PrZEFTERA * ceftobiprole medocaril for Injection Sterile, lyophilized powder for Intravenous Infusion 500 mg/vial ceftobiprole as ceftobiprole medocaril Antibacterial Agent This Product Monograph is the exclusive property of Janssen-Ortho Inc. It may not be copied in whole or in part without the written permission of Janssen-Ortho Inc. Janssen-Ortho Inc. 19 Green Belt Drive Toronto, Ontario M3C 1L9 www.janssen-ortho.com Date of Preparation: June 26, 2008 Submission Control Number: 112752 All trademark rights used under license (c) 2008 JANSSEN-ORTHO Inc.

PART I: HEALTH PROFESSIONAL INFORMATION 3 SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 6 DRUG INTERACTIONS 9 DOSAGE AND ADMINISTRATION 10 OVERDOSAGE 13 ACTION AND CLINICAL PHARMACOLOGY 13 STORAGE AND STABILITY 16 SPECIAL HANDLING INSTRUCTIONS 17 DOSAGE FORMS, COMPOSITION AND PACKAGING 17

PART II: SCIENTIFIC INFORMATION 18 PHARMACEUTICAL INFORMATION 18 CLINICAL TRIALS 19 DETAILED PHARMACOLOGY 21 MICROBIOLOGY 26 TOXICOLOGY 30 REFERENCES 45

PrZEFTERA * ceftobiprole medocaril for Injection Sterile, lyophilized powder for Intravenous Infusion 500 mg/vial ceftobiprole as ceftobiprole medocaril Antibacterial Agent

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

ZEFTERA (ceftobiprole medocaril for injection, henceforth known as ceftobiprole) is a cephalosporin antibiotic indicated for the treatment of the following infections when caused by susceptible strains of the designated microorganisms in patients 18 years of age and older:

Complicated skin and skin structure infections (cSSSI), including non-limb threatening diabetic foot infections without concomitant osteomyelitis caused by: Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Staphylococcus aureus (including methicillin-resistant isolates), and Streptococcus pyogenes (see DOSAGE AND ADMINISTRATION).

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZEFTERA and other antibacterial drugs, ZEFTERA should be used only to treat or prevent infections that are proven or suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to ceftobiprole. Empiric therapy with ZEFTERA may be initiated before the results of these tests are known. Once these results are available, antimicrobial therapy should be adjusted (see DOSAGE AND ADMINISTRATION). Geriatrics (>= 65 years of age): Evidence from clinical studies suggests that use in the geriatric population is not associated with significant differences in safety or effectiveness (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics). Population pharmacokinetic data showed there is no independent effect of age on the pharmacokinetics of ceftobiprole. Dosage adjustment is not required in elderly patients with normal renal function (see DOSAGE AND ADMINISTRATION, Patients with Renal Impairment).

Pediatrics (<18 years of age): WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics)

No data available (see

CONTRAINDICATIONS

ZEFTERA is contraindicated in patients with known serious hypersensitivity to ceftobiprole, any of the excipients, other cephalosporins, or in patients who have demonstrated anaphylaxis to ss- lactam antibiotics.

WARNINGS AND PRECAUTIONS

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving ss-lactam antibiotics. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. Anaphylaxis, including anaphylactic shock, has been observed with ZEFTERA. Before therapy with ZEFTERA is instituted, careful inquiry should be made to determine whether the patient has had a previous hypersensitivity reaction to other cephalosporins, penicillins or other allergens. SERIOUS ACUTE HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS REQUIRE EMERGENCY TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES (see

As with other antibiotics, prolonged use of ZEFTERA may result in overgrowth of non- susceptible organisms, including fungi. Appropriate measures should be taken if evidence of super-infection occurs during therapy. Patients with necrotizing fasciitis, gas gangrene, eczema, neutropenia, neoplasia, and immuno- compromised patients, were not enrolled in these studies, therefore ZEFTERA is not recommended for use in treating such patients. The every 12-hour dosing regimen has not been studied in patients with diabetic foot infections (see DOSAGE AND ADMINISTRATION). Hyponatremia was observed in clinical trials with ZEFTERA. For patients at risk of hyponatremia, consideration should be given to the choice of infusion solution for ZEFTERA (see DOSAGE AND ADMINISTRATION).

As with other beta-lactams, patients may experience seizures during treatment with ZEFTERA. Seizures associated with ZEFTERA have occurred most commonly in patients with pre-existing CNS/seizure disorders; therefore caution is advised when treating these patients.

SERIOUS ACUTE HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS REQUIRE EMERGENCY TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, IV FLUIDS, IV ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.

Infusion site reactions, including pain and phlebitis, have been observed in clinical trials (see ADVERSE DRUG REACTIONS).

Clostridium difficile-associated disease (CDAD) has been reported with use of many antibacterial agents, including ZEFTERA. CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of the colon subsequent to the administration of any antibacterial agent. CDAD has been reported to occur over 2 months after the administration of antibacterial agents. Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy. If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridium difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should be instituted as clinically indicated since surgical intervention may be required in certain severe cases (see ADVERSE REACTIONS).

In patients with moderately or severely impaired renal function (CrCl 10 to < 50 mL/min), dosage adjustment is required (see DOSAGE AND ADMINISTRATION, Patients with Renal Impairment). There is no experience in patients with end stage renal disease (CrCl < 10 mL/min) or in patients on dialysis. The concomitant administration of aminoglycosides and some cephalosporins has caused nephrotoxicity. Concomitant administration of ZEFTERA with known nephrotoxic agents has not been studied.

Pregnant Women: PART II: SCIENTIFIC INFORMATION, TOXICOLOGY).

No clinical studies have been performed in pregnant women. ZEFTERA should not be used during pregnancy unless the expected benefit to the mother outweighs the potential risk to the fetus. Reproductive studies in animals at doses up to two and eight times the human dose have not revealed any evidence of impaired fertility or harm to the fetus. Animal reproduction studies are not always predictive of a human response (see

Nursing Women: PART II: SCIENTIFIC INFORMATION, TOXICOLOGY).

It is not known whether ceftobiprole is excreted in human breast milk. Breastfeeding should be discontinued during treatment with ZEFTERA. Studies in animals have shown that the concentration of ceftobiprole excreted in animal milk is ~20% of the maternal plasma levels (see

Pediatrics (< 18 years of age):

Safety and effectiveness in pediatric patients below the age of 18 have not been established. Therefore, use in patients under 18 years of age is not recommended.

Geriatrics (> 65 years of age):

Of the total number of subjects in clinical studies treated with ZEFTERA, 22% were 65 and over, while 6% were 75 and over.

Dosage adjustment is not required in elderly patients with normal renal function (see DOSAGE AND ADMINISTRATION, Patients with Renal Impairment). Since elderly patients may have impaired renal function, creatinine clearance should be taken into consideration when determining dose in elderly patients.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The most common adverse drug reactions in patients treated with ZEFTERA are: nausea (9.1%), dysgeusia (5.6%), vomiting (4.8%), diarrhea (4.8%), and headache (4.5%) The majority (92.6%) of adverse events were reported as mild to moderate in severity. Ceftobiprole was discontinued due to an adverse event in 3.8% of subjects compared with 4.1% for all comparators. During clinical trials, adverse drug reactions that led to ZEFTERA discontinuation were rash (0.6%), nausea (0.5%), vomiting (0.4), hypersensitivity reactions (0.3%), and hyponatremia (0.3%). For comparators, adverse drug reactions leading to discontinuation were rash (0.9%), hypersensitivity reactions (0.9%), nausea (0.5%), infusion site reactions (0.5%) and diarrhea (0.5%).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under widely varying conditions, adverse drug reaction rates observed in clinical trials of a drug cannot be compared directly to rates from clinical trials of other drugs and may not reflect rates observed in practice.

The safety of ZEFTERA in patients with complicated skin and skin structure infections (including patients with diabetic foot infections without concomitant osteomyelitis) was evaluated in two Phase 3 double-blind, active controlled trials involving 1,593 adult patients (932 of whom received ZEFTERA). All study treatments were administered for 7 to 14 days. Adverse drug reactions due to ZEFTERA 500 mg administered every 8 or 12 hours as a 120 or 60-minute infusion that occurred at a rate >= 1 % (as judged by investigator to be remotely, possibly or probably related to ZEFTERA) are listed in Table 1.

Table 1: Adverse Drug Reactions (%) Observed in Two Phase 3 Clinical Trials Occurring at a Rate >= 1%

Body System or Organ Class 1

Ceftobiprole Comparator

Preferred Term N = 932

N =661 (%)

Gastrointestinal disorders

Nausea 9.1 5.3

Diarrhea 4.8 3.5

Vomiting 4.8 3.3

Constipation 1.2 2.0

Dyspepsia 1.1 0.6

Nervous system disorders

Dysgeusia 5.6 0.9

Headache 4.5 2.4

Dizziness 2.7 0.8

General disorders and administration site conditions

Pyrexia 1.3 0.9

Fatigue 1.1 0.9

Chills 1.0 0.6

Skin and subcutaneous tissue disorders

Rash 2.7 2.6

Pruritus 1.7 4.7

Investigations

Alanine aminotransferase increased 1.6 2.0

Aspartate aminotransferase increased 1.3 1.2

Vascular disorders

Phlebitis 1.9 0.8

Metabolism and nutrition disorders

Hyponatremia 1.1 0

Vancomycin in the study that enrolled patients with gram-positive infections; vancomycin plus ceftazidime in the study that enrolled patients with gram-positive and gram-negative infections

The majority of cases of nausea were mild, self-limited and did not lead to discontinuation of ZEFTERA. Nausea occurred at a lower frequency in those patients who received a 120-minute infusion (7%) compared with patients who received a 60-minute infusion (12%). Anaphylaxis, including anaphylactic shock, Clostridium difficile colitis and seizures were adverse drug reactions that occurred at a rate of less than 1% in these clinical trials. There is limited experience in patients receiving more than 14 days of therapy (N= 18). The adverse events profile of subjects who received greater than 14 days of therapy was similar to the adverse event profile of subjects who received 14 days or less of therapy (see PART II: SCIENTIFIC INFORMATION, CLINICAL TRIALS).

