Recommended Dosage Regimen for AVYCAZ (ceftazidime and avibactam) b. AVYCAZ 1.25 grams (ceftazidime 1 gram and avibactam 0.25 grams) every 8 hours

Transcription

1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use AVYCAZ sfely nd effectively. See full prescribing informtion for AVYCAZ. AVYCAZ (ceftzidime nd vibctm) for injection, for intrvenous use Initil U.S. Approvl: INDICATIONS AND USAGE AVYCAZ is combintion of ceftzidime, cephlosporin, nd vibctm, bet-lctmse inhibitor, indicted for the tretment of ptients 18 yers or older with the following infections cused by designted susceptible Grm-negtive microorgnisms: Complicted Intr-bdominl Infections (ciai), used in combintion with metronidzole (1.1) Complicted Urinry Trct Infections (cuti), including Pyelonephritis (1.2) To reduce the development of drug-resistnt bcteri nd mintin the effectiveness of nd other ntibcteril drugs, AVYCAZ should be used only to tret infections tht re proven or strongly suspected to be cused by susceptible bcteri. (1.3) DOSAGE AND ADMINISTRATION AVYCAZ 2.5 grms (ceftzidime 2 grms nd vibctm 0.5 grms) for injection dministered every 8 hours by intrvenous (IV) infusion over 2 hours in ptients 18 yers of ge nd older with cretinine clernce (CrCl) greter thn 50 ml/min. For tretment of ciai, metronidzole should be given concurrently (2.1). Recommended durtion of tretment: (2.1) ciai: 5 to 14 dys cuti including pyelonephritis: 7 to 14 dys Dosge in ptients with renl impirment (2.2) Estimted Cretinine Clernce (ml/min) Recommended Dosge Regimen for AVYCAZ (ceftzidime nd vibctm) b 31 to 50 AVYCAZ 1.25 grms (ceftzidime 1 grm nd vibctm 0.25 grms) every 8 hours 16 to 30 AVYCAZ 0.94 grms (ceftzidime 0.75 grms nd vibctm 0.19 grms) every 12 hours c AVYCAZ 0.94 grms (ceftzidime 0.75 grms nd vibctm 0.19 grms) 6 to 15 every 24 hours Less thn or equl to 5 c AVYCAZ 0.94 grms (ceftzidime 0.75 grms nd vibctm 0.19 grms) every 48 hours As clculted using the Cockcroft-Gult formul. b All doses of re dministered over 2 hours c Both ceftzidime nd vibctm re hemodilyzble; thus, dminister fter hemodilysis on hemodilysis dys. See Full Prescribing Informtion for instructions for constituting supplied dry powder nd subsequent required dilution. (2.3) See Full Prescribing Informtion for drug comptibilities. (2.4) DOSAGE FORMS AND STRENGTHS AVYCAZ 2.5g (ceftzidime nd vibctm) for injection is supplied s sterile powder for constitution in single-dose vils contining ceftzidime 2 grms (equivlent to grms of ceftzidime penthydrte/sodium crbonte powder) nd vibctm 0.5 grms (equivlent to grms of vibctm sodium). (3) CONTRAINDICATIONS AVYCAZ is contrindicted in ptients with known serious hypersensitivity to the components of AVYCAZ (ceftzidime nd vibctm), vibctm-contining products or other members of the cephlosporin clss. (4) WARNINGS AND PRECAUTIONS Decresed efficcy in ciai ptients with bseline CrCl of 30 to less thn or equl to 50 ml/min. Monitor CrCl t lest dily in ptients with chnging renl function nd djust the dose of AVYCAZ ccordingly. (5.1) Hypersensitivity rections: Includes nphylxis nd serious skin rections. Cross-hypersensitivity my occur in ptients with history of penicillin llergy. If n llergic rection occurs, discontinue AVYCAZ. (5.2) Clostridium difficile-ssocited dirrhe: Clostridium difficile-ssocited dirrhe (CDAD) hs been reported with nerly ll systemic ntibcteril gents, including AVYCAZ. Evlute if dirrhe occurs. (5.3) Centrl Nervous System Rections: Seizures nd other neurologic events my occur, especilly in ptients with renl impirment. Adjust dose in ptients with renl impirment. (5.4) ADVERSE REACTIONS The most common dverse rections in ciai ( 5%, when used with metronidzole) ptients re dirrhe, nuse nd vomiting. The most common dverse rections in (3%) of cuti ptients re dirrhe nd nuse. (6.1) To report SUSPECTED ADVERSE REACTIONS, contct Allergn t or FDA t FDA-1088 or See 17 for PATIENT COUNSELING INFORMATION Revised: 01/2017 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Complicted Intr-bdominl Infections (ciai) 1.2 Complicted Urinry Trct Infections (cuti), including Pyelonephritis 1.3 Usge 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosge 2.2 Dosge Adjustments in Ptients with Renl Impirment 2.3 Preprtion of the AVYCAZ Solution for Administrtion 2.4 Drug Comptibility 2.5 Storge of Constituted Solutions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Decresed Clinicl Response in ciai Ptients with Bseline Cretinine Clernce of 30 to Less Thn or Equl to 50 ml/min 5.2 Hypersensitivity Rections 5.3 Clostridium difficile-ssocited Dirrhe 5.4 Centrl Nervous System Rections 5.5 Development of Drug-Resistnt Bcteri 6 ADVERSE REACTIONS 6.1 Clinicl Tril Experience 7 DRUG INTERACTIONS 7.1 Probenecid 7.2 Drug/Lbortory Test Interctions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.2 Lcttion 8.4 Peditric Use 8.5 Geritric Use 8.6 Renl Impirment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.2 Phrmcodynmics 12.3 Phrmcokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 14 CLINICAL STUDIES 14.1 Complicted Intr-bdominl Infections 14.2 Complicted Urinry Trct Infections, Including Pyelonephritis 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing informtion re not listed FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Complicted Intr-bdominl Infections (ciai) AVYCAZ (ceftzidime nd vibctm) in combintion with metronidzole, is indicted for the tretment of complicted intr-bdominl infections (ciai) cused by the following susceptible Grm-negtive microorgnisms: Escherichi coli, Klebsiell pneumonie, Proteus mirbilis, Enterobcter cloce, Klebsiell oxytoc, Citrobcter freundii complex, nd Pseudomons eruginos in ptients 18 yers or older. 1.2 Complicted Urinry Trct Infections (cuti), including Pyelonephritis AVYCAZ (ceftzidime nd vibctm) is indicted for the tretment of complicted urinry trct infections (cuti) including pyelonephritis cused by the following susceptible Grm-negtive microorgnisms: Escherichi coli, Klebsiell pneumonie, Enterobcter cloce, Citrobcter freundii complex, Proteus mirbilis, nd Pseudomons eruginos in ptients 18 yers or older. 1.3 Usge To reduce the development of drug-resistnt bcteri nd mintin the effectiveness of AVYCAZ nd other ntibcteril drugs, AVYCAZ should be used to tret only indicted infections tht re proven or strongly suspected to be cused by susceptible bcteri. When culture nd susceptibility informtion re vilble, they should be considered in selecting or modifying ntibcteril therpy. In the bsence of such dt, locl epidemiology nd susceptibility ptterns my contribute to the empiric selection of therpy. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosge The recommended dosge of AVYCAZ is 2.5 grms (ceftzidime 2 grms nd vibctm 0.5 grms) dministered every 8 hours by intrvenous (IV) infusion over 2 hours in ptients 18 yers of ge nd older in ptients with norml renl function. For tretment of ciai, metronidzole should be given concurrently. The guidelines for dosge of AVYCAZ in ptients with cretinine clernce [CrCl] greter thn 50 ml/min re listed in Tble 1.

