDOGRVHVHOHFWLRQIRUDQHOGHUO\SDWLHQWVKRXOGEHFDXWLRXVUHÀHFWLQJWKHJUHDWHUIUHTXHQF\RIGHFUHDVHGKHSDWLFUHQDORUFDUGLDFIXQFWLRQDQGRI concomitant disease or other drug therapy. ADVERSE REACTIONS: 7KHUHKDYHEHHQRFFDVLRQDOUHSRUWVRIGHDWKIROORZLQJPDOLJQDQWK\SHUWKHUPLDFULVLVHYHQZKHQWUHDWHGZLWKLQWUDYHQRXVGDQWUROHQH LQFLGHQFH¿JXUHVDUHQRWDYDLODEOHWKHSUHGDQWUROHQHPRUWDOLW\RIPDOLJQDQWK\SHUWKHUPLDFULVLVZDVDSSUR[LPDWHO\0RVWRIWKHVHGHDWKVFDQEHDFFRXQWHG IRUE\ODWHUHFRJQLWLRQGHOD\HGWUHDWPHQWLQDGHTXDWHGRVDJHODFNRIVXSSRUWLYHWKHUDS\LQWHUFXUUHQWGLVHDVHDQGRUWKHGHYHORSPHQWRIGHOD\HGFRPSOLFDWLRQV VXFKDVUHQDOIDLOXUHRUGLVVHPLQDWHGLQWUDYDVFXODUFRDJXORSDWK\,QVRPHFDVHVWKHUHDUHLQVXI¿FLHQWGDWDWRFRPSOHWHO\UXOHRXWWKHUDSHXWLFIDLOXUHRIGDQWUROHQH 7KHUHDUHUHSRUWVRIIDWDOLW\LQPDOLJQDQWK\SHUWKHUPLDFULVLVGHVSLWHLQLWLDOVDWLVIDFWRU\UHVSRQVHWRLYGDQWUROHQHZKLFKLQYROYHSDWLHQWVZKRFRXOGQRWEH ZHDQHGIURPGDQWUROHQHDIWHULQLWLDOWUHDWPHQW The administration of intravenous DantriumWRKXPDQYROXQWHHUVLVDVVRFLDWHGZLWKORVVRIJULSVWUHQJWKDQGZHDNQHVVLQWKHOHJVDVZHOODVGURZVLQHVV and dizziness. 7KHIROORZLQJDGYHUVHUHDFWLRQVDUHLQDSSUR[LPDWHRUGHURIVHYHULW\ 7KHUHDUHUDUHUHSRUWVRISXOPRQDU\HGHPDGHYHORSLQJGXULQJWKHWUHDWPHQWRIPDOLJQDQWK\SHUWKHUPLDFULVLVLQZKLFKWKHGLOXHQWYROXPHDQGPDQQLWRO QHHGHGWRGHOLYHULYGDQWUROHQHSRVVLEO\FRQWULEXWHG 7KHUHKDYHEHHQUHSRUWVRIWKURPERSKOHELWLVIROORZLQJDGPLQLVWUDWLRQRILQWUDYHQRXVGDQWUROHQHDFWXDOLQFLGHQFH¿JXUHVDUHQRWDYDLODEOH7LVVXHQHFURVLV VHFRQGDU\WRH[WUDYDVDWLRQKDVEHHQUHSRUWHG 7KHUHKDYHEHHQUDUHUHSRUWVRIXUWLFDULDDQGHU\WKHPDSRVVLEO\DVVRFLDWHGZLWKWKHDGPLQLVWUDWLRQRILYDantrium7KHUHKDVEHHQRQHFDVHRIDQDSK\OD[LV ,QMHFWLRQVLWHUHDFWLRQVSDLQHU\WKHPDVZHOOLQJFRPPRQO\GXHWRH[WUDYDVDWLRQKDYHEHHQUHSRUWHG 1RQHRIWKHVHULRXVUHDFWLRQVRFFDVLRQDOO\UHSRUWHGZLWKORQJWHUPRUDODantriumXVHVXFKDVKHSDWLWLVVHL]XUHVDQGSOHXUDOHIIXVLRQZLWKSHULFDUGLWLVKDYH EHHQUHDVRQDEO\DVVRFLDWHGZLWKVKRUWWHUPDantrium Intravenous therapy. 7KHIROORZLQJHYHQWVKDYHEHHQUHSRUWHGLQSDWLHQWVUHFHLYLQJRUDOGDQWUROHQHDSODVWLFDQHPLDOHXNRSHQLDO\PSKRF\WLFO\PSKRPDDQGKHDUWIDLOXUH6HH SDFNDJHLQVHUWIRUDantrium (dantrolene sodium) Capsules for a complete listing of adverse reactions.) 