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Adverse drug reactions that were possibly or probably related to ZEFTERA with an incidence of <1.0% and >0.3% in Phase 3 clinical studies were:

Blood and lymphatic system:

anemia

Gastrointestinal:

abdominal pain, dyspepsia, stomach discomfort, dry mouth

General disorders & administration site conditions:

asthenia, chills, fatigue, peripheral oedema, pyrexia, infusion site pain, catheter site phlebitis, feeling hot

Infections and Infestations:

vulvovaginal mycotic infection, fungal infection

Immune System Disorders:

hypersensitivity

Investigations:

blood creatinine increased, blood lactate dehydrogenase increased, eosinophil count increased, gamma-glutamyltransferase increased, liver function test abnormal, platelet count increased, decreased creatinine clearance, increase blood triglycerides, increased basophils, increased blood triglycerides

Metabolism and nutrition:

hyperglycaemia

Musculoskeletal and connective tissue:

muscle spasms, back pain, pain in extremity

Nervous system:

somnolence

Psychiatric:

agitation, insomnia, anxiety

Renal and urinary:

urine odour abnormal, pollakiuria

Respiratory, thoracic and mediastinal:

dyspnoea, pharyngeal pain

Skin and subcutaneous tissue:

dermatitis allergic, hyperhidrosis, erythema, rash maculopapular, urticaria

Vascular:

hot flush, thrombophlebitis, hypertension

Abnormal Hematologic and Clinical Chemistry Findings

See Table 1 and Less Common Clinical Trial Adverse Drug Reactions (<1%).

DRUG INTERACTIONS

induction studies were conducted with ceftobiprole at 5mM. The anticipated maximal plasma concentration of ceftobiprole in humans administered 500 mg of ceftobiprole q8h over 2 hour infusion is approximately 65mM. The studies demonstrated minimal inhibition and no induction potential with CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The potential of ceftobiprole to affect the CYP450 dependent metabolic clearance of co-administered drugs is low on the basis of these studies, and because the distribution of ceftobiprole is restricted to the extracellular compartment. The potential for other drugs to interact with ceftobiprole is minimal since only a small fraction of ceftobiprole is metabolized. Therefore, no relevant metabolic drug- drug interactions are anticipated.

In vitro experiments were conducted to determine whether ceftobiprole is a substrate or inhibitor for the drug (efflux) transporter P-gp. Ceftobiprole was not found to be a P-gp substrate or inhibitor. When using specific catalyzed cytochrome-P450 (CYP450) reactions in human microsomes, ceftobiprole showed no significant inhibition of the tacrine 1- and 7-hydroxylation (CYP1A2), diclofenac 4'-hydroxylation (CYP2C9), S-mephenytoin 4'-hydroxylation (CYP2C19), bufuralol 1'-hydroxylation (CYP2D6), and testosterone 6-b-hydroxylation (CYP3A4); only a slight (8% to 28%) inhibitory potential was apparent in the highest concentration range tested (50 to 100 uM). In another experiment using cultured human hepatocytes, 5 uM ceftobiprole caused no induction of CYP1A2, CYP2B6, CYP2C9, CYP2C19 or CYP3A4/5. Since ceftobiprole does not undergo tubular secretion and only a fraction is reabsorbed, renal drug-drug interactions are not expected.

Clinical drug-drug interaction studies have not been performed. Population pharmacokinetic analyses failed to demonstrate an effect of the following concomitant medications on the pharmacokinetics of ceftobiprole: fentanyl, lidocaine, acetaminophen, diclofenac, acetylsalicylic acid, heparin, diphenhydramine, propofol, hydromorphone hydrochloride, methadone, hydrocodone bitartrate, metamizole sodium, furosemide.

DOSAGE AND ADMINISTRATION

On the basis of pharmacokinetic data in patients with moderate to severe renal impairment, the dose of ZEFTERA should be adjusted (see Recommended Dose and Dosage Adjustment, Patients with Renal Impairment).

In patients with mild renal impairment (i.e. creatinine clearance (CrCl) 50 to 80 mL/min), no dosage adjustment is necessary. In patients with moderate renal impairment (CrCl 30 to < 50 mL/min), the dosage of ZEFTERA should be 500 mg administered every 12 hours as a 120- minute intravenous infusion. In patients with severe renal impairment (CrCl < 30 mL/min), the dosage of ZEFTERA should be 250 mg administered every 12 hours as a 120-minute intravenous infusion (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency). The experience in patients with severe renal impairment is limited. There is no experience in patients with end stage renal disease (CrCl < 10 mL/min) or in patients on dialysis. The following formula may be used to estimate CrCl. The serum creatinine used in the formula should represent a steady state of renal function. Males: Creatinine clearance (mL/min) = weight (kg) x (140 - age in years) 72 x serum creatinine (mg/dL) Females: Creatinine clearance (mL/min) = 0.85 x value calculated for males

There is no experience in patients with hepatic impairment. However, as ceftobiprole undergoes minimal hepatic metabolism and is eliminated predominantly by the kidney, no dosage adjustment is necessary in patients with hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency).

ACTION AND CLINICAL PHARMACOLOGYSpecial Populations and Conditions)

No dosage adjustment is recommended solely based on age (18 years of age and older), gender or race (see

ZEFTERA is to be reconstituted and then further diluted prior to administration by intravenous infusion over a period of one or two hours. Each vial is for single use only.

Reconstitution:

Parenteral Products:

The lyophilized powder should only be reconstituted with 10 mL water for injection or 5% dextrose solution for injection. The vial should be vigorously shaken. Complete dissolution may take up to 10 minutes. Before dilution into the infusion solution, any foam should be allowed to dissipate.

Dilution:

10 mL of the reconstituted solution should be removed from the vial and injected into a suitable container (e.g. PVC or PE infusion bags, glass bottles) containing 250 mL of 0.9% sodium chloride, 5% dextrose injection, or Lactated Ringer's injection infusion solution. The infusion solution should be gently inverted 5-10 times to form a homogenous solution. Vigorous agitation should be avoided to prevent foaming. For detailed infusion solution storage conditions and stability, please see STORAGE AND STABILITY. For patients with severe renal impairment (see Recommended Dose and Dosage Adjustment, Patients with Renal Impairment), 5 mL of the reconstituted solution should be diluted into 125 mL of 0.9% sodium chloride, 5% dextrose injection or Lactated Ringer's injection infusion solution. The infusion solution should be inspected visually for particulate matter prior to administration, and discarded if particulate matter is visible.

The compatibility of ZEFTERA with other drugs has not been established. ZEFTERA should not be mixed with or physically added to solutions containing other drugs.

OVERDOSAGE

Information on overdosage with ZEFTERA in humans is not available. The highest total daily dose administered in Phase 1 trials was 3 g (1 g every 8 hours). If overdosage should occur, it should be treated symptomatically. For management of a suspected drug overdose, contact you regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Ceftobiprole medocaril is the water-soluble prodrug of ceftobiprole, a prototypical cephalosporin with bactericidal activity against a broad spectrum of gram-positive bacteria, including methicillin-resistant Staphylococcus species. Ceftobiprole is also active against many gram- negative bacteria, including many Enterobacteriaceae.

Ceftobiprole has a bactericidal mode of action that involves tight binding to many common essential penicillin-binding proteins (PBPs) in both gram-positive and gram-negative bacteria. Ceftobiprole has distinctive bactericidal activity against methicillin-resistant staphylococci primarily due to its novel strong binding to the staphylococcal PBP2a, the PBP that is chiefly responsible for ss-lactam resistance in methicillin-resistant staphylococci including methicillin- resistant S. aureus (MRSA).

Ceftobiprole is resistant to hydrolysis by S. aureus penicillinases, and is resistant to hydrolysis by many class C and class A ss-lactamases found in gram-negative bacteria. Like most cephalosporins, ceftobiprole is hydrolyzed by extended spectrum ss-lactamases (ESBLs), serine carbapenemases and metallo ss-lactamases.

Resistance to ceftobiprole due to spontaneous mutation in vitro is a rare occurrence. Although cross-resistance has been observed between ceftobiprole and some other advanced generation cephalosporins, some microorganisms resistant to other cephalosporins may be susceptible to ceftobiprole.

The effect of ceftobiprole on healthy subjects was evaluated in a QT/QTc study. Ceftobiprole had no effect on heart rate or other ECG parameters in healthy adults after administration of single intravenous therapeutic and supratherapeutic doses (see PART II: SCIENTIFIC INFORMATION, DETAILED PHARMACOLOGY). Convulsions were observed after direct administration into the brain in mice and may be attributed to inhibition of GABA receptor-mediated neurotransmission (see DETAILED PHARMACOLOGY, Animal Pharmacology).

The mean pharmacokinetic parameters of ceftobiprole in adults for a single 500 mg dose administered as a 60-minute infusion and multiple 500 mg doses administered every 8 hours as 120-minute infusions are summarized in Table 2. Pharmacokinetic characteristics were similar with single and multiple dose administration.

Table 2: Mean (Standard Deviation) pharmacokinetic parameters of ceftobiprole in adults

Ceftobiprole exhibits linear and time-independent pharmacokinetics. The Cmax and AUC of ceftobiprole increase in proportion to dose over a range of 125 mg to 1 g. Steady-state drug concentrations are attained on the first day of dosing; no appreciable accumulation occurs with q8h and q12h dosing in subjects with normal renal function (see PART II: SCIENTIFIC INFORMATION, DETAILED PHARMACOLOGY).

Absorption:

Distribution:

Ceftobiprole binds minimally (16%) to plasma proteins and binding is independent of concentration. Ceftobiprole steady-state volume of distribution (18 L) approximates extracellullar fluid volume in humans.

Metabolism:

Conversion from the prodrug ceftobiprole medocaril, to the active moiety ceftobiprole, occurs rapidly and is mediated by plasma esterases. Prodrug concentrations are negligible and are measurable in plasma and urine only during infusion.

Ceftobiprole undergoes minimal metabolism to the open-ring metabolite, which is microbiologically inactive. Systemic exposure of the open-ring metabolite was considerably lower than for ceftobiprole, accounting for approximately 4% of the parent exposure.

Excretion

: Ceftobiprole is eliminated primarily unchanged by renal excretion and the predominant mechanism responsible for elimination is glomerular filtration, with some active reabsorption. In preclinical studies, probenecid did not affect the pharmacokinetics of ceftobiprole, thereby indicating no involvement of active tubular secretion mechanisms. Elimination half-life of the open-ring metabolite was slightly longer, approximately 5 hours compared with ceftobiprole, which was approximately 3 hours. Following single dose administration, approximately 89% of the administered dose is recovered in the urine as active ceftobiprole (83%), the open-ring metabolite (5%) and ceftobiprole medocaril (<1%).

Pediatrics:

The pharmacokinetics of ceftobiprole have not been established in patients under 18 years of age.

