prescription drug Approval No. solution Attached dissolving (Content per kit) Flomoxef sodium 1 g (potency) Sodium chloride 50 mg

Transcription

1 Shioogi & Co., Ltd. Revised: Jue 9 (9th versio) Stadard Commodity Classificatio o. of Japa 87 - Oxacephem atibiotic aget - FLUMARI for Itraveous Ijectio. g FLUMARI for Itraveous Ijectio g FLUMARI Kit for Itraveous Ijectio g The Japaese Pharmacopoeia Flomoxef sodium for ijectio prescriptio drug Storage Store at room temperature. (See PRECAUTIOS FOR HADLIG sectio) Expiratio date Idicated o the package, etc. (Expiratio period: Two years) Approval o.. g for IV Ij. EMZ 8 g for IV Ij. EMZ 9 g Kit for IV Ij. AMZ 7 Date of listig i the HI reimbursemet price May 988 May 988 ov Date of iitial marketig i Japa May 988 May 988 Ja Date of latest reexamiatio Dec 99 Dec 99 - Date of latest reevaluatio Sep Sep Sep Date of latest approval of idicatios Aug 99 Aug 99 - Cautio - Use oly as directed by a physicia COTRAIDICATIOS (FLUMARI is cotraidicated i the followig patiets.) Patiets with a history of shock followig exposure to ay of the igrediets i this product RELATIVE COTRAIDICATIOS (As a geeral rule, FLUMARI is cotraidicated i the followig patiets. If the use of FLUMARI is cosidered essetial, it should be admiistered with care.) Patiets with a history of hypersesitivity to ay of the igrediets i this product or to other cephalospori atibiotics DESCRIPTIO. Compositio Brad ame IV Ij.. g Igrediet / cotet (Cotet per vial or kit) Additives Flomoxef sodium. g (potecy) Sodium chloride mg. Product descriptio Brad ame IV Ij.. g A white to light yellowish white, Descriptio light mass or powder (Ijectio) ph Osmotic pressure ratio.-. mg (potecy) / ml aqueous solutio Approx. g (potecy) / IV Ij. g Flomoxef sodium g (potecy) Sodium chloride mg IV Ij. g A white to light yellowish white, light mass or powder (Ijectio).-. mg (potecy) / ml aqueous solutio Approx. g (potecy) / FLUMARI Kit for IV Ij. g Flomoxef sodium g (potecy) Sodium chloride mg FLUMARI Kit for IV Ij. g A white to light yellowish white powder (Ijectio).-. g (potecy) / ml isotoic sodium chloride solutio Approx. g (potecy) (to isotoic sodium chloride solutio) Attached dissolvig solutio (Cotet per kit) ml aqueous solutio ml aqueous solutio - - / ml isotoic sodium chloride solutio Japaese pharmacopoeia (JP) isotoic sodium chloride solutio ml Kit: A ijectable form i a plastic cotaier with two chambers separated by a partitio, the upper chamber filled with flomoxef sodium ad the lower oe filled with dissolvig solutio. IDICATIOS <Susceptible strais> Flomoxef sodium susceptible strais of Staphylococcus sp., Streptococcus sp., Peumococcus sp., eisseria goorrhoeae, Moraxella (Brahamella) catarrhalis, Escherichia coli, Klebsiella sp., Proteus sp., Morgaella morgaii, Providecia sp., Haemophilus ifluezae, Peptostreptococcus sp., Bacteroides sp., Prevotella sp. (excludig Prevotella bivia) <Idicatios> Septicemia, ifectious edocarditis (Superficial) secodary ifectios i trauma, burs, surgical wouds, etc. Pharygolarygitis, tosillitis, acute brochitis, secodary ifectios i chroic respiratory diseases Cystitis, pyeloephritis, prostatitis (acute, chroic) Urethritis Peritoitis, itraabdomial abscess Cholecystitis, cholagitis Bartholiitis, itrauterie ifectio, uterie adexitis, parametritis

2 Shioogi & Co., Ltd. Otitis media, siusitis DOSAGE AD ADMIISTRATIO. Itraveous Ijectio. g ad Itraveous Ijectio g Usually, for adults, - g (potecy) of flomoxef sodium daily is ijected or ifused itraveously i divided doses. Usually, for childre, -8 mg (potecy)/kg daily is ijected or ifused itraveously i to divided doses. Usually, for premature ifats ad eoates, a dose of mg (potecy)/kg is ijected or ifused itraveously - times daily withi days after birth ad - times daily from the th day after birth. The dosage should be adjusted accordig to the age of patiet ad severity of the symptoms. I refractory or severe ifectios, the dose may be icreased to g (potecy) daily i to