7KHSXEOLVKHGOLWHUDWXUHKDVLQFOXGHGVRPHUHSRUWVRIDantriumXVHLQSDWLHQWVZLWK1HXUROHSWLF0DOLJQDQW6\QGURPH106Dantrium Intravenous is not LQGLFDWHGIRUWKHWUHDWPHQWRI106DQGSDWLHQWVPD\H[SLUHGHVSLWHWUHDWPHQWZLWKDantrium Intravenous. )RUPHGLFDODGYLFHDERXWDGYHUVHUHDFWLRQVFRQWDFW\RXUPHGLFDOSURIHVVLRQDO7RUHSRUW6863(&7('$'9(56(5($&7,216FRQWDFW-+3DW RU0(':$7&+DW)'$RUKWWSZZZIGDJRYPHGZDWFK OVERDOSAGE: %HFDXVHDantrium IntravenousPXVWEHDGPLQLVWHUHGDWDORZFRQFHQWUDWLRQLQDODUJHYROXPHRIÀXLGDFXWHWR[LFLW\RIDantrium could not EHDVVHVVHGLQDQLPDOV,QGD\VXEDFXWHVWXGLHVWKHLQWUDYHQRXVIRUPXODWLRQRIDantriumZDVUHODWLYHO\QRQWR[LFWRUDWVDWGRVHVRIPJNJGD\DQG PJNJGD\:KLOHPJNJGD\LQGRJVIRUGD\VHYRNHGOLWWOHWR[LFLW\PJNJGD\IRUGD\VFDXVHGKHSDWLFFKDQJHVRITXHVWLRQDEOHELRORJLFVLJQL¿FDQFH 6\PSWRPVZKLFKPD\RFFXULQFDVHRIRYHUGRVHLQFOXGHEXWDUHQRWOLPLWHGWRPXVFXODUZHDNQHVVDQGDOWHUDWLRQVLQWKHVWDWHRIFRQVFLRXVQHVVHJOHWKDUJ\ coma), vomiting, diarrhea, and crystalluria. )RUDFXWHRYHUGRVDJHJHQHUDOVXSSRUWLYHPHDVXUHVVKRXOGEHHPSOR\HG ,QWUDYHQRXVÀXLGVVKRXOGEHDGPLQLVWHUHGLQIDLUO\ODUJHTXDQWLWLHVWRDYHUWWKHSRVVLELOLW\RIFU\VWDOOXULD$QDGHTXDWHDLUZD\VKRXOGEHPDLQWDLQHGDQGDUWL¿FLDO UHVXVFLWDWLRQHTXLSPHQWVKRXOGEHDWKDQG(OHFWURFDUGLRJUDSKLFPRQLWRULQJVKRXOGEHLQVWLWXWHGDQGWKHSDWLHQWFDUHIXOO\REVHUYHG7KHYDOXHRIGLDO\VLVLQ DantriumRYHUGRVHLVQRWNQRZQ DOSAGE AND ADMINISTRATION:$VVRRQDVWKHPDOLJQDQWK\SHUWKHUPLDUHDFWLRQLVUHFRJQL]HGDOODQHVWKHWLFDJHQWVVKRXOGEHGLVFRQWLQXHGWKH DGPLQLVWUDWLRQRIR[\JHQLVUHFRPPHQGHGDantrium IntravenousVKRXOGEHDGPLQLVWHUHGE\FRQWLQXRXVUDSLGLQWUDYHQRXVSXVKEHJLQQLQJDWDPLQLPXP GRVHRIPJNJDQGFRQWLQXLQJXQWLOV\PSWRPVVXEVLGHRUWKHPD[LPXPFXPXODWLYHGRVHRIPJNJKDVEHHQUHDFKHG ,IWKHSK\VLRORJLFDQGPHWDEROLFDEQRUPDOLWLHVUHDSSHDUWKHUHJLPHQPD\EHUHSHDWHG,WLVLPSRUWDQWWRQRWHWKDWDGPLQLVWUDWLRQRIDantrium Intravenous VKRXOGEHFRQWLQXRXVXQWLOV\PSWRPVVXEVLGH7KHHIIHFWLYHGRVHWRUHYHUVHWKHFULVLVLVGLUHFWO\GHSHQGHQWXSRQWKHLQGLYLGXDO¶VGHJUHHRIVXVFHSWLELOLW\WR