2 Tble 1. Dosge of AVYCAZ 2.5 grms (ceftzidime 2 grms nd vibctm 0.5 grms) by Indiction Infection Dosge Frequency Complicted Intr-bdominl Infections [used in combintion with metronidzole] Complicted Urinry Trct Infections including Pyelonephritis 2.5 grms 2.5 grms Every 8 hours Every 8 hours Infusion Time (hours) Durtion of Tretment 2 5 to 14 dys 2 7 to 14 dys 2.2 Dosge Adjustments in Ptients with Renl Impirment The recommended AVYCAZ dosge in ptients with vrying degrees of renl function is presented in Tble 2. For ptients with chnging renl function, monitor CrCl t lest dily nd djust the dosge of ccordingly [see Wrnings nd Precutions (5.1), Use in Specific Popultions (8.6) nd Clinicl Phrmcology (12.3)]. Tble 2. Dosge of AVYCAZ in Ptients with Renl Impirment Estimted Cretinine Recommended Dosge Regimen for Clernce (ml/minute) AVYCAZ (ceftzidime nd vibctm) b AVYCAZ 1.25 grms (ceftzidime 1 grm nd 31 to 50 vibctm 0.25 grms) intrvenously every 8 hours AVYCAZ 0.94 grms (ceftzidime 0.75 grms nd 16 to 30 vibctm 0.19 grms) intrvenously every 12 hours c AVYCAZ 0.94 grms (ceftzidime 0.75 grms nd 6 to 15 vibctm 0.19 grms) intrvenously every 24 hours Less thn or equl to 5 c AVYCAZ 0.94 grms (ceftzidime 0.75 grms nd vibctm 0.19 grms) intrvenously every 48 hours As clculted using the Cockcroft-Gult formul b All doses of re dministered over 2 hours c Both ceftzidime nd vibctm re hemodilyzble; thus, dminister fter hemodilysis on hemodilysis dys 2.3 Preprtion of the AVYCAZ Solution for Administrtion AVYCAZ is supplied s dry powder, which must be constituted nd subsequently diluted, using septic technique prior to intrvenous infusion. ) Constitute the powder in the AVYCAZ vil with 10 ml of one of the following solutions: sterile wter for injection, USP 0.9% of sodium chloride injection, USP (norml sline) 5% of dextrose injection, USP ll combintions of dextrose injection nd sodium chloride injection, USP, contining up to 2.5% dextrose, USP, nd 0.45% sodium chloride, USP, or lctted Ringer s injection, USP b) Mix gently. The constituted AVYCAZ solution will hve n pproximte ceftzidime concentrtion of grms/ml nd n pproximte vibctm concentrtion of grms/ml. The finl volume is pproximtely 12 ml. The constituted solution is not for direct injection. The constituted solution must be diluted before intrvenous infusion. c) Prepre the required dose for intrvenous infusion by withdrwing the pproprite volume determined from Tble 3 from the constituted vil. Tble 3. Preprtion of AVYCAZ Doses Volume to Withdrw from Constituted Vil for AVYCAZ (ceftzidime nd vibctm) Dose Further Dilution to 50 to 250 ml 2.5 grms (2 grms nd 0.5 grms) 12 ml (entire contents) 1.25 grms (1 grm nd 0.25 grms) 6 ml 0.94 grms (0.75 grms nd 0.19 grms) 4.5 ml d) Before infusion, dilute the withdrwn volume of the constituted AVYCAZ solution further with the sme diluent used for constitution of the powder (except sterile wter for injection), to chieve totl volume between 50 ml (ceftzidime 0.04 grms/ml nd vibctm 0.01 grms/ml) to 250 ml (ceftzidime grms/ml nd vibctm grms/ml) in n infusion bg. If sterile wter for injection ws used for constitution, use ny of the other pproprite constitution diluents for dilution. e) Mix gently nd ensure tht the contents re dissolved completely. Visully inspect the diluted AVYCAZ solution (for dministrtion) for prticulte mtter nd discolortion prior to dministrtion (the color of the AVYCAZ infusion solution for dministrtion rnges from cler to light yellow). f) Use the diluted AVYCAZ solution in the infusion bgs within 12 hours when stored t room temperture. g) The diluted AVYCAZ solution in the infusion bgs my be stored under refrigertion t 2 to 8 C (36 to 46 F) up to 24 hours following dilution nd used within 12 hours of subsequent storge t room temperture. 2.4 Drug Comptibility The AVYCAZ solution for dministrtion t the rnge of diluted concentrtions of ceftzidime g/ml nd vibctm g/ml to ceftzidime 0.04 g/ml nd vibctm 0.01 g/ml is comptible with the more commonly used intrvenous infusion fluids in infusion bgs (including Bxter Mini-Bg Plus ) such s: 0.9% sodium chloride injection, USP 5% dextrose injection, USP ll combintions of dextrose injection nd sodium chloride injection, USP, contining up to 2.5% dextrose, USP, nd 0.45% sodium chloride, USP lctted Ringer s injection, USP, nd Bxter Mini-Bg Plus contining 0.9% sodium chloride injection or 5% dextrose injection Comptibility of AVYCAZ solution for dministrtion with other drugs hs not been estblished. 2.5 Storge of Constituted Solutions Upon constitution with pproprite diluent, the constituted AVYCAZ solution my be held for no longer thn 30 minutes prior to trnsfer nd dilution in suitble infusion bg. Following dilution of the constituted solutions with the pproprite diluents, AVYCAZ solutions in the infusion bgs re stble for 12 hours when stored t room temperture. Following dilution of the constituted solutions with the pproprite diluents, AVYCAZ solutions in the infusion bgs my lso be refrigerted t 2 to 8 C (36 to 46 F) for up to 24 hours; nd then should be used within 12 hours of subsequent storge t room temperture. 3 DOSAGE FORMS AND STRENGTHS AVYCAZ 2.5 grms (ceftzidime nd vibctm) for injection is supplied s white to yellow sterile powder for constitution in single-dose, sterile, cler glss vil contining ceftzidime 2 grms (equivlent to grms of ceftzidime penthydrte/sodium crbonte powder) nd vibctm 0.5 grms (equivlent to grms of vibctm sodium). 4 CONTRAINDICATIONS AVYCAZ is contrindicted in ptients with known serious hypersensitivity to the components of AVYCAZ (ceftzidime nd vibctm), vibctm-contining products, or other members of the cephlosporin clss [see Wrnings nd Precutions (5.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Decresed Clinicl Response in ciai Ptients with Bseline Cretinine Clernce of 30 to Less Thn or Equl to 50 ml/min In Phse 3 ciai tril, clinicl cure rtes were lower in subgroup of ptients with bseline CrCl of 30 to less thn or equl to 50 ml/min compred to those with CrCl greter thn 50 ml/min (Tble 4). The reduction in clinicl cure rtes ws more mrked in ptients treted with AVYCAZ plus metronidzole compred to meropenem-treted ptients. Within this subgroup, ptients treted with AVYCAZ received 33% lower dily dose thn is currently recommended for ptients with CrCl 30 to less thn or equl to 50 ml/min. The decresed clinicl response ws not observed for ptients with moderte renl impirment t bseline (CrCl of 30 to less thn or equl to 50 ml/min) in the Phse 3 cuti trils. Monitor CrCl t lest dily in ptients with chnging renl function nd djust the dosge of AVYCAZ ccordingly [see Dosge nd Administrtion (2.2), nd Adverse Rections (6.1)]. Tble 4. Clinicl Cure Rte t Test of Cure in Phse 3 ciai Tril, by Bseline Renl Function mmitt Popultion AVYCAZ + Metronidzole % (n/n) Meropenem % (n/n) Norml function / mild impirment 85% (322/379) 86% (321/373) (CrCl greter thn 50 ml/min) Moderte impirment 45% (14/31) 74% (26/35) (CrCl 30 to less thn or equl to 50 ml/min) Microbiologicl modified intent-to-tret (mmitt) popultion included ptients who hd t lest one bcteril pthogen t bseline nd received t lest one dose of study drug. 5.2 Hypersensitivity Rections Serious nd occsionlly ftl hypersensitivity (nphylctic) rections nd serious skin rections hve been reported in ptients receiving bet-lctm ntibcteril drugs. Before therpy with AVYCAZ is instituted, creful inquiry bout previous hypersensitivity rections to other cephlosporins, penicillins, or crbpenems should be mde. Exercise cution if this product is to be given to penicillin or other bet-lctm-llergic ptient becuse cross-sensitivity mong bet-lctm ntibcteril drugs hs been estblished. Discontinue the drug if n llergic rection to AVYCAZ occurs. 5.3 Clostridium difficile-ssocited Dirrhe Clostridium difficile-ssocited dirrhe (CDAD) hs been reported for nerly ll systemic ntibcteril drugs, including AVYCAZ, nd my rnge in severity from mild dirrhe to ftl colitis. Tretment with ntibcteril drugs lters the norml flor of the colon nd my permit overgrowth of C. difficile. C. difficile produces toxins A nd B which contribute to the development of CDAD. Hypertoxin producing strins of C. difficile cuse incresed morbidity nd mortlity, s these infections cn be refrctory to ntimicrobil therpy nd my require colectomy. CDAD must be considered in ll ptients who present with dirrhe following ntibcteril use. Creful medicl history is necessry becuse CDAD hs been reported to occur more thn 2 months fter the dministrtion of ntibcteril drugs. If CDAD is suspected or confirmed, ntibcteril drugs not directed ginst C. difficile my need to be discontinued. Mnge fluid nd electrolyte levels s pproprite, supplement protein intke, monitor ntibcteril tretment of C. difficile, nd institute surgicl evlution s cliniclly indicted. 5.4 Centrl Nervous System Rections Seizures, nonconvulsive sttus epilepticus (NCSE), encephlopthy, com, sterixis, neuromusculr excitbility, nd myocloni hve been reported in ptients treted with ceftzidime, prticulrly in the setting of renl impirment. Adjust dosing bsed on cretinine clernce [see Dosge nd Administrtion (2.2)]. 5.5 Development of Drug-Resistnt Bcteri Prescribing AVYCAZ in the bsence of proven or strongly suspected bcteril infection is unlikely to provide benefit to the ptient nd increses the risk of the development of drug-resistnt bcteri [see Indictions nd Usge (1.3)]. 6 ADVERSE REACTIONS The following dverse rections re discussed in greter detil in the Wrnings nd Precutions section: Hypersensitivity Rections [see Wrnings nd Precutions (5.2)] Clostridium difficile-associted Dirrhe [see Wrnings nd Precutions (5.3)] Centrl Nervous System Rections [see Wrnings nd Precutions (5.4)] 6.1 Clinicl Tril Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes observed in the clinicl trils of drug cnnot be directly compred to rtes in the clinicl trils of nother drug nd my not reflect the rtes observed in prctice.

