DESCRIPTION 1. Composition

Transcription

1 Shioogi & Co., Ltd. 1 Revised: Jue 2009 (8th versio) Stadard Commodity Classificatio No. of Japa Oxacephem atibiotic aget - SHIOMARIN for Itraveous Ijectio 1 g < Latamoxef sodium for ijectio > prescriptio drug Storage Store at room temperature. Expiratio date Idicated o the package, etc. (Expiratio period: Two years) Approval No EMZ01442 Date of listig i the NHI reimbursemet price December 1981 Date of iitial marketig i Japa Jauary 1982 Date of latest reexamiatio September 1989 Date of latest reevaluatio September 2004 Cautio - Use oly as directed by a physicia CONTRAINDICATIONS (SHIOMARIN is cotraidicated i the followig patiets.) Patiets with a history of shock followig exposure to ay of the igrediets i this product RELATIVE CONTRAINDICATIONS (As a geeral rule, SHIOMARIN is cotraidicated i the followig patiets. If the use of this product 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 DESCRIPTION 1. Compositio Brad ame Igrediet/cotet (Cotet per 1 vial) Additive SHIOMARIN 1 g for IV Ij. Latamoxef sodium D-Maitol 150 mg 1 g (potecy) 2. Product descriptio Brad ame SHIOMARIN 1 g for IV Ij. A white to light yellowish white, light Descriptio mass or powder, without odor; very soluble i water. (Ijectio) ph 100 mg (potecy)/ml aqueous solutio Osmotic pressure ratio (Ratio agaist isotoic sodium chloride solutio) Approx. 2 1 g (potecy)/10 ml aqueous solutio INDICATIONS <Susceptible strais> Latamoxef sodium susceptible strais of Escherichia coli, Citrobacter sp., Klebsiella sp., Eterobacter sp., Serratia sp., Proteus sp., Morgaella morgaii, Providecia sp., Haemophilus ifluezae, Bacteroides sp., Prevotella sp. (excludig Prevotella bivia) <Idicatios> Septicemia Acute brochitis, peumoia, lug abscess, pyothorax, secodary ifectio i chroic respiratory diseases Cystitis, pyeloephritis Peritoitis Cholecystitis, cholagitis, liver abscess Itrauterie ifectio, uterie adexitis, parametritis Meigitis puruleta DOSAGE AND ADMINISTRATION Usually, for adults, 1-2 g (potecy) daily is ijected or ifused itraveously i 2 divided doses. Usually, for childre, mg (potecy)/kg daily is ijected or ifused itraveously i 2 to 4 divided doses. 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 4 g (potecy) daily for adults, ad 150 mg (potecy)/kg daily for childre, i 2 to 4 divided doses. Referece: Preparatio of ijectable solutio This product should be dissolved by shakig well after additio of ot less tha 4 ml of water for ijectio, 5% 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. < 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.