divided doses for adults, ad mg (potecy)/kg daily i to divided doses for premature ifats, eoates ad childre.. FLUMARI Kit for Itraveous Ijectio g Usually, for adults, - g (potecy) of flomoxef sodium daily is ifused itraveously i divided doses. Usually, for childre, -8 mg (potecy)/kg daily is ifused itraveously i to divided doses. Usually, for premature ifats ad eoates, a dose of mg (potecy)/kg is ifused itraveously - times daily withi days after birth ad - times daily from the th day after birth. The dosage should be adjusted accordig to the age of patiet ad severity of the symptoms. I refractory or severe ifectios, the dose may be icreased to g (potecy) daily i to divided doses for adults, ad mg (potecy)/kg daily i to divided doses for premature ifats, eoates ad childre. For referece: Preparatio of ijectable solutio. Itraveous Ijectio. g (potecy) ad g (potecy) each i ml vial. This product should be dissolved by shakig well after additio of ot less tha ml of water for ijectio, % glucose solutio for ijectio or isotoic sodium chloride solutio. Whe this product is ifused itraveously, water for ijectio must ot be used as solvet, because, with water for ijectio, this product does't become isotoic.. FLUMARI Kit for Itraveous Ijectio g (potecy) Flomoxef sodium should be dissolved i the attached dissolvig solutio by pressig o the side of the bag where the dissolvig solutio (isotoic sodium chloride solutio (JP)) is filled, to break the partitio betwee the drug ad dissolvig solutio, ad the pressig repeatedly o the bag to recostitute the drug substace thoroughly. (For further details, refer to Dissolutio Procedure prited o the outer plastic packagig ad alumium cover sheet of the kit product.) Precautios. As a geeral rule, the duratio of admiistratio of this drug should be limited to the miimum period required for the treatmet of the patiet s coditio, after susceptibility of the microorgaism to the drug has bee cofirmed, i order to prevet the emergece of drug-resistat microorgaisms.. Whe usig this drug i low birth weight ifats (premature ifats) or eoates, the umber of weeks spet i fetal period ad the body weight should be cosidered. [See Pediatric Use ad PHARMA-COKIETICS sectio] PRECAUTIOS. Careful Admiistratio (FLUMARI should be admiistered with care i the followig patiets.) () For the use of vial ad kit product ) Patiets with a history of hypersesitivity to peicillis ) Patiets with a persoal or familial predispositio to allergic reactios such as brochial asthma, rash ad urticaria ) Patiets with severe real dysfuctio [Sice blood cocetratios of this product are maitaied for log duratio, the product should be admiistered with dosage adjustmet such as reductio of the dose or prologig dose iterval. (See PHAR- MACO-KIETICS sectio)] ) Patiets of poor oral igestio, patiets receivig pareteral feedig, or patiets i poor geeral coditio [Sice vitami K deficiecy symptoms may occur, patiets should be carefully observed.] ) Elderly patiets [See Use i the Elderly sectio] () For the use of kit product oly ) Patiets with cardiac or circulatory dysfuctio [Sice icreased sodium load ad circulatory blood volume o their hearts may put a strai, dysfuctio symptoms may be worseed.] ) Patiets with real dysfuctio [Dysfuctio symptoms may be aggravated, retetio of fluid ad sodium chloride may be facilitated.]. Importat Precautios Sice there is o way of predictig the developmet of shock or aaphylactoid reactio by this product properly, the followig measures should be take: () The patiets should be carefully iterviewed about previous history, etc. prior to use. A history of allergy to atibiotics, etc. should surely be cofirmed. () Emergecy facilities should surely be prepared beforehad for developmet of shock, etc. () From the begiig of admiistratio to after the ed of admiistratio of this product, patiets should be kept at rest ad uder adequate supervisio. The patiets should be observed especially carefully immediately after the begiig of admiistratio.. Drug Iteractios