3 AVYCAZ ws evluted in five ctive-controlled clinicl trils in ptients with ciai or cuti, including pyelonephritis. These trils included two Phse 2 trils, one in ciai nd one in cuti, s well s three Phse 3 trils, one in ciai, one in cuti (Tril 1), nd one in ciai or cuti due to ceftzidime non-susceptible pthogens (Tril 2). Dt from Tril 1 served s the primry dtset for AVYCAZ sfety findings in cuti s there ws single comprtor. Tril 2 hd n open-lbel design s well s multiple comprtor regimens which prevented pooling, but provided supportive informtion. The five clinicl trils included totl of 1373 dult ptients treted with nd 1375 ptients treted with comprtors. Complicted Intr-bdominl Infections The Phse 3 ciai tril included 529 dult ptients treted with AVYCAZ 2.5 grms (ceftzidime 2 grms nd vibctm 0.5 grms) dministered intrvenously over 120 minutes every 8 hours plus 0.5 grms metronidzole dministered intrvenously over 60 minutes every 8 hours nd 529 ptients treted with meropenem. The medin ge of ptients treted with AVYCAZ ws 50 yers (rnge 18 to 90 yers) nd 22.5% of ptients were 65 yers of ge or older. Ptients were predominntly mle (62%) nd Cucsin (76.6%). Tretment discontinution due to n dverse rection occurred in 2.6% (14/529) of ptients receiving AVYCAZ plus metronidzole nd 1.3% (7/529) of ptients receiving meropenem. There ws no specific dverse rection leding to discontinution. Adverse rections occurring t 5% or greter in ptients receiving AVYCAZ plus metronidzole were dirrhe, nuse nd vomiting. Tble 5 lists dverse rections occurring in 1% or more of ptients receiving AVYCAZ plus metronidzole nd with incidences greter thn the comprtor in the Phse 3 ciai clinicl tril. Tble 5. Incidence of Selected Adverse Rections Occurring in 1% or more of Ptients Receiving AVYCAZ in the Phse 3 ciai Tril Preferred term AVYCAZ plus metronidzole Meropenem b (N=529) (N=529) Nervous system disorders Hedche 3% 2% Dizziness 2% 1% Gstrointestinl disorders Dirrhe 8% 3% Nuse 7% 5% Vomiting 5% 2% Abdominl Pin 1% 1% 2.5 grms (ceftzidime 2 grms nd vibctm 0.5 grms) IV over 120 minutes every 8 hours (with metronidzole 0.5 grms IV every 8 hours) b 1 grm IV over 30 minutes every 8 hours Incresed Mortlity In the Phse 3 ciai tril, deth occurred in 2.5% (13/529) of ptients who received AVYCAZ plus metronidzole nd in 1.5% (8/529) of ptients who received meropenem. Among subgroup of ptients with bseline CrCl 30 to less thn or equl to 50 ml/min, deth occurred in 19.5% (8/41) of ptients who received AVYCAZ plus metronidzole nd in 7.0% (3/43) of ptients who received meropenem. Within this subgroup, ptients treted with AVYCAZ received 33% lower dily dose thn is currently recommended for ptients with CrCl 30 to less thn or equl to 50 ml/min [see Dosge nd Administrtion (2.2) nd Wrnings nd Precutions (5.1)]. In ptients with norml renl function or mild renl impirment (bseline CrCl greter thn 50 ml/min), deth occurred in 1.0% (5/485) of ptients who received AVYCAZ plus metronidzole nd in 1.0% (5/484) of ptients who received meropenem. The cuses of deth vried nd contributing fctors included progression of underlying infection, bseline pthogens isolted tht were unlikely to respond to the study drug, nd delyed surgicl intervention. Complicted Urinry Trct Infections, Including Pyelonephritis Tril 1 included 511 dult ptients treted with AVYCAZ 2.5 grms (ceftzidime 2 grms nd vibctm 0.5 grms) dministered intrvenously over 120 minutes every 8 hours nd 509 ptients treted with doripenem; in some ptients prenterl therpy ws followed by switch to n orl ntimicrobil gent [see Clinicl Studies (14.2)]. Medin ge of ptients treted with AVYCAZ ws 54 yers (rnge 18 to 89 yers). Ptients were predominntly femle (68.3%) nd Cucsin (82.4%). Ptients with CrCl less thn 30 ml/min were excluded. There were no deths in Tril 1. Tretment discontinution due to dverse rections occurred in 1.4% (7/511) of ptients receiving nd 1.2% (6/509) of ptients receiving doripenem. There ws no specific dverse rection leding to discontinution. The most common dverse rections occurring in 3% of cuti ptients treted with AVYCAZ were nuse nd dirrhe. Tble 6 lists dverse rections occurring in 1% or more of ptients receiving nd with incidences greter thn the comprtor in Tril 1. Tble 6. Incidence of Selected Adverse Drug Rections Occurring in 1% or more of Ptients Receiving AVYCAZ in Tril 1 Phse 3 cuti Tril Preferred term (N=511) Doripenem b (N=509) Gstrointestinl disorders Nuse 3% 2% Dirrhe 3% 1% Constiption 2% 1% Upper bdominl pin 1% < 1% 2.5 grms (ceftzidime 2 grms nd vibctm 0.5 grms) IV over 120 minutes every 8 hours b 0.5 grms IV over 60 minutes every 8 hours Other Adverse Rections of nd Ceftzidime The following selected dverse rections were reported in AVYCAZ-treted ptients t rte of less thn 1% in the Phse 3 trils nd re not described elsewhere in the lbeling. Blood nd lymphtic disorders - Thrombocytopeni Generl disorders nd dministrtion site conditions - Injection site phlebitis Infections nd infesttions - Cndidisis Investigtions - Incresed sprtte minotrnsferse, Incresed lnine minotrnsferse, Incresed gmm-glutmyltrnsferse Metbolism nd nutrition disorders - Hypoklemi Nervous system disorders - Dysgeusi Renl nd urinry disorders - Acute renl filure, Renl impirment, Nephrolithisis Skin nd subcutneous tissue disorders - Rsh, Rsh mculo-ppulr, Urticri, Pruritus Psychitric disorders - Anxiety Additionlly, dverse rections reported with ceftzidime lone tht were not reported in AVYCAZtreted ptients in the Phse 3 trils re listed below: Blood nd lymphtic disorders - Agrnulocytosis, Hemolytic nemi, Leukopeni, Lymphocytosis, Neutropeni, Thrombocytosis, Eosinophili Generl disorders nd dministrtion site conditions - Infusion site inflmmtion, Injection site hemtom, Injection site thrombosis Heptobiliry disorders Jundice Investigtions - Incresed blood lctte dehydrogense, Prolonged prothrombin time Nervous system disorders - Presthesi Renl nd urinry disorders - Tubulointerstitil nephritis Reproductive nd brest disorders - Vginl inflmmtion Skin nd subcutneous tissue disorders - Angioedem, Erythem multiforme, Stevens-Johnson syndrome, Toxic epiderml necrolysis Lbortory Chnges Seroconversion from negtive to positive direct Coombs test result t ny time up to the lst visit occurred in 31/240 (12.9%) of ptients receiving AVYCAZ plus metronidzole with initil negtive Coombs test nd t lest one follow up test nd in 7/235 (3.0%) of ptients receiving meropenem in the Phse 3 ciai tril. Seroconversion from negtive to positive direct Coombs test result t ny time up to the lst visit occurred in 7/216 (3.2%) of ptients receiving AVYCAZ with initil negtive Coombs test nd t lest one follow up test nd 2/214 (0.9%) of ptients receiving doripenem in the Phse 3 cuti tril. No dverse rections representing hemolytic nemi were reported in ny tretment group. 