Geriatrics: DOSAGE AND ADMINISTRATIONPatients with Renal Impairment

Population pharmacokinetic data showed there is no independent effect of age on the pharmacokinetics of ceftobiprole. Dosage adjustment is not required in elderly patients with normal renal function (see

Gender:

Systemic exposure to ceftobiprole was higher in females than males (21% for Cmax and 15% for AUC), however, the %T>MIC was similar in both males and females. Therefore, dosage adjustments based on gender are not required.

Race:

Population pharmacokinetic analyses (including Caucasians and a limited number of African-Americans and Other groups) showed no effect of race on the pharmacokinetics of ceftobiprole. Therefore, dosage adjustments based on race are not required.

Hepatic Insufficiency: DOSAGE AND ADMINISTRATIONPatients with Hepatic Impairment

The pharmacokinetics of ceftobiprole in patients with hepatic impairment have not been established. As ceftobiprole does not appear to undergo significant hepatic metabolism, the systemic clearance of ceftobiprole is not expected to be significantly affected by hepatic impairment. Due to the low protein binding of ceftobiprole, differences in albumin concentrations associated with hepatic impairment are not expected to significantly affect the free fraction of ceftobiprole. Therefore, dosage adjustments are not indicated for patients with hepatic impairment (see

Renal Insufficiency: The pharmacokinetics of ceftobiprole is similar in healthy volunteers and patients with mild renal impairment (CrCl > 50 to <= 80 mL/min). Ceftobiprole AUC was 2.5- and 3.5-fold higher in patients with moderate (CrCl >= 30 to <= 50 mL/min) and severe (CrCl < 30 mL/min) renal impairment, respectively, than in healthy subjects with normal renal function. Dosage adjustment is recommended in patients with moderate to severe renal impairment (see DOSAGE AND ADMINISTRATION, Patients with Renal Impairment).

A two-hour infusion administered every eight hours increases the T>MIC for both gram-positive and gram-negative pathogens. A one-hour infusion administered every 12 hours provides sufficient T>MIC for documented gram-positive infections (see PART II: SCIENTIFIC INFORMATION, DETAILED PHARMACOLOGY).

STORAGE AND STABILITY

Storage of Vials:

ZEFTERA vials should be stored refrigerated at 2-8degC in the carton in order to protect from light prior to constitution.

Storage of the Reconstituted and Infusion Solutions:

Chemical, physical and microbiological in-use stability data support the total times for reconstitution, dilution and infusion described in the table below:

The reconstituted and infusion solutions should not be frozen. The reconstituted and infusion solutions should not be exposed to direct sunlight. If the infusion solution is stored in the refrigerator, it should be equilibrated to room temperature prior to administration. The infusion solution does not need to be protected from light during administration. Please refer to DOSAGE AND ADMINISTRATION, Administration for method of preparation. Keep out of reach of children

SPECIAL HANDLING INSTRUCTIONS

Each vial is for single use only. ZEFTERA must be reconstituted and then further diluted prior to infusion (see DOSAGE AND ADMINISTRATION, Administration).

DOSAGE FORMS, COMPOSITION AND PACKAGING

ZEFTERA is supplied as sterile single use clear 20 mL glass vials containing 500 mg ceftobiprole lyophilized powder (as 666.6 mg of ceftobiprole medocaril). Supplied as 10 vials per carton. ZEFTERA contains the following inactive ingredients: citric acid monohydrate, sodium hydroxide.

PHARMACEUTICAL INFORMATION

Drug Substance

Physicochemical properties: Ceftobiprole medocaril is produced through chemical modification of a fermentation product. Ceftobiprole medocaril is freely soluble in water. White to yellowish or slightly brownish powder. Ceftobiprole medocaril is a prodrug; the active moiety is ceftobiprole. pH: The pH of a 1% solution in water is 4.52. pKa value of 2.8 at 25degC for carboxylic acid moiety of BAL5788. A second pKa at around 9 is assigned to the hydroximino (oxime) functional group.

CLINICAL TRIALS

Complicated Skin and Skin Structure Infections including Diabetic Foot Infections

Randomized, double-blind study of ceftobiprole medocaril versus vancomycin plus ceftazidime in the treatment of cSSSI, including diabetic foot infections

Treatment: i.v. infusion of ceftobiprole medocaril (500 mg equivalents of ceftobiprole) q8h over 120 min plus placebo q12h over 60 min, or 1000 mg vancomycin q12h over 60 min plus 1000 mg ceftazidime q8h over 120

Surgical, traumatic and burn wound infections were present in 26% of patients, abscesses in 38%, cellulitis in 18% and non-limb threatening diabetic foot infections in 18% of patients at baseline. Only Trial 2 enrolled patients with diabetic foot infections (without evidence of osteomyelitis) comprising 31% of patients enrolled in this trial.

Study results

Table 4. Clinical Cure Rates at Test of Cure Visit1 in a Phase 3 Trial in Complicated Skin and Skin Structure Infections

Comparator
	N	Cured	%	N	Cured	%
Clinically evaluable	282	263	93.3	277	259	93.5
Intent-to-treat	397	309	77.8	387	300	77.5

Table 5. Clinical Cure Rates at Test of Cure Visit1 in a Phase 3 Trial in Complicated Skin and Skin Structure Infections

Trial 2: Gram-positive and gram negative infections including diabetic foot infections

Table 6. Clinical Cure Rate at TOC Visit1 in Complicated Skin and Skin Structure Infections Caused by Gram Positive Pathogens Isolated at Baseline.

Staphylococcus aureus (methicillin-susceptible) 96 (121/126) 96 (108/112) Staphylococcus aureus (methicillin-resistant) 92 (56/61) 90 (54/60) Streptococcus pyogenes 73 (8/11) 88 (15/17) 1 Test of cure visit 7 to 14 days after completing therapy

Table 7. Clinical Cure Rate at TOC Visit1 in Complicated Skin and Skin Structure Infections Caused by Gram Positive and Gram Negative Pathogens, Including Diabetic Foot Infections, Isolated at Baseline.

Staphylococcus aureus (methicillin-susceptible) 94 (150/160) 93 (84/90) Staphylococcus aureus (methicillin-resistant) 90 (78/87) 86 (31/36) Streptococcus pyogenes 90 (18/20) 92 (11/12) Gram-negative

There is limited experience in patients receiving more than 14 days of therapy (see ADVERSE REACTIONS).

DETAILED PHARMACOLOGY ANIMAL PHARMACOLOGY

Safety Pharmacology

Safety pharmacology studies demonstrate that administration of BAL5788 (ceftobiprole medocaril) by i.v. infusion is associated with minimal or absent effects on cardiovascular, respiratory and CNS parameters at exposures exceeding those obtained in human clinical studies.

Convulsions were observed after administration of BAL 9141 directly into the brain in mice. The median effective dose (ED50) of BAL9141 (ceftobiprole) for centrally-mediated convulsions was determined to be 2.55 ug in a central nervous system (CNS) safety study in mice administered single intra-cerebroventricular (i.c.v.) injections of 0.3 to 30 ug BAL9141. The convulsant activity of ceftobiprole may be attributed to inhibition of GABA receptor- mediated neurotransmission. After intravenous (i.v.) bolus injection of BAL5788, doses <=125 mg/kg were tolerated without effect. Signs of nephrotoxicity (related to drug precipitation in distal and collecting tubules) due to low solubility of the drug as early as 0.5 h after drug administration were reported. Reduced renal function manifested as high plasma levels of BUN in all along with increased creatinine in some animals and incidences of mortality were noted at doses >= 250 mg/kg. Delayed convulsions, also observed in mice at doses >=250 mg/kg, were attributed to high levels of drug exposure (8 times greater than the human dose) caused by marked nephrotoxicity, which was considered to lead to reduced renal clearance of BAL9141, and thus, sustained elevated plasma and brain levels.

BAL5788 had no effect on airway resistance (RL) or dynamic lung compliance (dyn) of respiratory function in anesthetized, ventilated Sprague-Dawley rats administered doses of 125, 250, and 500 mg/kg via a 4-h i.v. infusion.

The cardiovascular (CV) safety of i.v. administered BAL5788 was evaluated in studies in hypertensive rats, conscious normotensive marmosets, and conscious beagle dogs. No drug- related CV effects were seen at 30 mg/kg (rats) or 35 mg/kg (marmosets). A slight, persistent increase in mean arterial blood pressure (MAP) was noted in rats and marmosets with a delayed onset following administration of a single i.v. bolus injection of BAL5788 at 100 mg/kg. At the 100-mg/kg dose level, a slight increase in heart rate (HR) was seen in marmosets, but not in rats. When marmosets were administered the same dose via a 1-h infusion, however, only a borderline effect was seen. No drug-related effects on CV parameters (heart rate, blood pressure, amplitude or interval of the ECG parameters) were noted in dogs (1 male and one female) receiving single i.v. doses of BAL5788 at 50 or 100 mg/kg via a 4-h infusion. In a HERG assay, treatment with 5 mM BAL9141 produced no statistically significant inhibition of HERG tail current recorded from stably transfected HEK293 cells. The final concentration of BAL9141 tested in the HERG assay was 12.4 times below the Cmax observed in humans (approximately 62 mM, corresponding to 33 mg/mL). Due to low solubility of BAL9141, concentrations higher than 5 mM could not be attained under conditions comparable with the HERG assay.

In vivo Protection Studies: Acute Infections Due to Gram-Positive and Gram-Negative Bacteria

The efficacy of ceftobiprole against MSSA and MRSA was examined in a murine skin and soft tissue infection model. Female Skh-1 mice were injected s.c. on the left flank with 0.2 mL S. aureus Smith OC 4172 in brain heart infusion (BHI)-dextrin beads, and on the right flank with MRSA OC 8525 in BHI-dextrin beads. The animals received ceftobiprole subcutaneously. Ceftobiprole achieved a >1.7 log10 CFU/g reduction of MSSA in skin tissue compared to the initial inoculum at doses of 1.6 to 100 mg/kg/day. Against MRSA, ceftobiprole showed similar or improved reduction in bacterial load at doses of 1.6 to 100 mg/kg/day against comparators. Ceftobiprole was effective in reducing the lesion volume at the infection site in animals infected with either MSSA or MRSA.

The in vivo antibacterial efficacy of ceftobiprole was examined in a number of experimental murine septicemia infection models. Ceftobiprole was effective in treating experimental septicemia following subcutaneous administration, with ED50 values <3 mg/kg for strains with ceftobiprole MIC values <=2 ug/mL. These strains include MSSA, MRSA (except MRSA 8525 for which the ED50 was 4.9 mg/kg), E. coli, K. pneumoniae, and P. mirabilis.