3 Shioogi & Co., Ltd. Precautios for coadmiistratio (FLUMARI should be admiistered with care whe coadmiistered with the followig drugs.) s, Symptoms, ad Drugs Mechaism ad Risk Factors Treatmet Diuretics Furosemide etc. Real impairmet may occur or may be exacerbated. I case of coadmiistratio, care should be take about real fuctios. The mechaism is ot clear, but has bee proposed as follows: Cocetratios of atibacterial drugs i tubular cells are elevated due to ihibitio of water uptake ito cells by diuretics.. Adverse Reactios Out of, cases evaluated for safety before approval ad at the latest approval of idicatio, adverse reactios were observed i 78 cases (.%). I additio, out of, cases evaluated for safety by coductig laboratory tests, abormal chages i the laboratory values were observed i cases (.9%). ) Out of 7, cases evaluated for safety at the ed of the reexamiatio period, adverse reactios icludig abormal chages i laboratory values were observed i 8 cases (.9%). ) (The frequecy of adverse reactio is based upo the results of aalysis at the time of approvals, latest reexamiatios ad spotaeously submitted reports.) () Cliically sigificat adverse reactios ) Shock, aaphylactoid reactio (.%): Sice shock or aaphylactoid reactio (dyspea, geeralized flushig, edema, etc.) may occur, patiets should be closely observed. If ay symptom occurs, the therapy should be discotiued ad appropriate ) Acute real failure (.%): Sice serious real impairmet such as acute real failure may occur, patiets should be closely observed by periodically coductig laboratory tests. If ay abormality is observed, the therapy should be discotiued ad appropriate ) Pacytopeia, agraulocytosis (.%), thrombocytopeia, hemolytic aemia (Icidece ukow): Pacytopeia, agraulocytosis, thrombocytopeia or hemolytic aemia may occur. If ay abormality is observed, the therapy should be discotiued ad appropriate ) Pseudomembraous colitis (.%): Serious colitis with bloody stools such as pseudomembraous colitis may occur. If abdomial pai or frequet diarrhea occurs, appropriate measures such as immediate discotiuatio of this product should be take. ) Muco-cutaeo-ocular sydrome (Steves-Johso sydrome), toxic epidermal ecrolysis (Lyell sydrome) (.%): Muco-cutaeo-ocular sydrome (Steves-Johso sydrome) or toxic epidermal ecrolysis (Lyell sydrome) may occur. Patiets should be carefully observed, ad if such symptoms occur, the therapy should be discotiued ad appropriate ) Iterstitial peumoia, PIE sydrome (.%): Iterstitial peumoia, PIE sydrome, etc., accompaied with fever, cough, dyspea, abormal chest X-ray fidigs, eosiophilia, etc. may occur. If such symptoms occur, the therapy should be discotiued ad appropriate treatmet such as corticosteroid therapy should be take. 7) Hepatic dysfuctio, jaudice (Icidece ukow): Icreases i SGOT (AST), SGPT (ALT), Al-P, gamma-gtp ad LAP or jaudice may occur, patiets should be closely observed by periodically coductig laboratory tests. If ay abormality is observed, the therapy should be discotiued ad appropriate () Other adverse reactios Icidece Body system Hypersesitivity Hematologic ) Real Icreased ote ) Hepatic Icreased ote %.%.% Rash Aemia (decreased RBC, decreased hemoglobi, decreased hematocrit), eosiophilia, graulocytopeia SGOT (AST), icreased SGPT (ALT), icreased Al-P, icreased gamma-gtp Urticaria, pruritus, redess, fever, facial hot flushes, ski paraesthesia Thrombocytopeia or thrombocytosis, BU, icreased creatiie, proteiuria Jaudice, icreased LAP Icidece ukow Oliguria Gastroitestial Diarrhea Soft stools, ausea, vomitig, feelig of elarged abdome Microbial substitutioasis Stomatitis, cadidi- Hypovitamiosis Vitami K deficiecy symptoms (hypoprothrom-biaemi a, bleedig tedecy, etc.), vitami B complex deficiecy symptoms (glossitis, stomatitis, aorexia, euritis, etc.) Others Dull headache, geeralized malaise, strage sesatio of urethra, icreased serum amylase, icreased uriary amylase ote ) If ay symptom (abormality) is observed, the therapy should be discotiued ad appropriate