7 DRUG INTERACTIONS 7.1 Probenecid In vitro, vibctm is substrte of OAT1 nd OAT3 trnsporters which might contribute to the ctive uptke from the blood comprtment, nd thereby its excretion. As potent OAT inhibitor, probenecid inhibits OAT uptke of vibctm by 56% to 70% in vitro nd, therefore, hs the potentil to decrese the elimintion of vibctm when co-dministered. Becuse clinicl interction study of AVYCAZ or vibctm lone with probenecid hs not been conducted, co-dministrtion of AVYCAZ with probenecid is not recommended [see Clinicl Phrmcology (12.3)]. 7.2 Drug/Lbortory Test Interctions The dministrtion of ceftzidime my result in flse-positive rection for glucose in the urine with certin methods. It is recommended tht glucose tests bsed on enzymtic glucose oxidse rections be used. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy Risk Summry There re no dequte nd well-controlled studies of AVYCAZ, ceftzidime, or vibctm in pregnnt women. Neither ceftzidime nor vibctm were tertogenic in rts t doses 40 nd 9 times the recommended humn clinicl dose. In the rbbit, t twice the exposure s seen t the humn clinicl dose, there were no effects on embryofetl development with vibctm. The bckground risk of mjor birth defects nd miscrrige for the indicted popultion is unknown. The bckground risk of mjor birth defects is 2-4% nd of miscrrige is 15-20% of cliniclly recognized pregnncies within the generl popultion. Becuse niml reproduction studies re not lwys predictive of humn response, this drug should be used in pregnncy only if clerly needed. Dt Animl Dt Ceftzidime Reproduction studies hve been performed in mice nd rts t doses up to 40 times the humn dose nd showed no evidence of hrm to the fetus due to ceftzidime. Avibctm Avibctm ws not tertogenic in rts or rbbits. In the rt, intrvenous studies with 0, 250, 500 nd 1000 mg/kg/dy vibctm during gesttion dys 6-17 showed no embryofetl toxicity t doses up to 1000 mg/kg/dy, pproximtely 9 times the humn dose bsed on exposure (AUC). In rt pre- nd post-ntl study t up to 825 mg/kg/dy intrvenously (11 times the humn exposure bsed on AUC), there were no effects on pup growth nd vibility. A dose-relted increse in the incidence of renl pelvic nd ureter dilttion ws observed in femle wening pups tht ws not ssocited with pthologicl chnges to renl prenchym or renl function, with renl pelvic dilttion persisting fter femle wening pups becme dults. Rbbits dministered intrvenous vibctm on gesttion dys 6-19 t 0, 100, 300 nd 1000 mg/kg/dy showed no effects on embryofetl development t dose of 100 mg/kg, twice the humn exposure (AUC). At higher doses, incresed post-implnttion loss, lower men fetl weights, delyed ossifiction of severl bones nd other nomlies were observed. 8.2 Lcttion Risk Summry Ceftzidime is excreted in humn milk in low concentrtions. It is not known whether vibctm is excreted into humn milk, lthough vibctm ws shown to be excreted in the milk of rts. No informtion is vilble on the effects of ceftzidime nd vibctm on the brest-fed child or on milk production.

4 The developmentl nd helth benefits of brestfeeding should be considered long with the mother s clinicl need for nd ny potentil dverse effects on the brestfed child from AVYCAZ or from the underlying mternl conditions. Dt In rt pre- nd post-ntl study t doses up to 825 mg/kg/dy intrvenously (11 times the humn exposure bsed on AUC), the exposure to vibctm ws miniml in the pups in comprison to the dms. Exposure to vibctm ws observed in both pups nd milk on PND Peditric Use Sfety nd effectiveness in ptients less thn 18 yers of ge hve not been estblished. 8.5 Geritric Use Of the 1373 ptients treted with AVYCAZ in the Phse 2 nd Phse 3 clinicl trils 385 (28%) were 65 yers of ge nd older, including 173 (15.3 %) ptients 75 yers of ge nd older. In the pooled Phse 2 nd Phse 3 ciai AVYCAZ clinicl trils, 20% (126/630) of ptients treted with AVYCAZ were 65 yers of ge nd older, including 49 (7.8%) ptients 75 yers of ge nd older. The incidence of dverse rections in both tretment groups ws higher in older ptients ( 65 yers of ge) nd similr in both tretment groups; clinicl cure rtes for ptients 65 yers of ge or older were 73.0% (73/100) in the AVYCAZ plus metronidzole rm nd 78.6% (77/98) in the meropenem rm. In the Phse 3 cuti tril, 30.7% (157/511) of ptients treted with AVYCAZ were 65 yers of ge or older, including 78 (15.3%) ptients 75 yers of ge or older. The incidence of dverse rections in both tretment groups ws lower in older ptients ( 65 yers of ge) nd similr between tretment groups. Among ptients 65 yers of ge or older in the Phse 3 cuti tril, 66.1% (82/124) of ptients treted with AVYCAZ hd symptomtic resolution t Dy 5 compred with 56.6% (77/136) of ptients treted with doripenem. The combined response (microbiologicl cure nd symptomtic response) observed t the test-of-cure (TOC) visit for ptients 65 yers of ge or older were 58.1% (72/124) in the rm nd 58.8% (80/136) in the doripenem rm. Ceftzidime nd vibctm re known to be substntilly excreted by the kidney; therefore, the risk of dverse rections to ceftzidime nd vibctm my be greter in ptients with decresed renl function. Becuse elderly ptients re more likely to hve decresed renl function, cre should be tken in dose selection nd it my be useful to monitor renl function. Helthy elderly subjects hd 17% greter exposure reltive to helthy young subjects when dministered the sme single dose of vibctm, which my hve been relted to decresed renl function in the elderly subjects. Dosge djustment for elderly ptients should be bsed on renl function [see Dosge nd Administrtion (2.2) nd Clinicl Phrmcology (12.3)]. 8.6 Renl Impirment Dosge djustment is required in ptients with modertely or severely impired renl function (CrCl 50 ml/min or less). For ptients with chnging renl function, CrCl should be monitored t lest dily, prticulrly erly in tretment, nd dosge of djusted ccordingly. Both ceftzidime nd vibctm re hemodilyzble; thus, AVYCAZ should be dministered fter hemodilysis on hemodilysis dys [see Dosge nd Administrtion (2.2) nd Clinicl Phrmcology (12.3)]. 10 OVERDOSAGE In the event of overdose, discontinue nd institute generl supportive tretment. Ceftzidime nd vibctm cn be removed by hemodilysis. In subjects with end-stge renl disese (ESRD) dministered 1 grm ceftzidime, the men totl recovery in dilyste following 4-hour hemodilysis session ws 55% of the dministered dose. In subjects with ESRD dministered 100 mg vibctm, the men totl recovery in dilyste following 4-hour hemodilysis session strted 1 hour fter dosing ws pproximtely 55% of the dose. No clinicl informtion is vilble on the use of hemodilysis to tret AVYCAZ overdosge [see Clinicl Phrmcology (12.3)]. 