2 2 Shioogi & Co., Ltd. PRECAUTIONS 1. Careful Admiistratio (SHIOMARIN should be admiistered with care i the followig patiets.) (1) Patiets with a history of hypersesitivity to peicillis (2) Patiets with a persoal or familial predispositio to allergic reactios such as brochial asthma, rash ad urticaria (3) Patiets with severe real impairmet [Sice blood cocetratios of this product maitai for log duratio, the product should be admiistered with dosage adjustmet such as reductio of the dose or prologig dose iterval. [See PHARMACOKINETICS sectio] (4) 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.] (5) Elderly patiets [See Use i the Elderly sectio] 2. Importat Precautios (1) Sice there is o way of predictig the developmet of shock or aaphylactoid reactio by this product properly, the followig measures should be take: 1) The patiets should be carefully iterviewed about previous history, etc. prior to use. A history of allergy to atibiotics, etc. should surely be cofirmed. 2) Emergecy facilities should surely be prepared beforehad for developmet of shock, etc. 3) 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. (2) Alcohol itake should be avoided durig admiistratio ad at least oe week after admiistratio. [See Drug iteractios sectio] 3. Drug Iteractios Precautios for coadmiistratio (SHIOMARIN should be admiistered with care whe coadmiistered with the followig drugs.) Sigs, Symptoms, ad Mechaism ad Risk Drugs etc. Treatmet Factors Diuretics Furosemide etc. Alcohol Real disfuctio may occur or may be exacerbated. I case of coadmiistratio, care should be take about real fuctios. Sigs, Symptoms: Alcohol itake may lead to facial hot flush, palpitatio, dizziess, headache, ausea etc.. Treatmet: Alcohol itake should be abstaied durig admiistratio ad at least for 1 week after admiistratio. The mechaism is ot clear, but has bee proposed as follows: Cocetratios of the atibacterial drug i cells of real tubules are elevated due to decreased reabsorptio of water ito the cells caused by diuretic. Methyltetrazolthiol group at positio 3- side chai ihibits aldehyde dehydrogease i metabolic process of alcohol, by which the blood levels of acetaldehyde icreases, resultig i occurrece of disulfiram-like-reactio. 4. Adverse Reactios Out of 1,938 cases (itraveous ijectio, itraveous ifusio ad itramuscular ijectio icluded) evaluated for safety before NDA approval, adverse reactios icludig abormal chages i laboratory values were observed i 124 cases (6.40%). 1) ( Maufacture of SHIOMARIN for Itramuscular ijectio has bee ceased.) Out of 29,000 cases (itraveous ijectio, itraveous ifusio ad itramuscular ijectio icluded) evaluated for safety at the ed of the reexamiatio period, adverse reactios icludig abormal chages i laboratory values were observed i 1,204 cases (4.15%). 1) (1) Cliically sigificat adverse reactios 1) Shock, aaphylactoid reactio (< 0.1%): Sice shock or aaphylactoid reactio (dyspea, geeralized flushig, edema, etc.) may occur, patiets should be carefully observed. If such symptoms occur, the therapy should be discotiued ad appropriate measures should be take. 2) Acute real failure (< 0.1%): Sice severe real impairmet such as acute real failure may occur, patiets should be carefully observed by periodically coductig laboratory tests. If ay abormalities are observed, the therapy should be discotiued ad appropriate measures should be take. 3) Pacytopeia, hemolytic aemia (< 0.1%): Pacy-topeia or hemolytic aemia may occur. Therefore, if ay abormalities are foud, the therapy should be discotiued ad appropriate measures should be take. 4) Pseudomembraous colitis (< 0.1%): Serious colitis with bloody stools such as pseudomembraous colitis may occur. If abdomial pai or frequet diarrhea occur, appropriate measures such as immediate discotiuatio of this product should be take. 5) Muco-cutaeo-ocular sydrome (Steves Johso sydrome), toxic epidermal ecrolysis (Lyell sydrome) (< 0.1%): 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 measures should be take. 6) Iterstitial peumoia, PIE sydrome (< 0.1%): 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) Covulsios (Icidece ukow): Neurologic symptoms such as covulsio may be caused by large doses admiistratio i patiets with real failure. Therefore, If such symptoms occur, the therapy should be discotiued ad appropriate measures should be take.

3 Shioogi & Co., Ltd. 3 (2) Other adverse reactios Icidece Body system Hypersesitivity ote 1) Hematologic ote 1) ote 1) Real ote 2) Hepatic Gastroitestial sub- Microbial stitutio Hypovitamiosis Others 5% or Icidece ukow Rash, urticaria, redess, pruritus, fever, etc. 5% > 0.1% <0.1% Eosiophilia, aemia (decreased RBC, decreased hemoglobi, decreased hematocrit), graulocyto-peia, thrombocy-topeia, prologed prothrombi time Icreased BUN, icreased creatiie, oliguria, proteiurea Icreased SGOT (AST), icreased SGPT (ALT), icreased Al-P, icreased bilirubi Nausea, vomitig, aorexia, diarrhea, etc. Stomatitis, cadidiasis Vitami K deficiecy sysmptoms (hypoprothrombiemia, bleedig tedecy, etc.), vitami B complex deficiecy symptoms (glossitis, stomatitis, aorexia, euritis, etc.) Headache, geeralized malaise Note 1) If ay symptom (abormality) is observed, the therapy should be discotiued ad appropriate measures should be take. Note 2) If ay abormality is observed, appropriate measures such as discotiuatio of the therapy should be take. 5. Use i the Elderly This product should be admiistered to elderly people carefully with attetio to the followig poits, ad the dose ad admiistratio iterval should be cosidered uder a close observatio of the patiet's coditios. (1) Sice the elderly ofte have a physiological hypofuc-tio, adverse reactios teds to occur more frequetly. (2) I elderly patiets, bleedig tedecy due to vitami K deficiecy may occur. 7. Effects o Laboratory Tests Care should be take about positive reactios i the direct Coombs' test. 8. Precautios cocerig Use (1) Method of preparatio: This product should be used immediately after recostitutio. If the recostituted drug is stored by ecessity, it should be used withi 24 hours whe stored at temperature, or withi 72 hours whe stored i a refrigerator. (2) 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. 9. Other Precautios Atrophy of the testis ad suppressio of spermatogeesis have bee reported i subcutaeous admiistratio to ifat rats. PHARMACOKINETICS 1. Blood cocetratio (1) Healthy adults 2) (Plasma cocetratios ad pharma-cokietic parameters after IV ijectio, IV ifusio) IV ijectio Sig Figure 1: Plasma cocetratios after IV ijectio Table 1: Pharmacokietic parameters (Healthy adults, IV ijectio) C 15mi * T 1/2 ( ) [g (potecy)] ( g / ml) (hr) (aalytical method: bioassay) ( S.D.) * Cocetratios i plasma (15 miute-value after admiistratio) 1-hr. IV ifusio 6. 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.]