4 Shioogi & Co., Ltd. ote ) If ay abormality is observed, appropriate measures such as discotiuatio should be take.. Use i the Elderly This product should be carefully admiistered to elderly patiets with attetio to the followig poits, ad the dose ad admiistratio iterval should be cosidered uder a close cliical observatio of the patiet's coditios. () Sice the elderly ofte have reduced physiological fuctios, adverse reactios ted to occur more frequetly. () I elderly patiets, bleedig tedecy due to vitami K deficiecy may occur.. Use durig Pregacy, Delivery or Lactatio This product should be admiistered to wome who are or may become pregat oly if the expected therapeutic beefits are evaluated to exceed ay possible risk associated with treatmet. [The safety of this product i pregat wome has ot yet bee established.] 7. Pediatric Use This product should be admiistered with care i low birth weight ifats (premature ifats) because high blood cocetratio may persist for a log period due to the prologatio of the blood cocetratio half-life caused by the immature kidey. [See Precautios i DOSAGE AD ADMIISTRATIO ad PHARMACOKI- ETI-CS sectio] 8. Effects o Laboratory Tests () Sice false-positive results may occur i urie sugar tests with Beedict's solutio. Fehlig's solutio ad Cliitest except Tes-Tape, cautio should be paid. () Care should be take about positive reactios i the direct Coombs' test. 9. Precautios cocerig Use () Preparatio: This product should be used immediately after recostitutio. If the recostituted drug is stored by ecessary, it should be used withi hours whe stored at room temperature, or withi hours whe stored i a refrigerator. For the kit product, residual solutio must ot be used i ay way. () Cautio i itraveous admiistratio: As high itraveous doses may cause vascular pai, phlebitis or burig sesatio, care should be take about preparatio of the ijectio solutio, ijectio site, ijectio method, etc., ad the rate of ijectio should be as slow as possible to avoid such complicatio.. Other Precautios It is desirable that periodic examiatios of liver fuctio, real fuctio, blood, etc. are coducted durig admiistratio of this drug. PHARMACOKIETICS. Blood cocetratio () Healthy adults ) (s ad pharmacokietic parameters after IV ijectio or durig/after IV ifusio) IV ijectio 9 8 Table : Pharmacokietic parameters (Healthy adults, IV ijectio) C mi [g (potecy)] T / ( ) (mi) (aalytical method: bioassay) (mea) ote ) s (values miutes after admiistratio) 8 -hr. IV ifusio 8 Table : Pharmacokietic parameters (Healthy adults, -hr. IV ifusio) Cmax [g (potecy)] T / ( ) (mi) (aalytical method: bioassay) (mea) () Childre with ormal real fuctio ) (s ad pharmacokietic parameters after IV ijectio or durig/after IV ifusio)

5 Shioogi & Co., Ltd. 9 IV ijectio Table : Pharmacokietic parameters (Childre with ormal real fuctio, IV ijectio) [mg (potecy) / kg] (years) C mi T / ( ) (mi) (aalytical method: bioassay) (mea) ote ) s (values miutes after admiistratio) 9 -mi. IV ifusio Table : Pharmacokietic parameters (Childre with ormal real fuctio, -mi. IV ifusio) [mg (potecy) / kg] (years) 7 C max T / ( ) (mi) (aalytical method: bioassay) (mea) () Low birth weight ifats (premature ifats) ad eoates ) (Plasma cocetratios ad pharmacokietic parameters after IV ijectio) Low birth weight ifats (premature ifats) IV ijectio of mg (potecy)/kg Table : Pharmacokietic parameters (Premature ifats) C mi (days) T / ( ) (aalytical method: bioassay) (mea) ote ) Plasma cocetratios (values miutes after admiistratio) Plasma cocetratio eoates IV ijectio of mg (potecy)/kg 8 Table : Pharmacokietic parameters (eoates) C mi (days) T / ( ) (aalytical method: bioassay) (mea) ote) Plasma cocetratios (values miutes after admiistratio) () Patiets with real impairmet -7) (s ad pharmacokietic parameters after IV ijectio) Prologatio of blood half-life ad retardatio of uriary excretio were observed with the decrease of real fuctio. Therefore, adequate adjustmets of the dose ad admiistratio iterval are ecessary for admiistratio to patiets with real impairmet. IV ijectio of g (potecy) Plasma cocetratio 8 7 8