11 DESCRIPTION AVYCAZ is n ntibcteril combintion product consisting of the semisynthetic cephlosporin ceftzidime penthydrte nd the bet-lctmse inhibitor vibctm sodium for intrvenous dministrtion. Ceftzidime Ceftzidime is semisynthetic, bet-lctm ntibcteril drug. It is the penthydrte of (6R,7R,Z)- 7-(2-(2-minothizol-4-yl)-2-(2-crboxypropn-2-yloxyimino)cetmido)-8-oxo-3-(pyridinium-1- ylmethyl)-5-thi-1-z-bicyclo[4.2.0]oct-2-ene-2-crboxylte. Its moleculr weight is The empiricl formul is C 22 H 32 N 6 O 12 S 2. Figure 1 Chemicl structure of ceftzidime penthydrte Avibctm Avibctm sodium chemicl nme is sodium [(2S,5R)-2-crbmoyl-7-oxo-1,6-dizbicyclo[3.2.1] octn-6-yl] sulfte. Its moleculr weight is The empiricl formul is C 7 H 10 N 3 O 6 SN. Figure 2 Chemicl structure of vibctm sodium AVYCAZ 2.5 grms (ceftzidime nd vibctm) for injection is white to yellow sterile powder for constitution consisting of ceftzidime penthydrte nd vibctm sodium pckged in glss vils. The formultion lso contins sodium crbonte. Ech AVYCAZ 2.5 grms single-dose vil contins ceftzidime 2 grms (equivlent to grms sterile ceftzidime penthydrte/sodium crbonte) nd vibctm 0.5 grms (equivlent to grms sterile vibctm sodium). The sodium crbonte content of the mixture is mg/vil. The totl sodium content of the mixture is pproximtely 146 mg (6.4 meq)/vil. 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action AVYCAZ is n ntibcteril drug [see Clinicl Phrmcology (12.4)] Phrmcodynmics As with other bet-lctm ntimicrobil drugs, the time tht unbound plsm concentrtions of ceftzidime exceeds the AVYCAZ minimum inhibitory concentrtion (MIC) ginst the infecting orgnism hs been shown to best correlte with efficcy in neutropenic murine thigh infection model with Enterobctericee nd Pseudomons eruginos. The time bove threshold concentrtion hs been determined to be the prmeter tht best predicts the efficcy of vibctm in in vitro nd in vivo nonclinicl models. Crdic Electrophysiology In thorough QT study, suprtherpeutic dose of ceftzidime (3 grms) ws investigted for QT effects in combintion with suprtherpeutic dose of vibctm (2 grms) given s 30-minute single infusion. No significnt effect on QT c F intervl ws detected t pek plsm concentrtion or t ny other time. The lrgest 90% upper bound for the plcebo corrected men chnge from bseline ws 5.9 ms. There were no QT c F intervls greter thn 450 ms, nor were there ny QT c F intervl chnges from bseline greter thn 30 ms Phrmcokinetics The men phrmcokinetic prmeters for ceftzidime nd vibctm in helthy dult mle subjects with norml renl function fter single nd multiple 2-hour intrvenous infusions of AVYCAZ 2.5 grms (ceftzidime 2 grms nd vibctm 0.5 grms) dministered every 8 hours re summrized in Tble 7. Phrmcokinetic prmeters of ceftzidime nd vibctm were similr for single nd multiple dose dministrtion of nd were similr to those determined when ceftzidime or vibctm were dministered lone. Tble 7. Phrmcokinetic Prmeters (Geometric Men [%CV]) of Ceftzidime nd Avibctm Following Administrtion of AVYCAZ 2.5 grms (ceftzidime 2 grms nd vibctm 0.5 grms) in Helthy Adult Mle Subjects Ceftzidime Avibctm Prmeter Single AVYCAZ 2.5 grms Dose Administered s 2-hour Infusion (n = 16) Multiple AVYCAZ 2.5 grms Doses Administered every 8 hours s 2-hour Infusions for 11 Dys (n = 16) Single AVYCAZ 2.5 grms Dose Administered s 2-hour Infusion (n = 16) Multiple AVYCAZ 2.5 grms Doses Administered every 8 hours s 2-hour Infusions for 11 Dys (n = 16) C mx (mg/l) 88.1 (14) 90.4 (16) 15.2 (14) 14.6 (17) AUC (mg-h/l) b 289 (15) c 291 (15) 42.1 (16) d 38.2 (19) T 1/2 (h) 3.27 (33) c 2.76 (7) 2.22 (31) d 2.71 (25) CL (L/h) 6.93 (15) c 6.86 (15) 11.9 (16) d 13.1 (19) V ss (L) 18.1 (20) c 17 (16) 23.2 (23) d 22.2 (18) CL = plsm clernce; C mx = mximum observed concentrtion; d T 1/2 = terminl elimintion hlf-life; V ss (L) = volume of distribution t stedy stte ceftzidime 2 grms nd vibctm 0.5 grms b AUC 0-inf (re under concentrtion-time curve from time 0 to infinity) reported for single-dose dministrtion; AUC 0-tu (re under concentrtion curve over dosing intervl) reported for multiple-dose dministrtion c n = 15 d n = 13 The C mx nd AUC of ceftzidime increse in proportion to dose. Avibctm demonstrted pproximtely liner phrmcokinetics cross the dose rnge studied (50 mg to 2000 mg) for single intrvenous dministrtion. No pprecible ccumultion of ceftzidime or vibctm ws observed following multiple intrvenous infusions of AVYCAZ 2.5 grms (ceftzidime 2 grms nd vibctm 0.5 grms) dministered every 8 hours for up to 11 dys in helthy dults with norml renl function. Distribution Less thn 10% of ceftzidime ws protein bound. The degree of protein binding ws independent of concentrtion. The binding of vibctm to humn plsm proteins ws low (5.7% to 8.2%) nd ws similr cross the rnge of concentrtions tested in vitro (0.5 to 50 mg/l). The stedy-stte volumes of distribution of ceftzidime nd vibctm were 17 L nd 22.2 L, respectively, in helthy dults following multiple doses of AVYCAZ 2.5 grms (ceftzidime 2 grms nd vibctm 0.5 grms) infused every 8 hours over 2 hours for 11 dys. Metbolism Ceftzidime is mostly (80% to 90% of the dose) eliminted s unchnged drug. No metbolism of vibctm ws observed in humn liver preprtions (microsomes nd heptocytes). Unchnged vibctm ws the mjor drug-relted component in humn plsm nd urine fter single intrvenous dose of 0.5 grms 14 C-lbelled vibctm. Excretion Both ceftzidime nd vibctm re excreted minly by the kidneys. Approximtely 80% to 90% of n intrvenous dose of ceftzidime is excreted unchnged by the kidneys over 24-hour period. After the intrvenous dministrtion of single 0.5-grms or 1-grm doses, pproximtely 50% of the dose ppered in the urine in the first 2 hours. An dditionl 20% ws excreted between 2 nd 4 hours fter dosing, nd pproximtely nother 12% of the dose ppered in the urine between 4 nd 8 hours lter. The elimintion of ceftzidime by the kidneys resulted in high therpeutic concentrtions in the urine. The men renl clernce of ceftzidime ws pproximtely 100 ml/min. The clculted plsm clernce of pproximtely 115 ml/min indicted nerly complete elimintion of ceftzidime by the renl route. Following dministrtion of single 0.5-grms intrvenous dose of rdiolbelled vibctm, n verge of 97% of dministered rdioctivity ws recovered from the urine, with over 95% recovered within 12 hours of dosing. An verge of 0.20% of dministered totl rdioctivity ws recovered in feces within 96 hours of dosing. An verge of 85% of dministered vibctm ws recovered from