4 4 Shioogi & Co., Ltd. (aalytical method: bioassay) ( S.D.) * Cocetratios i plasma (15 miute-value after admiistratio) Figure 2: Plasma cocetratios after 1-hr. IV ifusio Table 2: Pharmacokietic parameters (Healthy adults, 1-hr. IV ifusio) Sig [g (potecy)] C max ( g / ml) T 1/2 ( ) (hr) (aalytical method: bioassay) ( S.D.) 1-hr. IV ifusio IV ifusio for 2 hours Figure 5: Serum cocetratios after 1-hr. IV ifusio Table 5: Pharmacokietic parameters (Childre with ormal real fuctios, 1-hr. IV ifusio) Sig C max T 1/2 ( ) [mg (potecy) / kg] ( g / ml) (mi) (aalytical method: bioassay) ( S.D.) Figure 3: Plasma cocetratios after 2 hours IV ifusio Table 3: Pharmacokietic parameters (Healthy adults, 2 hours IV ifusio) Sig C max T 1/2 ( ) [g (potecy)] ( g / ml) (hr) (aalytical method: bioassay) ( S.D.) (3) Patiets with real impairmet 4)~6) (Serum cocetratios 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 patiets with real impairmet. (2) Childre with ormal real fuctios 3) (Serum cocetratios ad pharmacokietic parameters after IV ijectio, IV ifusio) IV ijectio 1 g (potecy) for IV ijectio Figure 4: Serum cocetratios after IV ijectio Table 4: Pharmacokietic parameters (Childre with ormal real fuctios, IV ijectio) Sig C 15mi * T 1/2 ( ) [mg (potecy) / kg] ( g/ml) (mi) Figure 6: Serum cocetratios after IV ijectio Table 6: Pharmacokietic parameters [Patiets with real impairmet, 1g (potecy) IV ijectio] Sigh Creatiie clearace (ml / mi) Serum cocetratios ( g / ml) 5 mi. 1 hr. T 1/2 ( ) (hr)

5 Shioogi & Co., Ltd. 5 < < 5 (uder hemodialysis 3 N.T therapy ) N.T.: ot tested (aalytical method: bioassay) () (4) Patiets uder hemodialysis therapy 7) (Blood cocetratios after IV ijectio, before hemodialysis or after hemodialysis) 1 g (potecy) for IV ijectio Figure 7: Blood cocetratios after IV ijectio It is reported that to patiets o hemodialysis admiistratio of 1 g (potecy) doses both before ad after hemodialysis is favorable sice accumulatio was ot observed i blood cocetratios i patiets who received hemodialyses 3 times cosecutively with 1 g (potecy) admiistratio before ad after each hemodialysis. 7) 2. Distributio Whe 1 g of SHIOMARIN was itraveously ijected to the patiets (=12) with a T tube, the biliary cocetratio reached the maximum level, 66 g/ml o the average, 3 to 4 hours after admiistratio, ad eve after 5 to 6 hours, it showed 48 g/ml o the average. I additio, trasfer to the followig body fluid ad tissues has bee foud: the cerebrospial fluid, sputum, gall bladder, itraperitoeal exudate, cord blood, amiotic fluid, uterus, adexa uteri ad pelvic dead space exudate. Latamoxef sodium is trasferred very little ito the milk. 8) 3. Metabolism Latamoxef sodium is ot metabolized i the body. 8) 4. Excretio Latamoxef sodium is excreted maily from the kidey. Uriary recovery was about 50-60% up to 2 hours ad about 75-80% up to 6 hours i healthy adults admiistered a sigle 0.5 g (potecy) (=8), or 1 g (potecy) (=26) dose by itraveous ijectio. Uriary recovery was about 45-55% up to 2 hours ad about 74-83% up to 6 hours i healthy adults admiisterd a sigle 1 g (potecy) (=15), or 2 g (potecy) (=6) dose by itraveous ifusio for 1 hour. I additio, the uriary cocetratio was about 145 g / ml at 6-8 hours after a 1 g (potecy) itraveous ijectio i healthy adults(=4). 8) 5. Others Serum protei bidig rate: Serum protei bidig rate was 60% measured by ultrafiltratio. 9) CLINICAL STUDIES I ope cliical studies performed before NDA approval, the umber of for cases evaluated for efficacy was 1,294 cases (itraveous ijectio, itraveous ifusio ad itramuscular ijectio icluded), ad the efficacy rate was 81.8% (1,058 cases). 10) ( Maufacture of SHIOMARIN for Itramuscular ijectio has bee ceased. ) Disease Septicemia Acute brochitis, peumoia, lug abscess, pyothorax, secodary ifectio i chroic respiratory diseases Cystitis Pyeloephritis Peritoitis Cholecystitis, cholagitis Liver abscess Itrauterie ifectio, uterie adexitis, parametritis Meigitis puruleta No. of effective cases / No. of cases evaluated for efficacy 25/32 391/ / /207 39/49 91/107 4/5 87/94 13/14 Efficacy rate (%) PHARMACOLOGY 1. Pharmacological activity Atibacterial activity Latamoxef sodium demostrates atibacterial activity i vitro agaist gram-egative microorgaisms such as Escherichia coli, Citrobacter sp., Klebsiella sp., Etetobacter sp., Serratia sp., Proteus sp., Morgaella morgaii, Providecia sp. ad Haemophilus ifluezae. Latamoxef sodium also demostrates atibacterial activity agaist aaerobes such as Bacteroides sp. ad Prevotella sp. (excludig Prevotella bivia). I additio, it is very stable toward iactivatig β-lactamases produced by various microorgaisms. 11)-13) 2. Mechaism of actio The atibacterial actio of latamoxef sodium results from the ihibitio of bacterial cell wall sythesis, ad this actio is bactericidal. Latamoxef sodium has bidig-affiity for peicilli-bidig proteis (PBP), ad demostrates atibacterial activity, especially by showig ihibitig actio to mullei-crosslikig ezymes. 11) PHYSICOCHEMISTRY Noproprietary ame: Latamoxef Sodium (JAN) (The Japaese Pharmacopoeia) Abbreviatio: LMOX