The efficacy of ceftobiprole medocaril was examined in a rabbit model of MRSA osteomyelitis. A localized osteomyelitis was induced by a percutaneous injection of 106 CFU of MRSA 168-1. Two weeks post-infection, proximal tibial osteomyelitis was confirmed radiographically, and animals were randomized into 4 treatment groups (n=15/group). Animals in the ceftobiprole group were administered the equivalent of 40 mg/kg q8h of ceftobiprole. Four weeks of treatment were followed by a 2 week washout period. Tibias were recovered, bone matrix and marrow was cultured on blood agar plates and bacterial counts per gram of tissue was determined. In the ceftobiprole group, the MIC and MBC values for ceftobiprole were 0.39 and 6.25 mg/mL, respectively. Following ceftobiprole treatment bacterial titers in all infected left tibiae from evaluable rabbits were below the level of detection, whereas only 73% of infected left tibiae from comparator treated animals had bacterial titers below the level of detection; mean ceftobiprole titers were 3-5 times higher in infected left tibias than in uninfected right tibiae. These results indicate that ceftobiprole provided effective parenteral treatment of osteomyelitis cause by MRSA in this rabbit model.

Pharmacokinetics

The oral absorption of BAL 5788 and its active BAL9141 has been investigated in rats. Oral bioavailability of BAL9141 and its pro-drug BAL5788 was very low (<1%) after a single p.o. dose of BAL5788 or BAL9141 in aqueous solutions. BAL9141-related radioactivity was rapidly distributed to tissues of rats and mice following administration of a single i.v. bolus dose of radiolabelled BAL9141. The highest levels were found in kidney (tissue to plasma ration = 1.3) followed by tooth pulp, liver, skin and lung. Penetration to the brain was minimal (tissue to plasma ratio = 0.01). Analysis of homogenates from brain and kidney showed that BAL9141 was the main component detected, indicating that the active drug rather than any predominant metabolites was responsible for the CNS and renal effects observed after administration of BAL5788. The elimination of radioactivity from tissues occurred in parallel to elimination from the blood, predominantly by renal excretion in the urine. There was no retention in any tissues with the exception of the kidney cortex in rats where the level at 48h post dose was 20% of that seen at the peak level, which occurred at 0.25h. There was no retention in pigmented tissues including the eye and skin of pigment rats. Metabolism of BAL5788 under in vitro conditions by different species resulted in hydrolytic cleavage of the carbamate moiety of BAL5788. The main metabolic reaction of BAL9141 was hydrolysis of the b-lactam ring of the drug RO65-2070. Metabolism of BAL 9141 during 24 hours was 59% in mouse, 64% in marmosets, 51% in humans, and 48% in rat and 43% in dog. Metabolic profiles were similar to those in hepatocytes. Excretion of BAL9141 was similar to glomerular filtration rate in all animal species. Elimination t1/2 ranged from 0.29 hr in mouse to 1.7 hour in cynomolgus monkeys. In rats, excretion of radioactivity in feces was 17%, in cage wash, GI Tract, and residual carcass was < 3% at 96 hrs post-dose.

Pharmacokinetic/Pharmacodynamic Parameters

Similar to other ss-lactam antimicrobial agents, the time that the plasma concentration of ceftobiprole exceeds the MIC (%T>MIC) of the infecting organism has been shown to best correlate with efficacy in pre-clinical pharmacokinetic/pharmacodynamic studies. For gram- positive bacteria (including 4 staphylococci and 4 pneumococci), the mean %T>MIC for ceftobiprole was 20 to 22% for a static dose. For gram-negative bacteria, the mean %T>MIC for stasis was 43% for 4 strains of Enterobacteriaceae and 58.6% for a representative isolate of P. aeruginosa.

HUMAN PHARMACOLOGY

Two studies were conducted using human plasma spiked with ceftobiprole. The protein binding of ceftobiprole was considered to be low, ~16%, and is independent of ceftobiprole concentration across the range of 0.5 to 100 ug/mL. Ceftobiprole at a concentration of 25 ug/mL (12.5 uM) is primarily bound to albumin (6.5% to 11.5%, i.e. 0.8 to 1.4 uM bound), and also bound to a-1 acid glycoprotein (4.8% to 6.8%, i.e. 0.6 to 0.9 uM bound). Binding of ceftobiprole to both proteins is low compared to their normal molar concentrations (albumin 530-760 uM; a-1 acid glycoprotein 10-40 uM).

In a degradation study, conversion of ceftobiprole medocaril to ceftobiprole was very rapid (t1/2 within 10 to 54 seconds) in the plasma of marmosets, cynomolgus monkeys, mice, and humans. In human plasma, the t1/2 was observed to be 38 seconds. Inhibition studies with ethylenediaminetetraacetic acid (EDTA) suggested that type A plasma esterases are involved in the cleavage of ceftobiprole medocaril to ceftobiprole. Cleavage of ceftobiprole medocaril to ceftobiprole was not inhibited by acetycholinesterase inhibitors such as neostigmine at 0.1 ug/mL, and moderately inhibited by dichlorvos, a known Type B esterase inhibitor. Rapid cleavage of ceftobiprole medocaril to ceftobiprole was also observed when ceftobiprole medocaril was incubated with hepatocytes derived from rats, dogs, cynomolgus monkeys, marmosets, and humans. Since hepatic conversion is not the sole pathway, type A esterases should be able to convert ceftobiprole medocaril to the active ceftobiprole in patients with hepatic impairment.

Study Measuring the Effects of QT and Corrected QT(QTc) Intervals

In a QT/QTc study conducted in healthy subjects, the effect of ceftobiprole on QT/QTc interval prolongation was similar to that of placebo after administration of single intravenous therapeutic (500 mg) and supratherapeutic (1000 mg) doses. Ceftobiprole had no effect on heart rate or other ECG parameters in healthy adults.

Following administration of ceftobiprole at doses of 500 mg to 1000 mg given over 30 minutes, peak concentration (Cmax) and area under the curve (AUC) increased proportionally with dose. Estimates of total systemic clearance (CLs), volume of distribution at steady state (VSS), and t1/2 were consistent across the dose range of 125 mg to 1000 mg, suggesting that the pharmacokinetics of ceftobiprole were linear and predictable. Approximately 60% to 80% of the dose was recovered in urine as unchanged ceftobiprole.

Table 8: Mean (SD) Ceftobiprole Pharmacokinetic Parameters Following Single Intravenous Infusions of Ceftobiprole

After repeated administration (q8h or q12h for up to 12 days), the pharmacokinetic properties of ceftobiprole were time independent. The observed accumulation factor ranged from 1.02 to 1.16 across studies, suggesting minimal accumulation from single to multiple doses. Overall the pharmacokinetics of ceftobiprole appeared to be independent of the infusion duration and the dosing interval.

Table 9: Mean (SD) Ceftobiprole Pharmacokinetic Parameters Following Multiple Intravenous Infusions of Ceftobiprole

Renal Insufficiency

Following a single infusion of ceftobiprole 250 mg over 30 minutes, systemic exposure in terms of AUC was 29% higher in subjects with mild renal impairment, and 2.5-fold, and 3.3-fold higher in subjects with moderate and severe renal impairment, respectively, compared to subjects with normal renal function. Total systemic clearance (CLs) and renal clearance (CLR) decreased with decreasing renal function such that the greatest reductions were noted in the moderately (62% for CLs and 78% for CLR) and severely (75% for CLs and 91% for CLR) renally impaired groups. Urinary recovery ranged from 74% to 32% in subjects with mild to severe renal impairment. Elimination half-life increased with decreasing renal function, such that subjects with severe renal impairment exhibited the longest t1/2 of 11 hours.

Table 10: Mean (SD) Ceftobiprole Pharmacokinetic Parameters In Healthy Subjects And Subjects With Various Degrees of Renal Impairment After a Single Intravenous Infusion of Ceftobiprole 250 mg For 30 Minutes (Study BAP00018; N=20)

Gender

Renal Function
	Normal CL CR :	Mild CL CR :	Moderate CL CR :	Severe CL CR :
>80 mL/min	50-80 mL/min	30-<50 mL/min	<30 mL/min
Parameter	N=5	N=5	N=5	N=5
C max ( m g/ml)	20.6 (2.06)	20.1 (1.45)	24.4 (1.65)	22.8 (3.48)
AUC 0- [?] ( m g * h/ml)	52.8 (6.91)	74.8 (15.6)	151 (21.6)	222 (71.00)
t 1/2 (h)	3.45 (0.37)	4.75 (0.81)	6.87 (1.12)	11.1 (1.96)
V S S (L)	15.8 (1.81)	18.0 (0.76)	14.2 (0.80)	16.9 (2.39)
CL S (L/h)	4.80 (0.61)	3.46 (0.71)	1.68 (0.25)	1.21 (0.36)

Systemic exposure to ceftobiprole was higher in females (Single dose: 32% for Cmax and 21% for AUC; Multiple dose: 16% for Cmax and 11% for AUC) than in males. Estimates of CLs and Vss were 15% and 20% lower, respectively in females as compared with males. Renal clearance and urinary excretion of ceftobiprole (83%) were similar in both genders. When these parameters were adjusted for body weight, parameter estimates between males and females were comparable. Systemic exposure to the open-ring metabolite was lower than that of ceftobiprole, accounting for approximately 4% parent ceftobiprole exposure, and increased approximately 33% for Cmax and 48% for AUC0-8h from Day 1 to Day 5, with an accumulation ratio of 1.5. The elimination half-life of the open-ring metabolite was slightly longer, ~5 hours, than ceftobiprole which was ~ 3 hours. Systemic exposure to ceftobiprole and the open-ring metabolite was higher in females compared to males, which normalized upon correction for dose per kg body weight.

Table 11: Mean (SD) Ceftobiprole Pharmacokinetic Parameters Following Single and Multiple (q8h) 2 Hour Intravenous Infusions of Ceftobiprole 500 mg in Healthy Males and Females

Pharmacokinetic/Pharmacodynamic Parameters

After single 30-minute i.v. infusion of 500 mg, 750 mg and 1000 mg doses, the mean %T>MIC for unbound ceftobiprole concentration ranged from 58%, 60% and 85%, respectively. For the regimen of 500 mg administered 3 times daily as a 2-hour infusion, the probability of target attainment assuming a fixed MIC of 4 mg/mL exceeded 89% for both the 30% and 50% T>MIC targets in subjects with normal renal function. For the regimen of 500 mg administered twice daily as a 1-hour infusion, the probability of target attainment assuming a fixed MIC of 4 mg/mL exceeded 89% for the 30% T>MIC target, in subjects with normal renal function , which is needed for activity against gram positive infections.