6 Shioogi & Co., Ltd. Table 7: Pharmacokietic parameters Creatiie clearace T / ( Ccr 9. Ccr.9 Ccr.8 Ccr Ccr. (aalytical method: bioassay, HPLC) (mea) () Patiets o hemodialysis 7) (s ad pharmacokietic parameters after IV ijectio) hemodialysis / / IV ijectio of g (potecy) out of hemodialysis T / =.7 mi (7. durig hrs ) hemodialysis T / =. mi (. (=) hrs.) (=) (aalytical method: bioassay) 8 (Mea S.D.) 8.. Distributio Flomoxef sodium showed good trasfer ito the followig body fluid ad tissues: Bile ), sputum ), itraperitoeal exudates ), itrapelvic dead space exudates ), gallbladder ), uterus ), adexa uteri ), mucosa of the middle ear 8) ad lug tissues ), etc. I lactatig mothers ( ), the average cocetratio i breastmilk was. g/ml or less after a itraveous ijectio of g (potecy) of this product. 9). Metabolism Flomoxef sodium is metabolized very little i the body, ad the majority of the drug (8-9% at hours after admi-istratio) is excreted ito the urie as uchaged form. Flomoxef oxide as a active metabolite ad hydroxy-ethyltetrazolethiol (HTT) as a iactive metabolite have bee cofirmed, ad their uriary recovery rates at hours were.-.% ad -%, respectively. ). Excretio Flomoxef sodium is excreted maily from the kidey. Idepedet of the dose, the uriary excretio rates o the average were -7% up to hours ad 8-9% up to hours, respectively, i healthy adults admiistered a dose of. g (potecy) ( ) or g (potecy) ( ) by IV ijectio, a dose of g (potecy) ( ) or g (potecy) ( ) by IV ifusio for hour, or a dose of. g (potecy) ( ), g (potecy) ( ) or g (potecy) ( ) by IV ifusio for hours. ). Others Serum protei bidig rate: Serum protei bidig rate was %, measured by ultrafiltratio. ) CLIICAL STUDIES I ope cliical studies performed before DA approval ad at the latest approval of idicatio, the umber of cases evaluated for efficacy was,cases, ad the efficacy rate was 7.% (, cases). ) Table 8: Cliical studies Disease o.of effective cases / o.of cases evaluated for efficacy Efficacy rate (%) Septicemia, ifectious edocarditis / 7.9 (Superficial) secodary ifectios i trauma, burs, surgical wouds, / 8.9 etc. Pharygolarygitis, tosillitis, acute brochitis / 9.8 Secodary ifectios i chroic respiratory diseases 99/ 79. Cystitis, Pyeloephritis /. Prostatitis (acute, chroic) 9/ 9. Peritoitis, itraabdomial abscess / 8. Cholecystitis, cholagitis /8 7.8 Bartholiitis / 9. Itrauterie ifectio 87/9 9. Uterie adexitis / 9.9 Parametritis 9/ 9.7 Otitis media /7. Siusitis 9/9 7. PHARMACOLOGY. Pharmacological activity Atibacterial activity Flomoxef sodium shows a broad spectrum of atibacterial activity i vitro agaist gram-positive ad gram-egative bacteria, icludig both aerobes ad aaerobes. Flomoxef sodium demostrates atibacterial activity agaist gram-positive microorgaisms such as Staphylococcus sp., Streptococcus sp., Peumococcus sp. Flomoxef sodium demostrates atibacterial activity agaist gram-egative microorgaisms such as eisseria goorrhoeae, Moraxella (Brahamella) catarrhalis, Escherichia coli, Klebsiella sp., Proteus sp., Morgaella morgaii, Providecia sp. ad Haemophilus ifluezae. Flomoxef sodium also demostrates atibacterial activity agaist aaerobes such as Peptostreptococcus sp., Bacteroides sp. ad Prevotella sp. (excludig Prevotella bivia). I additio, it is stable toward β-lactamases produced by various microorgaisms. ), ). Mechaism of actio The atibacterial actio of flomoxef sodium results from the ihibitio of bacterial cell wall sythesis, ad this actio is bactericidal. Flomoxef sodium has bidig-affiity for peicilli-bidig proteis (PBP), ad demostrates atibacterial activity, especially by showig ihibitig actio to murei-crosslikig ezymes. Besides, flomoxef sodium is characterized by its scarce iductio of PBP-, which is oe of the mai resistace, ) mechaisms of methicilli-resistat S. aureus.