6 6 Shioogi & Co., Ltd. Chemical ame: Disodium(6R,7R)-7-[2-carboxylato-2-(4-hydroxypheyl) acetylamio]-7-methoxy-3-(1-methyl-1h-tetrazol-5-ylsulfayl methyl)-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ee-2-carbo xylate Molecular formula: C 20 H 18 N 6 Na 2 O 9 S Molecular weight: ) Yoshida T. et al.: Chemotherapy,1980,28(S-7),194 [ ] 10) Matsumoto K.: Jp. J. Ati.,1982,35(3),704 [ ] 11) Yokota K. et al.: Chemotherapy,1980,28(S-7),29 [ ] 12) Goto S. et al.: Chemotherapy,1980,28(S-7),1 [ ] 13) Yoshida T. et al.: Chemotherapy,1980,28(S-7),86 [ ] Structural formula: Sodium cotet: 1 g (potecy) of latamoxef sodium cotais 88.4 mg (3.8 meq) of sodium. Descriptio: Latamoxef sodium occurs as white to light yellowish white, powder or masses. It is very soluble i water,freely soluble i methaol, ad slightly soluble i ethaol (95). REQUEST FOR LITERATURE SHOULD BE MADE TO: Drug Iformatio Ceter SHIONOGI & CO., LTD. 1-8, Doshomachi 3-chome, Chuo-ku, Osaka , Japa TEL: FAX: Maufactured ad Distributed by: SHIONOGI & CO., LTD. 1-8, Doshomachi 3-chome, Chuo-ku, Osaka , Japa Meltig poit: C (decompositio) Partitio coefficiet: (ethyl acetate/water system) PACKAGING SHIOMARIN for Itraveous Ijectio 1 g: 10 vials (10 ml vial) REFERENCES [Referece request No.] 1) Safety Divisio, Pharmaceutical Affairs Bureau, MHW: Adverse Drug Reactio Iformatio No. 101, 1990,pp [ ] 2) Summary data made by Shioogi & Co., Ltd. from 5 literatures icludig Yamada H. et al.: Chemotherapy, 1980,28(S-7), 251 [ ] 3) Summary data made by Shioogi & Co., Ltd. from 6 literatures icludig Meguro H. et al.: Jp. J. Atibiot., 1981,34(4), 599 [ ] 4) Aoki N. et al.: Chemotherapy, 1980,28(S-7), 361 [ ] 5) Nishimoto Y. et al.: Chemotherapy, 1980, 28(S-7), 523 [ ] 6) Ueda Y. et al.: Chemotherapy, 1980,28(S-7), 370 [ ] 7) Kitazima K. et al.: Jp. J. Cli. Dialysys, 1987,3(11), 1833 [ ] 8) Shimada J. et al.: The 27th Aual Meetig of Japa Society of Chemotherapy, Nishiiho Shibu Sokai, 1979, Osaka [ ]