MICROBIOLOGY

Ceftobiprole medocaril is the prodrug of ceftobiprole, which is rapidly converted in vivo to the active antibacterial agent ceftobiprole. It was not possible to determine the in vitro antibacterial activity of the prodrug.

Ceftobiprole is an expanded spectrum cephalosporin with activity against gram-positive and gram-negative aerobic bacteria, including methicillin-resistant S. aureus (MRSA). Ceftobiprole, a semi-synthetic cephalosporin antibiotic, has a bactericidal mode of action that involves tight binding to essential penicillin-binding proteins (PBPs) in gram-positive and gram-negative bacteria, thereby preventing completion of cell wall biosynthesis. In gram-positive bacteria, ceftobiprole differs from other cephalosporins and b-lactams due to its unique high affinity for PBP2a from methicillin-resistant staphylococci. Ceftobiprole has high affinity for the essential PBP 3 and PBP2 of E. coli.

Ceftobiprole evades both of the two major mechanisms of b-lactam resistance in staphylococci, (i.e. the production of an acquired PBP with reduced affinity for b-lactams and b-lactamase mediated drug hydrolysis) as it binds strongly to PBP2a and is not readily hydrolyzed by the staphylococcal penicillinases. Ceftobiprole is stable to hydrolysis by many Class A B- lactamases, such as staphylococcal penicillinases, TEM-1, TEM-2 and SHV-1, and Class C B- lactamases, i.e., AmpC cephalosporinases produced by gram-negative bacteria. However, ceftobiprole is not stable to most extended-spectrum b-lactamases (ESBLs) from the TEM, SHV and CTX-M families, to serine carbapenemases such as KPC or SME enzymes or to metallo-b- lactamases including members of the IMP or VIM families. Ceftobiprole also appears to be hydrolyzed by beta-lactamases from anaerobic bacteria. Ceftobiprole demonstrated low propensity for resistance in both single step and serial passage resistance experiments. In vivo use of ceftobiprole treatment in animal models of infection conducted in rat, mouse, and rabbit, did not produce resistant mutants of S. aureus, E. cloacae and ESBL-negative K. pneumoniae during the treatment periods.

Ceftobiprole has demonstrated in vivo and in vitro activity against a broad spectrum of gram- positive and gram-negative bacteria. Table 12 indicates the in vitro activity of ceftobiprole against strains of microorganisms for which clinical efficacy have been determined.

Table 12: In vitro activities of ceftobiprole against organisms for which the clinical efficacy of ceftobiprole has

Table 13 indicates the in vitro activity of ceftobiprole against clinical isolates, however the efficacy of ceftobiprole in treating clinical infections due to these microorganisms has not been established in clinical trials.

Table 13: In vitro activities of ceftobiprole against clinical isolates for which clinical efficacy has not been

* Unpublished surveillance studies of North American sites (including Canadian sites) reported isolates with a ceftobiprole MIC > 8mg/mL.

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. Standardized procedures are based on dilution method (broth, agar or microdilution) or equivalent using standardized inoculum and concentrations of ceftobiprole. 1 The MICs should be interpreted according to the criteria provided in Table 14.

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. This procedure uses paper disks impregnated with 30 mg ceftobiprole to test the susceptibility of microorganisms to ceftobiprole. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ceftobiprole. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 mg ceftobiprole disk should be interpreted according to criteria provided in Table 14.

The current absence of data on resistant strains precludes defining any category other than 'Susceptible'. If strains yield MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.

Disk Diffusion (zone diameter in mm)
Pathogen Staphylococcus aureus (including	S < 4	I -- a	R --	S >16	I --	R --
methicillin-resistant isolates)
Streptococcus spp. other than S.	< 0.5	--	--	>19	--	--
pneumoniae
Enterobacteriaceae	<1	2	4	>20	18-20	<18

A report of Susceptible indicates ceftobiprole is likely to inhibit the growth of the pathogen if ceftobiprole in the blood reaches the concentrations usually achievable. A report of Intermediate indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone, that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that ceftobiprole is not likely to inhibit the growth of the pathogen if ceftobiprole in the blood reaches the concentrations usually achievable; other therapy should be selected.

Note: Methicillin-resistant Staphylococcus spp. should be considered susceptible to ceftobiprole if the MIC is in the susceptible range irrespective of the oxacillin test or mecA detection results. Specialized testing conditions in media supplemented with 2% NaCl at 30oC to induce mecA production may result in one fold increase in MIC.

Standardized susceptibility test procedures require the use of control microorganisms to control the technical aspects of the test procedures. For the diffusion technique, the 30 mg ceftobiprole disk should provide the following zone diameters provided in Table 15 below.

Table 15 : Quality Control Microorganisms and corresponding MIC/Disk diffusion ranges

TOXICOLOGY

The toxicology of BAL5788 (ceftobiprole medocaril) was characterized in repeated-dose toxicity, mutagenicity, fertility, developmental toxicity, and pre- and postnatal toxicity studies, and in studies assessing local tolerability, potential antigenic and hematolytic effects, phototoxicity, and nephrotoxicity. Effects noted in animal toxicity studies occurred at high doses and included reversible renal toxicity due to drug precipitates at urine concentrations 5-10 fold higher than in humans, and convulsions. No single dose toxicity studies were conducted. Pilot 3-Day toxicity studies were conducted utilizing bolus, continuous and intermittent IV administration for evaluation of initial dose selection for repeat dose toxicity studies. Over dosage in these studies was associated with renal toxicity, decreased renal function and seizures. In a 4-week infusion study (4 h) in rats, once daily (q.d.) doses of BAL5788 were well tolerated up to 360 mg/kg/day. Dose-dependent minimal to slight cytoplasmic inclusions seen in renal proximal tubules at doses >=250mg/kg/day were not associated with any functional or other morphological changes in the kidneys, and were fully reversible following a 4-week recovery period. Based on these findings, the No Observed Adverse Effect Level (NOAEL) in this study was 360 mg/kg/day, a 12x multiple of the clinical dose. In a similar study in marmosets, doses of up to 200 mg/kg were well tolerated, with a NOAEL of 100mg/kg/day, a 3x multiple of the clinical dose. Minor and reversible changes (i.e., slightly increased blood urea nitrogen [BUN] levels, minimal occurrence of brown pigment in the distal tubular epithelium of the kidneys) were noted at 200 mg/kg/day. In a 2-week study in dogs, dose-dependent histaminergic reactions were observed, and these were attenuated by prolongation of the infusion duration from 0.5h to 2h following the first day of dosing. Slight eosinophilic droplets were observed in the proximal tubule epithelium in the kidney at 50 and 100 mg/kg/day. The NOAEL was below 25 mg/kg due to the occurrence of slight histaminergic reactions. In a 13-week study in rats, toxicity to the kidneys was observed at doses >=250 mg/kg with incidences of mortality due to acute renal failure observed at 250, 500 and 750 mg/kg/day, and was associated with the precipitation of drug-like material in the distal part of the nephron. Findings in the kidneys were dose-related and trended towards recoverability after 4 weeks. The NOAEL in this study was 125 mg/kg/day (a 4x multiple of the clinical dose). A 3-month repeat dose study in marmosets vomiting and reversible renal proximal tubule pigmentation were observed at 100 and 200 mg/kg and increases in plasma AST and LDH were observed at 200 mg/kg. The NOAEL was 100 and 50 mg/kg/day for males and females, respectively (3.3x and 1.7x multiples of the clinical dose, respectively. In a 13-week infusion toxicity study in beagle dogs at doses of 8 and 32 mg/kg/day, clogging of the surgically implanted cannula, resulting in an inability to dose, was the proximal cause of the premature sacrifice of 5 out of 6 dogs administered the q.d. (2-h) dose of 32 mg/kg BAL5788. No findings of toxicological importance were observed in these 5 animals, which received doses for 4 to 11 weeks. Clinical observations during the study were similar to those seen in the 2-week study in dogs, and consisted of findings of discolored urine seen at doses of 8 and 32 mg/kg (equivalent to one quarter of the clinical 500 mg TID dose, and one-fifth the clinical 500 mg BID dose), and of reddening of the skin and mucous membranes, which was attributed to histamine release. The NOAEL was 8/mg/kg/d (approximately 75% less than the clinical dose).

Lifetime studies in animals have not been conducted to evaluate the carcinogenic potential of ceftobiprole.

The genotoxic potential of BAL5788 and/or BAL9141 (ceftobiprole) was examined in a battery of in vitro (Ames, mouse lymphoma/thymidine kinase [ML/TK], human chromosome aberration [HCA]) and in vivo (mouse micronucleus test [MNT] and rat unscheduled DNA synthesis [UDS]) assays. BAL5788 exhibited clastogenic activity in the ML/TK test at cytotoxic concentrations after 3h incubation at 750 and 500 ug/ml (with and without metabolic activation respectively) and at 150 ug/ml at 24 h exposure period (without metabolic activation). BAL9141 induced an equivocal effect at high concentrations (2000mg/mL). In the HCA assay, BAL5788, but not BAL9141, was clastogenic under the described in vitro conditions at cytotoxic concentrations. The positive response was most probably attributed to the cleavage product diacetyl with no contribution from the active cephalosporin BAL9141. No genotoxic activity was seen in the in vivo micronucleus assay in mouse bone marrow and in an unscheduled DNA synthesis (UDS) by the uptake of radio-labelled thymidine assayed autoradiographically by utilizing 200 or 500 mg/kg Ro 65-5788. The in vitro genotoxic activity of diacetyl and other dicarbonyl compounds is thought to be mediated by an oxidative mechanism of action due to the formation of oxygen radicals. The presence of multiple anti-oxidative defense mechanisms in vivo, that are not present in the in vitro test systems, helps to account for the absence of genotoxicity in vivo. Furthermore, diacetyl, which is produced endogenously in humans, is rapidly metabolized in vivo by oxidoreductases acting on carbonyl compounds, resulting in the formation of nontoxic glycol metabolites. Based on these observations, a genotoxic liability of BAL5788 in man is not likely.

BAL5788 was neither teratogenic nor embryotoxic in rats and cynomolgus monkeys after i.v. infusion of doses up to 360 mg/kg/day (4 h) and 120 mg/kg/day (2 h), respectively, and had no effects on fertility and early embryonic development in rats after i.v. infusion of doses up to 360 mg/kg/day (4 h). In cynomolgus monkeys, reduced litter size and survival rate was observed at doses that cause maternal toxicity. Studies in rats have shown that the concentration of ceftobiprole excreted in animal milk is 20% of the maternal plasma levels. In a pre- and postnatal toxicity study in rats administered BAL7588 via i.v. infusion (4 h), the NOAEL in dams (F0 generation) was 175 mg/kg (a 6x multiple of the clinical dose) for maternal toxicity and 250 mg/kg/day (a 8x multiple of the clinical dose) for reproductive toxicity. Functional and physical development of the F1 and F2 generations was normal in all groups.