7 PHYSICOCHEMISTRY oproprietary ame: Flomoxef Sodium Shioogi & Co., Ltd. 7 REFERECES [Referece request o.] (JA) (Japaese pharmacopoeia) ) Summary data made by Shioogi & Co., Ltd. from literatures icludig Shimizu K. et al.: Jp. J. Atibiot., 988,(), 89 [988] Abbreviatio: FMOX Chemical ame: Moosodium(R,7R)-7- {[-(difluoromethylsulfayl)acetyl]amio}--[-(-hydroxye thyl)-h-tetrazol--ylsulfaylmethyl]-7-methoxy-8-oxo--oxa--azabicyclo[..]oct--ee--carboxylate Molecular formula: C H 7 F ao 7 S Molecular weight: 8. Structural formula: F F S O O H O O H CH CO a S OH Sodium cotet: g (potecy) of flomoxef sodium cotais. mg (. meq) of sodium. As preparatios, FLUMARI. g ad FULMARI g cotai. mg (.m Eq) ad. mg (.9 meq), respectively, of sodium. Descriptio: Flomoxef Sodium occurs as white to light yellowish white, powder or masses. It is very soluble i water,freely soluble i methaol, ad sparigly soluble i ethaol (99.). Meltig poit: - C (decompositio) Partitio coefficiet:. (-octaol/water system) PRECAUTIOS FOR HADLIG Attetio should be paid to the followig poits whe hadlig the kit product.. To preserve the quality of the product, the seal o the outer bag should ot be broke util just before use.. The product should ot be used i the followig cases. ) MHW Pharmaceutical Affairs Bureau, IYAKUHI KEKYU, 997, (8), 9 [997] ) Shimizu K. et al.: Jp. J. Atibiot.,988, (), 89 [988] ) Fujii R. et al.: Jp. J. Atibiot., 99, (7), 8 [999] ) akamura M. et al.: SAISHI IGAKU, 987, (8), 7 [9879] ) Kumada T. et al.: Chemotherapy, 987,(S-), [9879] 7) Hojo T. et al.: Chemotherapy, 987,(S-), [9879] 8) Shiba T. et al.: The th Aual Meetig of Japa Society of Chemotherapy, Symposium, 98 Kurashiki [98] 9) Takase Z. et al.: Chemotherapy, 987,(S-), 79 [9879] ) Yasuaga K. et al.: Chemotherapy, 987,(S-), 9 [9879] ) Kimura Y. et al.: Chemotherapy, 987,(S-), [98799] ) Kameda Y. et al.: Chemotherapy, 987,(S-), 7 [98798] ) Goto S. et al.: Chemotherapy, 987, (S-), [9879] ) Yokota K. et al.: Chemotherapy, 987,(S-), [9879] ) Murakami K. et al.: Chemotherapy, 987,(S-),8 [98798] REQUEST FOR LITERATURE SHOULD BE MADE TO: Drug Iformatio Ceter SHIOOGI & CO., LTD. -8, Doshomachi -chome, Chuo-ku, Osaka -, Japa TEL: -9-7 () The outer bag is tor or the dissolvig solutio is leaked. FAX: -- () The drug has already bee dissolved before breakig the partitio. () The drug has become discolored or the dissolvig solutio is o loger colorless before recostitutio.. The scale o the cotaier should be used oly as a rough stadard. PACKAGIG FLUMARI for Itraveous Ijectio. g: vials ( ml vial) FLUMARI for Itraveous Ijectio g: vials ( ml vial) FLUMARI Kit for Itraveous Ijectio g: kits Maufactured ad Distributed by: SHIOOGI & CO., LTD. -8, Doshomachi -chome, Chuo-ku, Osaka -, Japa