5 the urine s unchnged drug within 96 hours, with over 50% recovered within 2 hours of the strt of the infusion. Renl clernce ws 158 ml/min, which is greter thn the glomerulr filtrtion, suggesting tht ctive tubulr secretion contributes to the excretion of vibctm in ddition to glomerulr filtrtion. Specific Popultions Ptients with Renl Impirment Ceftzidime is eliminted lmost solely by the kidneys; its serum hlf-life is significntly prolonged in ptients with impired renl function. The clernce of vibctm ws significntly decresed in subjects with mild (CrCl greter thn 50 to 80 ml/min, n = 6), moderte (CrCl 30 to less thn or equl to 50 ml/min, n = 6), nd severe (CrCl 30 ml/min or less, not requiring hemodilysis; n = 6) renl impirment compred to helthy subjects with norml renl function (CrCl greter thn 80 ml/min, n = 6) following dministrtion of single 100-mg intrvenous dose of vibctm. The slower clernce resulted in increses in systemic exposure (AUC) of vibctm of 2.6-fold, 3.8-fold, nd 7-fold in subjects with mild, moderte, nd severe renl impirment, respectively, compred to subjects with norml renl function. A single 100-mg dose of vibctm ws dministered to subjects with ESRD (n = 6) either 1 hour before or fter hemodilysis. The vibctm AUC following the post-hemodilysis infusion ws 19.5-fold the AUC of helthy subjects with norml renl function. Avibctm ws extensively removed by hemodilysis, with n extrction coefficient of 0.77 nd men hemodilysis clernce of 9.0 L/h. Approximtely 55% of the vibctm dose ws removed during 4-hour hemodilysis session. Dosge djustment of AVYCAZ is recommended in ptients with moderte nd severe renl impirment nd end-stge renl disese. Popultion PK models for ceftzidime nd vibctm were used to conduct simultions for ptients with impired renl function. Simultions demonstrted tht the recommended dose djustments [see Dosge nd Administrtion (2.2)] provide comprble exposures of ceftzidime nd vibctm in ptients with moderte nd severe renl impirment nd end-stge renl disese to those in ptients with norml renl function or mild renl impirment. Becuse the exposure of both ceftzidime nd vibctm is highly dependent on renl function, monitor CrCl t lest dily nd djust the dosge of ccordingly for ptients with chnging renl function [see Dosge nd Administrtion (2.2)]. Ptients with Heptic Impirment The presence of heptic dysfunction hd no effect on the phrmcokinetics of ceftzidime in individuls dministered 2 grms intrvenously every 8 hours for 5 dys. The phrmcokinetics of vibctm in ptients with heptic impirment hve not been estblished. Avibctm does not pper to undergo significnt heptic metbolism, therefore the systemic clernce of vibctm is not expected to be significntly ffected by heptic impirment. Dose djustments re not currently considered necessry for AVYCAZ in ptients with impired heptic function. Geritric Ptients Following single-dose dministrtion of 0.5 grms vibctm s 30-minute infusion the men AUC for vibctm ws 17% higher in helthy elderly subjects (65 yers of ge nd older, n = 16) thn in helthy young dult subjects (18 to 45 yers of ge, n = 17). There ws no sttisticlly significnt ge effect for vibctm C mx. No dose djustment is recommended bsed on ge. Dosge djustment for AVYCAZ in elderly ptients should be bsed on renl function [see Dosge nd Administrtion (2.2)]. Gender Following single-dose dministrtion of 0.5 grms vibctm s 30-minute infusion, helthy mle subjects (n = 17) hd 18% lower vibctm C mx vlues thn helthy femle subjects (n = 16). There ws no gender effect for vibctm AUC prmeters. No dose djustment is recommended bsed on gender. Drug Interctions Avibctm t cliniclly relevnt concentrtions does not inhibit the cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 nd CYP3A4/5 in vitro in humn liver microsomes. Avibctm showed no potentil for in vitro induction of CYP1A2, 2B6, 2C9 nd 3A4 isoenzymes in humn heptocytes. Aginst CYP2E1, vibctm showed slight induction potentil t very high concentrtions tht exceed ny cliniclly relevnt exposure. Ceftzidime ws evluted independently in humn heptocytes nd showed no induction potentil on the ctivity or mrna expression of CYP1A1/2, CYP2B6, nd CYP3A4/5. Neither ceftzidime nor vibctm ws found to be n inhibitor of the following heptic nd renl trnsporters in vitro t cliniclly relevnt concentrtions: MDR1, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, BSEP, MRP4, OCT1 nd OCT2. Avibctm ws not substrte of MDR1, BCRP, MRP4, or OCT2, but ws substrte of humn OAT1 nd OAT3 kidney trnsporters bsed on results generted in humn embryonic kidney cells expressing these trnsporters. Probenecid inhibits 56% to 70% of the uptke of vibctm by OAT1 nd OAT3 in vitro. Ceftzidime does not inhibit vibctm trnsport medited by OAT1 nd OAT3. The clinicl impct of potent OAT inhibitors on the phrmcokinetics of vibctm is not known. Co-dministrtion of AVYCAZ with probenecid is not recommended [see Drug Interctions (7.1)]. Administrtion of AVYCAZ 2.5 grms (ceftzidime 2 grms nd vibctm 0.5 grms) to helthy mle subjects (n = 28) s 2-hour infusion following 1-hour infusion of metronidzole every 8 hours for 3 dys, did not ffect the C mx nd AUC vlues for vibctm or ceftzidime compred to dministrtion of AVYCAZ 2.5 grms (ceftzidime 2 grms nd vibctm 0.5 grms) lone. Administrtion of 0.5 grms metronidzole to helthy mle subjects s 1-hour infusion before 2-hour infusion of AVYCAZ 2.5 grms (ceftzidime 2 grms nd vibctm 0.5 grms) every 8 hours for 3 dys did not ffect the C mx nd AUC of metronidzole compred to dministrtion of 0.5 grms metronidzole lone Microbiology Mechnism of Action The ceftzidime component of AVYCAZ is cephlosporin ntibcteril drug with in vitro ctivity ginst certin grm-negtive nd grm-positive bcteri. The bctericidl ction of ceftzidime is medited through binding to essentil penicillin-binding proteins (PBPs). The vibctm component of AVYCAZ is non-bet-lctm bet-lctmse inhibitor tht inctivtes some bet-lctmses nd protects ceftzidime from degrdtion by certin bet-lctmses. Avibctm does not decrese the ctivity of ceftzidime ginst ceftzidime-susceptible orgnisms. AVYCAZ demonstrted in vitro ctivity ginst Enterobctericee in the presence of some bet-lctmses nd extended-spectrum bet-lctmses (ESBLs) of the following groups: TEM, SHV, CTX-M, Klebsiell pneumonie crbpenemse (KPCs), AmpC, nd certin oxcillinses (OXA). lso demonstrted in vitro ctivity ginst P. eruginos in the presence of some AmpC bet-lctmses, nd certin strins lcking outer membrne porin (OprD). AVYCAZ is not ctive ginst bcteri tht produce metllo-bet lctmses nd my not hve ctivity ginst grm-negtive bcteri tht overexpress efflux pumps or hve porin muttions. Resistnce No cross-resistnce with other clsses of ntimicrobils hs been identified. Some isoltes resistnt to other cephlosporins (including ceftzidime) nd to crbpenems my be susceptible to AVYCAZ. Interction with Other Antimicrobils In vitro studies hve not demonstrted ntgonism between nd colistin, levofloxcin, linezolid, metronidzole, tigecycline, tobrmycin, or vncomycin. Activity ginst Ceftzidime-Nonsusceptible Bcteri in Animl Infection Models Avibctm restored ctivity of ceftzidime in niml models of infection (e.g. thigh infection, pyelonephritis, systemic infection induced by intrperitonel injection) cused by ceftzidime non-susceptible bet-lctmse-producing (e.g., ESBL, KPC nd AmpC) grm-negtive bcteri. Antimicrobil Activity AVYCAZ hs been shown to be