Other Studies:

In a guinea pig antigenicity study, signs of potential antigenicity were seen at i.v. bolus doses >=20 mg/kg or at subcutaneous (s.c.) doses of 50 mg/kg in combination with adjuvant. In a 2-week study in dogs, reddening of the skin and mucous membranes was observed which was attributed to histamine release. The NOAEL was 8 mg/kg/day, which is 75% less than the clinical dose.

No hemolysis or precipitation was observed in in vitro testing of dog plasma at concentrations <=1.25%. At higher concentrations, however, observations of hemolysis and marked to moderate plasma turbidity and precipitation were observed, and were similar to increased adverse reactions of precipitation, flocculation and coagulation seen in in vitro dilution of human, rat or marmoset plasma at concentrations >=12.5 mg/mL. The results demonstrate that concentrations >12.5 mg/mL (a 6x multiple of the clinical concentration) cause blood hemolysis and plasma precipitation and flocculation, which may be increased with increasing infusion volume, repeated dosing and or increasing infusion duration.

Three 13-week infusion toxicity studies were conducted in rats, beagle dogs, and marmosets. In rats administered BAL5788 via a q.d. 4-h infusion, the primary targets of toxicity were the kidneys and the infusion site, where local irritation and the presence of a yellowish-brown fibrinous material at the tip of the catheter were associated with thrombus formation. Similar dose-related venous irritation was also observed in the marmoset study (BAL5788 dosed q.d. 4-h infusions). In these studies, physical irritation of the veins by the catheter, possibly in combination with additional effects due to obstruction of blood flow, was considered to predispose the vessel wall to irritation from the compound; these effects were considered to be exacerbated by the length of the treatment period and by the infusion of high concentrations of test article, and they resulted in the release of emboli from thrombi at the injection site. Incidences of mortality attributed to thrombo-embolic changes in male rats were observed at 250, 500 and 750 mg/kg/day. In marmosets, mortalities were observed at 50, 100, and 200 mg/kg/day, and were preceded by a general decline in physical condition and convulsions.

The potential for a phototoxic skin response in humans is considered to be low, as results from both an in vitro test in cultured mouse fibroblasts and from an in vivo test in hairless rats revealed that neither BAL9141 nor BAL5788 exhibited phototoxic potential following ultraviolet A (UVA) irradiation. A summary of toxicology studies is presented in table 16.