PDOLJQDQWK\SHUWKHUPLDWKHDPRXQWDQGWLPHRIH[SRVXUHWRWKHWULJJHULQJDJHQWDQGWKHWLPHHODSVHGEHWZHHQRQVHWRIWKHFULVLVDQGLQLWLDWLRQRIWUHDWPHQW Pediatric Dose:([SHULHQFHWRGDWHLQGLFDWHVWKDWWKHGRVHRIDantrium Intravenous for pediatric patients is the same as for adults. Preoperatively: Dantrium IntravenousDQGRU Dantrium CapsulesPD\EHDGPLQLVWHUHGSUHRSHUDWLYHO\WRSDWLHQWVMXGJHGPDOLJQDQWK\SHUWKHUPLD VXVFHSWLEOHDVSDUWRIWKHRYHUDOOSDWLHQWPDQDJHPHQWWRSUHYHQWRUDWWHQXDWHWKHGHYHORSPHQWRIFOLQLFDODQGODERUDWRU\VLJQVRIPDOLJQDQWK\SHUWKHUPLD Dantrium Intravenous: The recommended prophylactic dose of Dantrium IntravenousLVPJNJVWDUWLQJDSSUR[LPDWHO\KRXUVEHIRUH DQWLFLSDWHGDQHVWKHVLDDQGLQIXVHGRYHUDSSUR[LPDWHO\KRXU7KLVGRVHVKRXOGSUHYHQWRUDWWHQXDWHWKHGHYHORSPHQWRIFOLQLFDODQGODERUDWRU\VLJQV RIPDOLJQDQWK\SHUWKHUPLDSURYLGHGWKDWWKHXVXDOSUHFDXWLRQVVXFKDVDYRLGDQFHRIHVWDEOLVKHGPDOLJQDQWK\SHUWKHUPLDWULJJHULQJDJHQWVDUHIROORZHG $GGLWLRQDODantrium IntravenousPD\EHLQGLFDWHGGXULQJDQHVWKHVLDDQGVXUJHU\EHFDXVHRIWKHDSSHDUDQFHRIHDUO\FOLQLFDODQGRUEORRGJDVVLJQVRI PDOLJQDQWK\SHUWKHUPLDRUEHFDXVHRISURORQJHGVXUJHU\VHHDOVR&/,1,&$/3+$50$&2/2*<:$51,1*6DQG35(&$87,216$GGLWLRQDOGRVHV PXVWEHLQGLYLGXDOL]HG Oral Administration of Dantrium Capsules:$GPLQLVWHUWRPJNJGD\RIRUDODantrium in three or four divided doses for 1 or 2 days prior to surgery, ZLWKWKHODVWGRVHEHLQJJLYHQZLWKDPLQLPXPRIZDWHUDSSUR[LPDWHO\WRKRXUVEHIRUHVFKHGXOHGVXUJHU\$GMXVWPHQWFDQXVXDOO\EHPDGHZLWKLQWKH UHFRPPHQGHGGRVDJHUDQJHWRDYRLGLQFDSDFLWDWLRQZHDNQHVVGURZVLQHVVHWFRUH[FHVVLYHJDVWURLQWHVWLQDOLUULWDWLRQQDXVHDDQGRUYRPLWLQJ6HH DOVRWKHSDFNDJHLQVHUWIRU Dantrium Capsules. Post Crisis Follow-Up: Dantrium CapsulesWRPJNJGD\LQIRXUGLYLGHGGRVHVVKRXOGEHDGPLQLVWHUHGIRUWRGD\VIROORZLQJDPDOLJQDQWK\SHUWKHUPLD crisis to prevent recurrence of the manifestations of malignant hyperthermia. Intravenous DantriumPD\EHXVHGSRVWRSHUDWLYHO\WRSUHYHQWRUDWWHQXDWHWKHUHFXUUHQFHRIVLJQVRIPDOLJQDQWK\SHUWKHUPLDZKHQRUDODantrium administration is not practical. The i.v. dose of