ctive ginst most isoltes of the following bcteri, both in vitro nd in clinicl infections [see Indictions nd Usge (1.1) nd (1.2)]. Complicted Intr-bdominl Infections (ciai) Aerobic Bcteri Grm-negtive Bcteri o Escherichi coli o Enterobcter cloce o Klebsiell pneumonie o Klebsiell oxytoc o Proteus mirbilis o Pseudomons eruginos o Citrobcter freundii complex Complicted Urinry Trct Infections (cuti), including Pyelonephritis Aerobic Bcteri Grm-negtive Bcteri o Citrobcter freundii complex o Escherichi coli o Pseudomons eruginos o Enterobcter cloce o Proteus mirbilis o Klebsiell pneumonie The following in vitro dt re vilble, but their clinicl significnce is unknown. At lest 90 percent of the following bcteri exhibit n in vitro minimum inhibitory concentrtion (MIC) less thn or equl to the susceptible brekpoint for ginst isoltes of similr genus or orgnism group. However, the efficcy of AVYCAZ in treting clinicl infections due to these bcteri hs not been estblished in dequte nd well-controlled clinicl trils. Grm-negtive Bcteri o Citrobcter koseri o Enterobcter erogenes o Morgnell morgnii o Providenci rettgeri o Providenci sturtii o Serrti mrcescens Susceptibility Test Methods When vilble, the clinicl microbiology lbortory should provide cumultive reports of in vitro susceptibility test results for ntimicrobil drugs used in locl hospitls nd prctice res s periodic reports tht describe the susceptibility profile of nosocomil nd community-cquired pthogens. These reports should id in the selection of n ntibcteril drug for tretment. Dilution Techniques Quntittive methods re used to determine ntimicrobil minimum inhibitory concentrtions (MICs). These MICs provide estimtes of the susceptibility of bcteri to ntimicrobil compounds. The MIC vlues should be determined using stndrdized test method (broth or gr) 1-3. MIC vlues should be determined using seril dilutions of ceftzidime combined with fixed concentrtion of 4 mcg/ml of vibctm. The MIC vlues should be interpreted ccording to the criteri in Tble 8. Diffusion Techniques Quntittive methods tht require mesurement of zone dimeters cn lso provide reproducible estimtes of the susceptibility of bcteri to ntimicrobil compounds. The zone size should be determined using stndrdized method 2,3. This procedure uses pper disks impregnted with 30 mcg of ceftzidime nd 20 mcg vibctm to test the susceptibility of bcteri to AVYCAZ. The disk interpretive criteri re provided in Tble 8. Tble 8. Susceptibility Interpretive Criteri for Ceftzidime/Avibctm Minimum Inhibitory Disk Diffusion Pthogen Concentrtion (mg/l) Zone Dimeter (mm) S R S R Enterobctericee 8/4 16/ Pseudomons eruginos 8/4 16/ A report of Susceptible (S) indictes tht the ntimicrobil drug is likely to inhibit growth of the pthogen if the ntimicrobil drug reches the concentrtion usully chievble t the site of infection. A report of Resistnt (R) indictes tht the ntimicrobil drug is not likely to inhibit growth of the pthogen if the ntimicrobil drug reches the concentrtions usully chievble t the site of infection; other therpy should be selected.

6 Qulity Control Stndrdized susceptibility test procedures require the use of lbortory controls to monitor nd ensure the ccurcy nd precision of supplies nd regents used in the ssy, nd the techniques of the individuls performing the test 1-3. Stndrd AVYCAZ powder should provide the following rnge of MIC vlues noted in Tble 9. For the diffusion technique using the 30 mcg ceftzidime/20-mcg vibctm disk, the criteri in Tble 9 should be chieved. Tble 9. Acceptble Qulity Control Rnges for Susceptibility Testing Qulity Control Orgnism Minimum Inhibitory Disk Diffusion Zone Concentrtion (mg/l) Dimeter (mm) Stphylococcus ureus ATCC Stphylococcus ureus ATCC Escherichi coli ATCC Escherichi coli ATCC Pseudomons eruginos ATCC Klebsiell pneumonie ATCC b Hemophilus influenze ATCC Hemophilus influenze ATCC Streptococcus pneumonie ATCC MIC for ceftzidime in the presence of fixed concentrtion of 4 mg/l of vibctm b K. pneumonie ATCC should be tested ginst ceftzidime nd vibctm nd ceftzidime lone to confirm the ctivity of vibctm in the combintion nd to ensure tht the plsmid encoding the bet-lctmse hs not been lost in this strin. The cceptble rnge for ceftzidime lone is greter thn 16 mg/l. 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility Ceftzidime nd vibctm were ech evluted for mutgenic potentil in severl in vitro nd in vivo ssys. Ceftzidime ws negtive for mutgenicity in mouse micronucleus test nd n Ames test. Avibctm ws negtive for genotoxicity in the Ames ssy, unscheduled DNA synthesis, chromosoml berrtion ssy, nd rt micronucleus study. Avibctm hd no dverse effects on fertility of mle nd femle rts given up to 1 g/kg/dy (pproximtely 20 fold higher thn the recommended clinicl dose on body surfce re bsis). There ws dose-relted increse in the percentge of pre- nd post-implnttion loss reltive to controls, resulting in lower men litter size t doses 0.5 g/kg nd greter with intrvenous dministrtion to femle rts beginning 2 weeks prior to mting. 14 CLINICAL STUDIES 14.1 Complicted Intr-bdominl Infections A totl of 1058 dults hospitlized with ciai were rndomized nd received tril medictions in multintionl, multi-center, double-blind tril compring AVYCAZ 2.5 g (ceftzidime 2 grms nd vibctm 0.5 grms) intrvenously every 8 hours plus metronidzole (0.5 grms intrvenously every 8 hours) to meropenem (1 grm intrvenously every 8 hours) for 5 to 14 dys of therpy. Complicted intr-bdominl infections included ppendicitis, cholecystitis, diverticulitis, gstric/ duodenl perfortion, perfortion of the intestine, nd other cuses of intr-bdominl bscesses nd peritonitis. The microbiologiclly modified intent-to tret (mmitt) popultion, which included ll ptients who hd t lest one bseline intr-bdominl pthogen, consisted of 823 ptients; the medin ge ws 51 yers nd 62.8% were mle. The mjority of ptients (64.9%) were from Estern Europe; 7.5% were from the United Sttes. Less thn 1.0% of ptients were of Pcific Islnd or Africn descent. The most common primry ciai dignosis ws ppendicel perfortion or peri-ppendicel bscess, occurring in 44.7% of ptients. Bcteremi t bseline ws present in 4.3% of ptients. Clinicl cure ws defined s complete resolution or significnt improvement in signs nd symptoms of the index infection t the test-of-cure (TOC) visit which occurred 28 to 35 dys fter rndomiztion. Tble 10 presents the clinicl cure in the mmitt popultion nd in the microbiologiclly evluble (ME) popultion, which included ll protocol-dherent mmitt ptients. AVYCAZ plus metronidzole ws non-inferior to meropenem with regrd to the primry endpoint (clinicl cure rte t the TOC visit in the mmitt popultion). Clinicl cure rtes t the TOC visit by pthogen in the mmitt popultion re presented in Tble 11. Tble 10. Clinicl Cure Rtes t TOC from the Phse 3 ciai Tril Anlysis popultion AVYCAZ plus