Table 16: Summary of toxicology studies
Type of Study	Species/Strain	Route	Dosage	Principal Effects Observed
	Sex/No. Per Group
3-Day Pilot	Rat; Wistar; 3	IV - slow bolus; BAL	Ranging from 0	Effects seen at lower (<100 mg/kg) primarily consisted of Cytoplasmic inclusions
Study	males/group	5788	to ,200 mg/kg,	(mild) in proximal renal tubules.
(116P97)			t.i.d.
				Effects seen at > 100 mg/kg included: mild \| body weight, moderate \| BUN, \|
				triglycerides, kidneys pale and enlarged with yellow foci, on microscopic examination
				moderate findings included dilation, vacuolation and basophilia of the distal tubules as
				well as distal tubule single cell necrosis, increased mitotic rate and intraluminal
				deposits; and cytoplasmic inclusions (mild) in proximal renal tubules.
3-Day Pilot Study 131P97	Rat; Wistar 2 males (control) 4 males, 2 females 2 males, 1 female	IV continuous infusion;	0, 600 mg/kg	600 mg/kg/day: Kidneys pale and enlarged, dilation, vacuolation and basophilia of the distal tubules, cytoplasmic inclusions (mild) in proximal renal tubules. Terminal BAL9141 plasma concentration at 0.08 hours (after termination of infusion) 42.5/37.4 ug/mL; at 1 hour (after termination of infusion) 11.5/13.2 ug/mL.
3-Day Pilot Study 207P98	Rat; Wistar; Control and High Dose: 5 males/group Low Dose: 7 males 2/group held for 14 day recovery period 1 male	Intermittent IV infusion; BAL5788	0, 250 b.i.d., 500 b.i.d.	250 mg/kg (b.i.d.) [12.5X clinical dose]: kidneys pale and enlarged with granulated surface, urinary bladder contents yellow-orange, on microscopic examination cytoplasmic inclusions were noted (mild) in proximal renal tubules. Plasma concentration of BAL9141 was 60.2 ug/mL. Brain concentration at termination was 0.33ug/mL. 500 mg/kg (b.i.d.) intermittent intravenous infusion: Following a 2-week recovery period distal tubule intraluminal deposits and increased tubular basophilia were evident. Individual BAL9141 plasma concentration 3 hours into the second 4-hour infusion on day 3: 209 ug/mL.
Type of Study Species/Strain Sex/No. Per Group	Route	Dosage	Principal Effects Observed
3-Day Pilot Study 817P97	Primate; marmoset; Placebo: 2 Males Low Dose: 1 Male Mid Dose: 3 Males High Dose: 1 Male	Intravenous injection - slow bolus; 0.9% sodium chloride/citric acid, NaOH/ BAL5788 plus vehicle	0, 20, 100, 200 mg/kg t.i.d.	Animal administered 20 mg/kg (t.i.d.) showed intermittent limb tremors on day 3. In animals administered 100 or 200 mg/kg (t.i.d. ): One animal killed in extremis following 7 doses (100 mg/kg), and one animal killed in extremis (200 mg/kg). Microscopically kidney findings were characterized by basophilia, hyperplasia, hypertrophy, single cell necrosis and increased mitoses of epithelial cells of cortical and medullary distal and collecting tubules. Dilation of cortical distal tubules, and brownish intraluminal deposits within cortical and medullary distal and collecting tubules were also noted. 200 mg/kg (t.i.d. ): There were no adverse effects at the injection sites that were attributed to injection of BAL5788. The limited plasma level monitoring of BAL9141 indicated that the marmosets were exposed to about the extent predicted from preliminary rat pharmacokinetics. Slightly higher plasma concentrations were found at higher dose levels. Occasional clonic convulsions were noticed with 200 mg/kg doses.
3-Day Pilot Study 903P99	Primate; marmosets; 3 males/group	Intermittent intravenous infusion; 0.9% sodium chloride/citrate buffer/BAL5788 plus vehicle	Three days (two 4 hour infusion periods/day at 12 hour intervals); 0, 250 mg/kg b.i.d. (2mL/kg/hour)	250 mg/kg (b.i.d. ): Test article colored urine evident in all treated animals. Mean BAL9141 plasma concentration 3 - 4 hours into the first and last 4-hour infusion: 181.1/173.3 ug/mL (first/last infusion).
Repeat Dose	Rat;	i.v. infusion (4 h)	2 weeks +	The non-toxic dose level of BAL5788 was 175 mg/kg/4h at which no necrotic or
Study 1003097	40 males	BAL5788	4 weeks recovery	degenerative changes were observed in the kidneys.
			0, 175, 250, 360
			(b.i.d.) mg/kg
Repeat Dose	Rat;	i.v. infusion (4h)	0, 175, 250, 360	No significant toxic changes were noted following administration of BAL5788 at 250
BAP00046	5 male and 5 female	BAL5788	mg/kg	mg/kg/4h. All changes noted during the dosing period disappeared during the 4-week
	per dose group			recovery period.
	3 male and 3 female
	for recovery group
Repeat Dose	Rat;	i.v. infusion (4-8hr)	13 weeks +	At >250 mg/kg/d dose, 5 animals died due to acute renal failure and thrombolytic
BAP00728	10-15 male and 10-	BAL5788	4 weeks recovery	effects. Occasional clonic convulsions and kidney changes were noticed with >=125
	15 female per dose		0, 125, 250, 376,	mg/kg/d dose. The non-toxic dose level of BAL5788 was considered to be 125
	group		500, 750 mg/kg	mg/kg/day for both males and females (~4.2 times the clinical dose).
Type of Study	Species/Strain	Route	Dosage	Principal Effects Observed
	Sex/No. Per Group
Repeat Dose	Dog/Beagle	i.v. infusion	2 weeks +	Dose dependent vomiting and reddening of the skin which was observed which was
BAP00230	3 male, 3 female per	30 minutes changed to	2 weeks recovery	attenuated by extension of dosing duration. No precipitation was noted in the kidneys
	dose group (2 male,	2 hours	0, 25, 50, 100	despite high urine concentrations of BAL 9141.
	2 female for 100	BAL 5788	mg/kg
	mg/kg group)
Repeat Dose	Dog/Beagle	i.v. infusion (2 h)	13 weeks	Doses of 8 or 32 mg/kg/day caused minor treatment related reddening of the skin
TOX7918	6 male, 6 female	BAL5788	0, 8, 32 mg/kg	during the first 4 weeks of treatment that were associated with histamine release at the
	low dose group; 3			32 mg/kg/day level. A dose level of 8 mg/kg/day was considered to be the NOAEL
	male, 3 female high			based on these findings. This dose is ~25% of the clinical dose.
	dose group
Repeat Dose	Marmoset	i.v. infusion (4 h)	2 weeks	The non-toxic dose level of BAL5788 was considered to be less than 175 mg/kg/h
1003329	3 male /group	BAL5788	0, 175, 250, 360	since organic changes (precipitates in the distal and collecting tubules, increased
			mg/kg/h	mitosis in the collecting tubule, and brown pigment in the collecting tubules) were
			(b.i.d)	noted in the kidney at this dose level.
Repeat Dose	Marmoset/ Callithrix	i.v. infusion (4 h, 2 x	2 weeks +	No significant toxic changes were noted following the administration of BAL5788 at
1003800	jacchus	per day, q12)	4 weeks recovery	100 or 50 mg/kg/4h. Mortality (n=1), vomiting, discoloured urine, deposition of brown
	3 males/group; 6	BAL 5788	0, 50, 100, 250	pigment in tubular epithelium was observed with 250 mg/kg/d dose.
	males for recovery		mg/kg
	period		(b.i.d)
Repeat Dose	Marmoset/ Callithrix	i.v., infusion (4 h)	4 weeks +	No significant changes were noted following the administration of BAL5788 at 100
BAP00045	jacchus	BAL5788	4 weeks recovery	mg/kg/4h. NOAEL was 100 mg/kg/d. All changes noted during the dosing period
	3 male, 3		0, 50, 100, 200	disappeared during the 4-week recovery period. In the 200mg/kg group, abnormal urine
	female/dose group;		mg/kg	colour and brown pigment in the tubular epithelium of the kidneys was observed.
	6male, 6 female for
	recovery period
Repeat Dose	Marmoset/ Callithrix	i.v., infusion (4 h)	13 weeks + 4	The indwelling catheter caused vascular irritation at the infusion site in all groups
TOX7154	jacchus	AL 5788	weeks recovery	which was exacerbated by the infused test article resulting in the formation of local
	8 male, 8 female for		0, 50, 100, 200	thrombi. The non-toxic dose levels of BAL5788 were considered to be 100 mg/kg/day
	high dose; 5 male, 5		mg/kg/d	(~3.3 times clinical dose) and 50 mg/kg/day (~1.7 times clinical dose) for males and
	female low and			females. In the 50 mg/kg/d group, 3 animals died.
	mid-dose
Type of Study	Species/Strain	Route	Dosage	Principal Effects Observed
	Sex/No. Per Group
Genotoxicity	Salmonella	In vitro	BAL5788: 1,	Cytotoxic Effects: strain dependent toxic effects starting at
	typhimurium ; TA98,	BAL5788	3.16, 10, 31.6,	31.6 ug/plate, with the exception of TA1535, where toxic effects started at 1 ug/plate.
Reverse point	TA100, TA1535,		100 mg/plate
mutation	TA97, TA102			Genotoxic Effects: No
(Ames Test)
(B-167'797)
Genotoxicity Forward gene mutation of TK locus (B-167'775)	Mouse lymphoma cells	In vitro BAL9141	BAL9141: 39.06 to 5000 mg/mL	Cytotoxic Effects: Toxicity was observed at doses =2000 ug/mL (3 h: -S-9) and = 1250 ug/mL (3 h:+S-9). Genotoxic Effects: Weakly positive (equivocal) effect at toxic concentrations = 3000 ug/mL (3 h: -S-9) and =2500 ug/mL (3 h: +S-9). BAL9141 induced an equivocal, positive effect with and without metabolic activation
Genotoxicity	Mouse lymphoma	In vitro	BAL5788: 125	Cytotoxic Effects: Toxicity seen after 3 h (-S-9/+S-9: 500 and 750 ug/mL) and 24 h (-
	cells	BAL5788	to 1250 mg/mL	S-9: 150 ug/mL) treatment with BAL5788.
Forward gene
mutation of				Genotoxic Effects: The mutation frequency increased at cytotoxic BAL5788 doses due
TK locus				to enhanced numbers of small colonies, indicating clastogenic activity.
(B-169'336)
Genotoxicity	Human peripheral	In vitro	BAL5788: 250	Exposure to BAL-9141 did not increase the occurrence of chromosomal aberrations.
	blood lymphocytes	BAL5788, BAL9141,	to 1000 mg/mL	Under similar exposure conditions Diacetyl induced significant increases of the
Chromosome	diacetyl		incidences structural aberrations. BAL5788 induced positive results with and without
aberration	BAL9141: 312.	metabolic activation at = 393.2 ug/mL. The positive response was attributed to the
(B169'918)	5 to 1250 mg/mL	cleavage product diacetyl.
Diacetyl: 77 to
215 ug/mL
Genotoxicity	Mouse; Fullinsdorf	Single IV injection	BAL5788: 72 to	Toxic/Cytotoxic Effects: Yes; mortality at high dose of 450 mg/kg.
	Moro Albino	BAL5788	450 mg/kg	Genotoxic Effects: No
Micronuclei in	(Bone marrow
bone marrow	erythrocytes			Under the experimental conditions described in this report BAL-5788 does not induce
(B169'919)	evaluated)			chromosomal aberrations i n vivo.
	10/dose group
Type of Study	Species/Strain	Route	Dosage	Principal Effects Observed
	Sex/No. Per Group
Genotoxicity	Rat; Han Wistar	Single IV injection,	BAL5788: 0,	Toxic/Cytotoxic Effects: Yes, clinical signs of toxicity at the high dose level of 500
		BAL5788	200, 500 mg/kg	mg/kg.. Genotoxic Effects: No
Unschedule	Hepatocytes
DNA synthesis	evaluated
(1003801)
Fertility and	Rat; Crj:CD(SD);	Intermittent IV	14 days prior to	No Observed Adverse Effect Level:
early	20males/conc. dose	infusion (4 hrs/day);	mating,	F0 Males General Toxicity: 250 mg/kg
embryonic	group (females not	5% dextrose/BAL5788	throughout	F0 Males Reproductive Performance: 360 mg/kg
development	dosed)	plus vehicle	mating, through	Early Embryonic Development: 360 mg/kg
toxicity			day 4-5 after end	NOAEL = 250 and 360 mg/kg/d (18 x clinical b.i.d dose, and 12 x the clinical t.i.d
(BAP00231)			of mating;	dose)
			0, 175, 250, 360
			mg/kg	BAL 9141 was excreted into milk samples of rats ~18 -21% of the corresponding
			(2mL/kg/hour)	maternal plasma concentrations of BAL 9141.
Fertility and	Rat; Crj:CD(SD);	Intermittent IV	14 days prior to	No Observed Adverse Effect Level:
early	20 females/conc.	infusion (4 hrs/day);	mating,	F0 Females General Toxicity: 360 mg/kg
embryonic	(males not dosed)	5% dextrose/BAL5788	throughout	F0 Females Reproductive Performance: 360 mg/kg
development		plus vehicle	mating, through	Early Embryonic Development: 360 mg/kg
toxicity			day 7 after
BAP00232			gestation;
			0, 175, 250, 360
			mg/kg
			(2mL/kg/hour)
Fertility and	Rat; Crj:CD(SD);	IV infusion; 4 hrs	GD 6-17 (Day of	No Observed Adverse-Effect Level: F0 Females: 360 mg/kg Embryo/Fetal
Embryo-fetal	29 females/conc.	5% dextrose/BAL5788	mating = GD 0,	Development: >360 mg/kg
development		plus vehicle	Day of C-section
(BAP00173)			= GD 20); 0,
			175, 250, 360
			mg/kg
Type of Study	Species/Strain	Route	Dosage	Principal Effects Observed
	Sex/No. Per Group
Dose	Primate;	IV infusion (2	3 weeks (one	No Observed Effect Level: 30 mg/kg (equivalent to clinical dose)
Determination	cynomologus;	hrs/infusion);	week at each
Study	3 females	Reconstitution	escalating dose);
in pregnant		solution/BAL5788	30, 60, 120
monkeys		plus vehicle	mg/kg
(BAP00074)			(2 mL/kg/hr once
			daily)
Fertility and	Primate;	IV infusion (2	GD 20-50;	No Observed Effect Level: Dams: 60 mg/kg (2 times the clinical dose); Fetuses: 120
Embryo-fetal	cynomologus;	hrs/infusion);	30, 60, 120	mg/kg (4 times the clinical dose)
development	10 females/conc.	5% dextrose/BAL5788	mg/kg
(BAP00229)		plus vehicle	(2 mL/kg/hr once
			daily)
Pre-and	Rat; Crj:CD(SD)	IV infusion (4 hrs/day)	GD 6 - GD 21	No Observed Adverse Effect Level:
Postnatal	24 pregnant		(F o females	F0 Females: 175 mg/kg maternal toxicity (~ 6 times clinical dose); 250 mg/kg
development	females/group; 40		only);	reproductive toxicity (~8 times clinical dose)
(BAP00640)	males		0, 175, 250, 360	F1 Males/Females: 360 mg/kg / 360 mg/kg
			mg/kg (2	F2 Litters: 360 mg/kg
			mL/kg/hr)
Local Tolerance (TOX7588)	Rabbit, Japanese White (Kbl: JW); 3 males/group	Bolus intravenous injection; 5%Dextrose/ BAL5788 plus vehicle	8 days; 2 mg/mL (0.05 mL)/injection site	In the auricles into which BAL5788 was injected, the degree and frequency of inflammation noted in macroscopic examination and histopathology were similar to those in the auricles into which physiological saline was injected. During the administration period, no abnormalities were observed in clinical signs or body weight in any animal.
Local Tolerance (TOX7904)	Rabbit, Japanese White (Kbt: JW); 3 males/group	Bolus intravenous injection; 5%Dextrose/ BAL5788 plus vehicle	8 days (dosing immediately after solution preparation or 30 hours after preparation); 2, 10 mg/mL (0.05 mL)/injection site	No clinical signs of toxicity or body weight effects were observed in any of the BAL5788 treated animals. It was concluded that 2 and 10 mg/mL BAL5788 when prepared immediately prior to dosing or when prepared 30 hours prior to dosing had no irritancy to the auricular veins of rabbits. "Aged" BAL 5788 solution contained high concentrations of BAL 9141 (approximately 35-39%), compared to "fresh" solution (approximately 2-4%). The high concentration of BAL9141 after 30 h is attributed to spontaneous conversion of BAL5788 to BAL9141 in the dosing solution during the storage period (30 h at room temperature).
Type of Study	Species/Strain Sex/No. Per Group	Route Dosage Principal Effects Observed
Antigenicity Study (B170'669)	Guinea Pig; Hartley; 10 males-test group, 5 males-control group	Intradermal induction: bi-distilled water/BAL5788 plus vehicle and Freunds Complete Adjuvant/physiological saline/BAL5788 plus vehicle Epidermal Induction: bi-distilled water/BAL5788 plus vehicle following pretreatment with 10% sodium lauryl sulfate Challenge: bi-distilled water/BAL5788	Induction: Single injection/test site on Day 1; 0.1 mL of 5% BAL5788 [25 X the clinical concentration] and 0.1 mL of 5% BAL5788 in a 1:1 mixture of Freunds Complete Adjuvant and saline Epidermal Application: patch containing 0.3 mL BAL5788 (25%) applied for 48 hours on Day 8.	None of the control or BAL5788 treated animals exhibited skin reactions following challenge with a test article concentration of 25% in bi-distilled water. BAL5788 was not considered to be a skin sensitizer in the Guinea Pig Maximization Model.
			Challenge: Two weeks following epidermal induction, patch containing 0.2 mL BAL5788 (25%) applied for 24 hours on Day 22.

Challenge (Passive Cutaneous Sensitization): Intravenous, once 4 hours after passive Sensitization;

0.1 mL/site (Sera from actively sensitized animals diluted 4-64 fold with saline prior to injection.)

*Four animals in the 50 mg/kg group were administered the test article at 20 mg/kg for sensitization administrations 5

10 mg/kg BAL5788 intravenously: No active systemic anaphylactic reaction was observed in any animal.

