CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 40334 DRAFT FINAL PRINTED LABELING“op / ; i aetie : Bf : mais |: Fluorouracil i ‘als Injection, USP - 3 z PHARMACY BULK PACKAGE NOT FOR DIRECT INFUSION . e : wane . Its recommended that tuororac be gven only by o under the supervision ‘of qua ig physica who fs exenence cance chemotherapy and who Ee iS well versed in he vse of potent antmelaboies. Because ofthe poss fo severe tx reactions. ti recommended thal patents be hosptazed at leat curing the intial course of tharapy ‘These instructions shouldbe thorough reviewed belore administration of ‘ivoururact nection + DESCRIPTION Fuorourac injection, an antineoplastic artimatabolte, is a colores to fait yllon ‘aueods, tele, nonpyogentemjecable solution avaiable in a 50 mL and 100 mL Pharmacy Buk Pekage for intravenous agitation. Each mL carans 60 mg fiuorouact in water for injection, USP, pH is adjusted To 8.6 to 9.4 wth soon : hydronce Chemically, Nworouraeh, 2 Nuornated pytimisin, Is Sluoro-2.4 (13H) pytimignetione. Ns a white to pracy wie crystaine powder Which _ Sparing sluble in water Te structural formulas 4 CP seston casero, Hh Mer wet 3008 é |A Pharmacy Bulk Package isa container of sterile preparation for parenteral use that conta many single oses, The contents ate intended fr use na pharmacy asmoaure progam and re restcted to te preparation of admixtures. fr intravenous fusion. 7 CLINICAL PHARMACOLOGY ‘Ther evidnoe that he metbatsm of fluorourac inthe anabolic pathway blocks {he methylation reaction of deoxyudyc acto thymidye ai, In tis manner, ‘voroural interferes wih ine synhesis of deeayibonultc acd (ONA) and 109 lager extent ints the formation of ibonutee aig (RNA). Since ONA and RNR. : ae essential for cel sion and grow the effect of uorcuraci may be to crete 2 thymine deficiency wich provokes unbalnoed growth and death ofthe cel. The tttects of DNA and ANA depmation ae mast marked on those calls which grow ‘ore rpiy and which take up Tworouraci ata moe rapid ate Flowing intravenous injection, fuorouract distributes into tumors, inlestna ‘ueosa, bone marrow, ver an other tissues throughout the body. In ste of ts Swed pi solubiy, Muorouach duces ready across the blood-brain bart ‘ng distbutes into cerebrospinal fad and brain issue ‘Seven percent o 20% ofthe parent drug is excreted unchanged inthe urine 6 hour; of is over 90% is excreted inthe fst hou, The remairing ercentage of the adminsteted. dose is metaboized, prmariy in the iver. The-catabolc ‘metabolism offuorouracl esis in degradation products (e 9. CO, wea and a: ‘iuoro-Balanine) which are inactve. The Inactive retaboltes are excreted in the tue over the next 3 to hours When Mugrourac Is labeled in the six carbon - Poston, thus preverting the “C metabolism to CO, approximately 90% of theft ‘adioactvty is excreted nthe urine. When fuorural is ebele nthe to carbon Dostion approximately 90% ofthe ttl radoacity is excreted in expired CO, Ninety percent of te dose le aszounted Yor during the Wst 24 nour following intravenous aéministaton.2 Following intravenous administration of fuorauracl, the” mean halle of ‘eimination from plasma is approximately 16 minutes, wih 2 range of 8 to 20 Trinuts, and i dose oependen No Intact drug can be detected m the plasma Shure ater an ravenous mecbon INDICATIONS AND USAGE Fuorourac is effective inthe paliatve management of carcinoma of the colon rectum, breast, stomach and paereas. CCONTRAINOICATIONS Fuorourac therapy is contraindicated for patents na poor nutritional state, hose wih depressed bone marrow function, those with potently senous nections or ‘hose with a town hypersenstly to Huarourac [WARNINGS (see bored WARNING) THE OAILY DOSE OF FLUOROURACIL 1S NOT TO EXGEED 200 MG_IT IS RECOMMENDED THAT PATIENTS. BE HOSPITALIZED OURING THEIR FIRST ‘COURSE OF TREATMENT. Fiuorouracl shoud be used with xtreme cation in poor risk paints wi history of high-dose pele radian or previous use falling agents, those wo have 4 wiaaspread volvement of tone martw by metas tumors oF those ih inated neva or renal uncton Rare, unexpctes, severe txicty (eg. stomatis, dara, neutropenia, and raurtoncty asstited wi Sluoraurack has Deen atbuted to deficiency of ‘pyndine Sehysrogenase activity. Tew paler have been rechallenged wih Sverowach ano desphe Sfvorouracl dese lowering, Toxety ecu 306 Drogessed wih worse morbidity, Absence of ths catatokc enzyme appears resut in prolonged clearance of §-fueroraci Pregnancy: TeratogentcEfects- Pregnancy Calegry D.Fuoroural may cause feta harm when administered toa pregnant woman, Fuorouracl has been shown to be teratogenic in Taboretory animals. Flvorouraci exhibited maximum teatogeniy when gen to mice 2s single inrapettonea jection of 19 to 40 rmghkg on ay 10 or 72 of gestation. Simla, ntrapentoneat doses of 1210 37 mg/Kg oven to rats between cays 9 and 72 f gestation and tramuscular Gases of ‘To $ mg gwen to namsters between days 8 and 1¥ of gestation wee teratogenc. iuatormationsinctuded cet plate, skeeal detects and deformed appendages paws and tis. The dosages which were teratogenic animals are 110 3times the ‘aximum reconmendea human ierapevt dose. monkeys, dived doses of 40 Imgikg given betwaen days 20 and 24 of gestation were nat eratgens, There are no adequate and wel-conrle studies with tuorouai in pregnant women Whe theres no evidence of tratogenty in humans duet lurauacl i should be kept in mind that other drugs which inhibit DNA synthesis (e.9. Imetnotreate and aminopern) have een reported to be teratogenic i humans Women of ehidbearing polenta shouldbe advises to wold becoming pear. 1 the org is used during pregnancy, or ft patent becomes pregnant whe taking the drug, the patent shouldbe tl ofthe potrl Nazar fo he fetus, Furouract Sto ew genannten estes he poeta fskro the Vetus Combination Trerapy: Any form of therapy which adds to testes ofthe patent Intereres wan ution oF depresses Done marrow functon wl crease the Tove of feorouract PRECAUTIONS Genera Forourai is a highly toxic drug with a narrow margin of salty Therefore, patents shoul be catty supetsed, since therapeu response is unity to GecuF without some evidenee of toxcty.Savere Pematologia foo, bistromtestia hemormage and even dean may result Yom the use of ficrourac ‘espe meticulous selection of patients and careul atjstment of dosage. Although ‘severe toc is more ley in poo risk pallets, fatalles may be encountered ‘Occasional even in patents in velately good consti, ‘Therapy isto be discontinued promptly whenever one ofthe following signs of toxiiy appears 1. Stomattis of esophapopharyngts the fst visible sign 2 Leukopena (WC under 3500) ora raphy fling Whi Baad count. 3. Vomiting, tractabe { Daarea, requert bowel moverents or watery soos 5, Gastoiniesina eration and Beoding. 6 Thrombocytopenia (platelets under 100,000), 7 Hemorthage from anys ‘The administation of S-tuorowacl nas been associated with the occurence of palmar planter erythvodysestnesa syndrome, also known as hand-oot syndrome ‘his syndrome has been characieized as 2 tnging sensation of hands an fet ich may progress over the next ew dys to pain when holding objects of walking