metronidzole Meropenem b Tretment Difference (95% CI) c mmitt 337/413 (81.6) 349/410 (85.1) -3.5 (-8.6, 1.6) ME 244/265 (92.1) 272/287 (94.8) -2.7 (-7.1, 1.5) AVYCAZ 2.5 grms (ceftzidime 2 grms nd vibctm 0.5 grms) IV every 8 hours + metronidzole 0.5 grms IV every 8 hours b 1 grm IV every 8 hours c The 95% confidence intervl (CI) ws clculted s n unstrtified Miettinen nd Nurminen method Of the 823 ptients in the mmitt popultion, 14 (1.7%) hd bseline E. coli bcteremi; 7/10 (70.0%) of ptients in the rm nd 3/4 (75.0%) of ptients in the meropenem rm hd clinicl cure. Tble 11. Clinicl Cure Rtes t TOC by Bseline Pthogen from the Phse 3 ciai Tril, mmitt Popultion Aerobic Grm-negtive group or pthogen AVYCAZ plus metronidzole Meropenem b Enterobctericee 272/334 (81.4) 305/353 (86.4) Escherichi coli 218/271 (80.4) 248/285 (87.0) Klebsiell pneumonie 40/51 (78.4) 37/49 (75.5) Klebsiell oxytoc 14/18 (77.8) 12/15 (80.0) Enterobcter cloce 11/13 (84.6) 16/19 (84.2) Citrobcter freundii complex 14/18 (77.8) 9/12 (75.0) Proteus mirbilis 5/8 (62.5) 7/9 (77.8) Pseudomons eruginos 30/35 (85.7) 34/36 (94.4) AVYCAZ 2.5 grms (ceftzidime 2 grms nd vibctm 0.5 grms) IV every 8 hours + metronidzole 0.5 grms IV every 8 hours b 1 grm IV every 8 hours At bseline, 111 ptients in the mmitt popultion hd Grm-negtive isoltes tht were not susceptible to ceftzidime, including 61 ptients with E. coli nd 26 ptients with K. pneumonie isoltes. Cure rtes were 39/47 (83.0%) in ptients who received nd 55/64 (85.9%) of ptients who received meropenem. In subset of Grm-negtive pthogens from both rms of the Phse 3 ciai tril tht met phenotypic screening criteri for the presence of bet-lctmse, genotypic testing identified certin ESBL groups (e.g., TEM-1, SHV-12, CTX-M-15, OXA-48) nd AmpC tht were expected to be inhibited by vibctm in isoltes from 105 (12.8%) of the 823 ptients in the mmitt popultion. Clinicl cure rtes in this subset were similr to the overll results Complicted Urinry Trct Infections, Including Pyelonephritis The efficcy of AVYCAZ in ptients with cuti ws evluted in two rndomized, ctively controlled clinicl trils (Tril 1 nd Tril 2) s described below. Tril 1: A totl of 1020 dults hospitlized with cuti were rndomized nd received tril medictions in multintionl, multi-center, double-blind tril compring AVYCAZ 2.5 g (ceftzidime 2 grms nd vibctm 0.5 grms) intrvenously every 8 hours to doripenem 0.5 grms intrvenously every 8 hours for 10 to 14 dys of totl therpy. A switch to n orl ntimicrobil gent ws llowed fter 5 dys of intrvenous dosing. Complicted urinry trct infections included cute pyelonephritis nd complicted lower urinry trct infections. The mmitt popultion, which included ll ptients who hd t lest one uropthogen isolted t bseline (greter or equl to 10 5 CFU/mL), consisted of 810 ptients; the medin ge ws 55 yers nd 69.8% were femle. The mjority of ptients (75.4%) were from Estern Europe; less thn 1% of ptients were from the United Sttes. The mjority of ptients were White (83%) or Asin (7.8%); other rcil subgroups were ech represented t less thn 1%. The most common dignosis ws cute pyelonephritis, occurring in 72% of ptients. Bcteremi ws present t bseline in 8.8% of ptients. Clinicl efficcy ws determined by compring the response rte of AVYCAZ to doripenem t both primry endpoints; symptom response rtes t Dy 5 nd combined microbiologicl cure nd symptom response rtes t the TOC visit (21 to 25 dys fter rndomiztion). A symptom response ws bsed on the resolution of ptient-reported cuti symptoms, defined s frequency/urgency/ dysuri/suprpubic pin, s well s n improvement in flnk pin for individuls with cute pyelonephritis. Microbiologicl cure ws defined s reduction of ll bseline uropthogens to less thn 10 4 CFU/mL in the urine. AVYCAZ ws noninferior to doripenem with regrd to both primry endpoints s presented in Tble 12. Tble 12. Clinicl nd Microbiologicl Cure Rtes from cuti Tril 1, mmitt Popultion Study endpoint Tretment Doripenem b Difference (95% CI) c Symptomtic response t Dy 5 276/393 (70.2) 276/417 (66.2) 4.0 (-2.4, 10.4) Combined symptomtic nd microbiologicl response t TOC 280/393 (71.2) 269/417 (64.5) 6.7 (0.3, 13.1) Microbiologicl cure t TOC 304/393 (77.4) 296/417 (71.0) 6.4 (0.3, 12.4) Symptomtic response t TOC 332/393 (84.5) 360/417 (86.3) -1.9 (-6.8, 3.0) AVYCAZ 2.5 grms (ceftzidime 2 grms nd vibctm 0.5 grms) IV every 8 hours b 0.5 grms IV every 8 hours c The 95% confidence intervl (CI) ws clculted using the unstrtified Miettinen nd Nurminen method Microbiologicl cure rtes by pthogen re presented in Tble 13. Microbiologicl cure in individuls with bcteremi t bseline ws chieved in 31/38 (81.6%) ptients in the rm nd 24/33 (72.7%) ptients in the doripenem rm t the TOC visit in the mmitt popultion. The most common pthogen isolted from blood ws Escherichi coli, for which 31/32 (96.9%) ptients in the AVYCAZ rm were microbiologicl cures, compred with 28/28 (100%) ptients in the doripenem rm. Tble 13. Microbiologicl Cure Rte t TOC by Bseline Pthogen from cuti Tril 1, mmitt Popultion Aerobic Grm-negtive group or pthogen Doripenem b Enterobctericee 299/382 (78.3) 281/398 (70.6) Escherichi coli 229/292 (78.4) 220/306 (71.9) Klebsiell pneumonie 33/44 (75.0) 35/56 (62.5) Proteus mirbilis 16/17 (94.1) 9/13 (69.2) Enterobcter cloce 6/11 (54.5) 9/13 (69.2) Pseudomons eruginos 12/18 (66.7) 15/20 (75.0) AVYCAZ 2.5 grms (ceftzidime 2 grms nd vibctm 0.5 grms) IV every 8 hours b 0.5 grms IV every 8 hours At bseline, 159 ptients in the mmitt popultion hd Grm-negtive isoltes tht were not susceptible to ceftzidime, including 75 ptients in the rm nd 84 in the doripenem rm. Microbiologicl nd clinicl cure rtes t TOC were 47/75 (62.7%) nd 67/75 (89.3%), respectively, in ptients who received AVYCAZ, compred to 51/84 (60.7%) nd 75/84 (89.3%) in ptients who received doripenem. In subset of Grm-negtive pthogens from both rms of the Phse 3 cuti tril tht met phenotypic screening criteri for the presence of bet-lctmse, genotypic testing identified certin ESBL groups (e.g., TEM-1, SHV-12, CTX-M-15, CTX-M-27, OXA-48) nd AmpC tht were expected to be inhibited by vibctm in isoltes from 176 (21.7%) of the 810 ptients in the mmitt popultion. Microbiologicl nd clinicl cure rtes in this subset were similr to the overll tril results. Tril 2: In multintionl, multi-center, open-lbel study of dults hospitlized with ceftzidime non-susceptible (CAZ-NS) Grm-negtive infections, 305 subjects with cuti were rndomized to receive AVYCAZ 2.5 g (ceftzidime 2 grms nd vibctm 0.5 grms) intrvenously every 8 hours or the best vilble intrvenous therpy (BAT) for 5 to 21 dys of tretment. There ws no optionl switch to orl therpy. The mjority (96.1%) of ptients in the BAT rm received monotherpy with crbpenem ntibcteril drug. Complicted urinry trct infections included cute pyelonephritis nd complicted lower urinry trct infections.