10 mg/kg BAL5788 subcutaneously: No active systemic anaphylactic reaction was observed in any animal.

20/50 mg/kg BAL5788 intravenously: Scratching and piloerection were observed in one of five animals.

50 mg/kg BAL5788 with FCA or FIA subcutaneously: Characteristic anaphylactic signs (anxiety, tremor, scratching, piloerection, dyskinesia, dyspnea, and/or convulsion) were observed in all animals, and one animal died.

It was concluded that, under the conditions of this study, BAL5788 possesses antigenic potential at > 20 mg/kg which is less than than human clinical dose.

Group 1: 6 daily IP injections followed by single IV injection on day 7; 100 mg/kg *

Immediately following the last administration the animals were exposed to increasing UV-light doses of 5, 10, 15, 20, 25, 30, and 35 Joule/cm2.

None of the experimental animals presented with cutaneous erythema responses throughout the experiment. BAL5788 did not induce a phototoxic skin reaction in vivo in the hairless rat under the experimental conditions used.

The risk that BAL5788 could cause a phototoxic skin response in man is considered to be low if any.

(Note: This study used a 13.33% solution of the Prodrug BAL5788, which corresponds to a 10% solution of the active drug, BAL9141.)

No significant hemolysis and plasma turbidity or precipitation was seen at test article concentrations up to 1.25% [12.5 mg/ml (~6.25 times the clinical dose)] of BAL9141, corresponding to 16.6 mg/mL of BAL5788.

At higher concentrations of BAL9141, = 2.5% (> 25 mg/mL; 12.5 times the clinical dose), corresponding to >33.2 mg/mL of BAL5788, hemolysis up to 7.3% and moderate to marked plasma turbidity and precipitation were observed.

Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedicinal Ingredients
Intravenous infusion	Sterile, lyophilized powder / 500 mg per vial ceftobiprole as ceftobiprole medocaril	None. For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section.

Infection	Pathogens	Recommended Dose	Intravenous Infusion	Treatment Duration
Complicated Skin and Skin Structure Infections without Diabetic Foot Infections	Gram positive only * Staphylococcus aureus (including Streptococcus pyogenes methicillin-resistant)	500 mg every 12 hours	60 minutes	7-14 days
	Gram negative only Escherichia coli Proteus mirabilis Enterobacter cloacae Klebsiella pneumoniae Gram negative and Gram positive	500 mg every 8 hours	120 minutes	7-14 days
Complicated Skin and Skin Structure Infections with Diabetic Foot Infections (non Limb Threatening without concomitant Osteomyelitis) * *	Gram positive - Staphylococcus aureus (including methicillin-resistant) Gram negative Escherichia coli Proteus mirabilis Enterobacter cloacae Klebsiella pneumoniae Gram negative with or without Gram positive	500 mg every 8 hours	120 minutes	7-14 days
* In documented cases of Gram positive infection only * * The every 12-hour dosing regimen has not been studied in patients with diabetic foot infections and therefore is not recommended in these patients. (See WARNING and PRECAUTIONS) .

Vial Size	Volume of Diluent to be Added to Vial	Approximate Available Volume	Nominal Concentration per mL
20 mL	10 mL	10.6 mL	50 mg/mL

Reconstitution Diluent (10 mL)	Max. shelf life of reconstituted solution		Infusion Solution Diluent (250 mL)	Total Time by which reconstitution, dilution and infusion must be completed
	Reconstituted solution stored at 25degC	Reconstituted solution stored at 2-8degC (refrigerator)		Infusion solutions stored at 25degC		Infusion solutions stored at 2-8degC (refrigerator)
	Protected from light	Protected from light		Protected from light	NOT protected from light	Protected from light
Water for Injection or 5% Dextrose	1 hr	24 hr	0.9% sodium chloride	24 hr	12 hr	96 hr
			5% dextrose	8 hr	8 hr	96 hr
			Lactated Ringer's	24 hr	12 hr	Do not refrigerate

Proper name	Ceftobiprole medocaril (prodrug)	Ceftobiprole (active moiety)
Chemical name	(6R,7R)-7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3- yl)-2-(hydroxyimino)acetyl]amino]-3-[(E)-[(3'R)- 1'-[[(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy] carbonyl]-2-oxo[1,3'-bipyrrolidin]-3-ylidene] methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2- ene-2-carboxylic acid, monosodium salt	(6 R ,7 R )-7-[[(2 Z )-2-(5-amino-1,2,4- thiadiazol-3-yl)-2-(hydroxyimino) acetyl]amino]-8-oxo-3-[( E )-[(3' R )-2- oxo-1,3'-bipyrrolidin-3-ylidene] methyl]-5-thia-1-azabicyclo[4.2.0]oct- 2-ene-2-carboxylic acid
Molecular formula	C 26 H 25 N 8 N aO 11 S 2	C 20 H 22 N 8 O 6 S 2
Molecular mass	712.64	534.27
Structural formula	OH N H N N S H 2 N N S N O N N O O O O O O O ONa	N OH H 2 N N H N S S N O N N O NH O O OH

Study No.	Trial design	Dosage, route of administration and duration	No. of subjects a	Demography: Gender
				Mean age
				(age range)
BAP00154	Randomized, double-blind study of	Treatment: i.v. infusion of ceftobiprole	784	454 M, 330 W
	ceftobiprole medocaril versus	medocaril (500 mg ceftobiprole		47.3 yrs

Dose (mg)	Infusion Duration	C max ( m g/mL)	AUC 0- [?] ( m g * h/mL)	t 1/2 (h)	V SS (L)	CL S (L/h)
500	0.5h	40.6 (7.38)	101 (9.04)	3.63 (0.48)	16.4 (2.11)	4.99 (0.46)
500	1h	34.2 (6.05)	116 (20.2)	2.85 (0.55)	11.0 (2.93)	4.46 (0.84)
500	2h	29.2 (5.52)	104 (13.9)	3.1 (0.3)	21.7 (3.37)	4.89 (0.687)
750	0.5h	60.7 (4.55)	156 (19.3)	3.64 (0.32)	16.3 (1.82)	4.85 (0.57)
1000	0.5h	72.2 (8.78)	151 (9.04)	3.25 (020)	18.9 (2.31)	6.64 (0.41)

C max	AUC t	t 1/2	V SS	CL SS
( m g/mL)	( m g * h/mL)	(h)	(L)	(L/h)
44.2 (10.8)	102 (20.0)	4.04 (0.31)	16.7 (3.58)	5.06 (0.95)

Organism	# of isolates	Range	50%	90%
Staphylococcus aureus (MSSA)	737	<=0.06-1	0.25	0.5
Staphylococcus aureus (MRSA)	730	<=0.06-4	1.0	2
Streptococcus pyogenes	10	<=0.008-0.12	0.03	0.06
Enterobacter cloacae	88	0.03->32	<=0.12	<=0.12
Escherichia coli	517	<=0.06->8	<=0.06	<=0.06
Klebsiella pneumoniae	79	<=0.016-16	<=0.06	<=0.25
Proteus mirabilis	60	<=0.06-0.25	<=0.06	<=0.06

Organism	# of isolates	Range	(mg/mL) 50%	90%
Gram-positive
Enterococcus faecalis (VSE)	413	<=0.06->8	0.5	1
Staphylococcus epidermidis	33	0.12 - 1	0.25	1
Streptococcus agalactiae	15	0.016-0.03	0.016	0.016
Coagulase-negative staphylococci (inc. S. haemolyticus, S.
		<=0.016 - 1	0.12	1

Streptococcus pneumoniae
penicillin-susceptible	291	<=0.016-0.03	<=0.016	<=0.016
penicillin-resistant	209	0.016-4	0.5	1
Viridans group streptococci	54	<=0.016-0.06	<=0.016	0.06
Gram-negative
Enterobacter spp .	163	<= 0.06->8	<= 0.06	4
Haemophilus influenzae	435	<=0.12-0.5	<=0.12	<=0.12
Moraxella catarrhalis	206	<=0.008-1	< 0.12	1
Neisseria gonorrhoeae	51	<=0.008 - 0.12	0.03	0.06, 0.12
Pseudomonas aeruginosa *	68	0.12-16	2	8

PRODUCT MONOGRAPH

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Pediatrics (<18 years of age): WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics)

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

SERIOUS ACUTE HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS REQUIRE EMERGENCY TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, IV FLUIDS, IV ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.

Pregnant Women: PART II: SCIENTIFIC INFORMATION, TOXICOLOGY).

Nursing Women: PART II: SCIENTIFIC INFORMATION, TOXICOLOGY).

Pediatrics (< 18 years of age):

Geriatrics (> 65 years of age):

ADVERSE REACTIONS

Blood and lymphatic system:

Gastrointestinal:

General disorders & administration site conditions:

Infections and Infestations:

Immune System Disorders:

Investigations:

Metabolism and nutrition:

Musculoskeletal and connective tissue:

Nervous system:

Psychiatric:

Renal and urinary:

Respiratory, thoracic and mediastinal:

Skin and subcutaneous tissue:

Vascular:

DRUG INTERACTIONS

DOSAGE AND ADMINISTRATION

ACTION AND CLINICAL PHARMACOLOGYSpecial Populations and Conditions)

Reconstitution:

Parenteral Products:

Dilution:

OVERDOSAGE

ACTION AND CLINICAL PHARMACOLOGY

Absorption:

Distribution:

Metabolism:

Excretion

Pediatrics:

Geriatrics: DOSAGE AND ADMINISTRATIONPatients with Renal Impairment

Gender:

Race:

Hepatic Insufficiency: DOSAGE AND ADMINISTRATIONPatients with Hepatic Impairment

STORAGE AND STABILITY

Storage of Vials:

Storage of the Reconstituted and Infusion Solutions:

SPECIAL HANDLING INSTRUCTIONS

DOSAGE FORMS, COMPOSITION AND PACKAGING

PHARMACEUTICAL INFORMATION

Drug Substance

CLINICAL TRIALS

Complicated Skin and Skin Structure Infections including Diabetic Foot Infections

Study results

DETAILED PHARMACOLOGY ANIMAL PHARMACOLOGY

Safety Pharmacology

In vivo Protection Studies: Acute Infections Due to Gram-Positive and Gram-Negative Bacteria

Pharmacokinetics

Pharmacokinetic/Pharmacodynamic Parameters

HUMAN PHARMACOLOGY

Study Measuring the Effects of QT and Corrected QT(QTc) Intervals

Renal Insufficiency

Gender

Pharmacokinetic/Pharmacodynamic Parameters

MICROBIOLOGY

TOXICOLOGY

Other Studies:

REFERENCES