DantriumLQWKHSRVWRSHUDWLYHSHULRGPXVWEHLQGLYLGXDOL]HGVWDUWLQJZLWKPJNJRUPRUHDVWKHFOLQLFDOVLWXDWLRQGLFWDWHV PREPARATION:(DFKYLDORIDantrium IntravenousVKRXOGEHUHFRQVWLWXWHGE\DGGLQJP/RIVWHULOHZDWHUIRULQMHFWLRQ863ZLWKRXWDEDFWHULRVWDWLFDJHQW DQGWKHYLDOVKDNHQXQWLOWKHVROXWLRQLVFOHDU'H[WURVH,QMHFWLRQ8636RGLXP&KORULGH,QMHFWLRQ863DQGRWKHUDFLGLFVROXWLRQVDUHQRWFRPSDWLEOHZLWK Dantrium Intravenous DQGVKRXOGQRWEHXVHG7KHFRQWHQWVRIWKHYLDOPXVWEHSURWHFWHGIURPGLUHFWOLJKWDQGXVHGZLWKLQKRXUVDIWHUUHFRQVWLWXWLRQ6WRUH UHFRQVWLWXWHGVROXWLRQVEHWZHHQWR&WR) 5HFRQVWLWXWHGDantrium IntravenousVKRXOGQRWEHWUDQVIHUUHGWRODUJHJODVVERWWOHVIRUSURSK\ODFWLFLQIXVLRQGXHWRSUHFLSLWDWHIRUPDWLRQREVHUYHGZLWKWKH XVHRIVRPHJODVVERWWOHVDVUHVHUYRLUV )RUSURSK\ODFWLFLQIXVLRQWKHUHTXLUHGQXPEHURILQGLYLGXDOYLDOVRIDantrium IntravenousVKRXOGEHUHFRQVWLWXWHGDVRXWOLQHGDERYH7KHFRQWHQWVRILQGLYLGXDO YLDOVDUHWKHQWUDQVIHUUHGWRDODUJHUYROXPHVWHULOHLQWUDYHQRXVSODVWLFEDJ6WDELOLW\GDWDRQ¿OHDW-+33KDUPDFHXWLFDOVLQGLFDWHFRPPHUFLDOO\DYDLODEOH VWHULOHSODVWLFEDJVDUHDFFHSWDEOHGUXJGHOLYHU\GHYLFHV+RZHYHULWLVUHFRPPHQGHGWKDWWKHSUHSDUHGLQIXVLRQEHLQVSHFWHGFDUHIXOO\IRUFORXGLQHVVDQGRU SUHFLSLWDWLRQSULRUWRGLVSHQVLQJDQGDGPLQLVWUDWLRQ6XFKVROXWLRQVVKRXOGQRWEHXVHG:KLOHVWDEOHIRUKRXUVLWLVUHFRPPHQGHGWKDWWKHLQIXVLRQEHSUHSDUHG immediately prior to the anticipated dosage administration time. 3DUHQWHUDOGUXJSURGXFWVVKRXOGEHLQVSHFWHGYLVXDOO\IRUSDUWLFXODWHPDWWHUDQGGLVFRORUDWLRQSULRUWRDGPLQLVWUDWLRQ HOW SUPPLIED: Dantrium Intravenous (NDCLVDYDLODEOHLQYLDOVFRQWDLQLQJDVWHULOHO\RSKLOL]HGPL[WXUHRIPJGDQWUROHQHVRGLXP PJPDQQLWRODQGVXI¿FLHQWVRGLXPK\GUR[LGHWR\LHOGDS+RIDSSUR[LPDWHO\ZKHQUHFRQVWLWXWHGZLWKP/VWHULOHZDWHUIRULQMHFWLRQ863ZLWKRXW DEDFWHULRVWDWLFDJHQW 6WRUHXQUHFRQVWLWXWHGSURGXFWEHWZHHQWR&WR)6HH863&RQWUROOHG5RRP7HPSHUDWXUH$YRLGSURORQJHGH[SRVXUHWROLJKW 5[RQO\ 3UHVFULELQJ,QIRUPDWLRQDVRI6HSWHPEHU 0DQXIDFWXUHG 'LVWULEXWHGE\ -+33KDUPDFHXWLFDOV//& 5RFKHVWHU0, Dantrium Intravenous (dantrolene sodium for injection) OSE_1404_part2_Layout 1 4/4/14 2:39 PM Page 80