CETIBUTEN, 30MCG, SENSI-DISC

K965159 · Becton Dickinson Microbiology Systems · JTN · Feb 4, 1997 · Microbiology

Device Facts

• Record ID: K965159
• Device Name: CETIBUTEN, 30MCG, SENSI-DISC
• Applicant: Becton Dickinson Microbiology Systems
• Product Code: JTN · Microbiology
• Decision Date: Feb 4, 1997
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.1620
• Device Class: Class 2

Intended Use

Antimicrobial Susceptibility Test Discs are used for semi-quantitative in vitro susceptibility testing by standardized agar diffusion test procedures. Ceftibuten Sensi-Discs® are intended for use in determining the susceptibility of gram-positive and gram-negative bacteria, including Streptococcus peuemoniae (penicillin-susceptible strains only), Streptococcus pyrogens, Haemophilus influenzae, (including β-lactamase-producing strains) and Moraxella catarrhalis (including β-lactamase-producing strains) species to Ceftibuten. Zone sizes used for interpretation of tests, including control organism limits, were determined by the antimicrobic manufacturer, Schering Corporation, and received FDA approval under NDA Nos. 50-685 and 50-686.

Device Story

Device consists of high-quality paper discs impregnated with 30 mcg of Ceftibuten; used in clinical microbiology laboratories. Discs are placed on Mueller Hinton Agar (or specialized media for specific organisms) inoculated with clinical bacterial isolates. Following incubation, healthcare providers measure zones of inhibition surrounding discs. Measured zone diameters are compared against established NCCLS/FDA-approved interpretive criteria to classify organisms as susceptible, intermediate, or resistant. Results assist clinicians in selecting appropriate antimicrobial therapy for patients with bacterial infections. Benefits include standardized, semi-quantitative assessment of antibiotic susceptibility to guide treatment decisions.

Clinical Evidence

Bench testing only. Performance is established by comparing zone of inhibition diameters against standardized NCCLS interpretive criteria (M2-A5, M100-S6). Quality control is maintained using specific reference strains (e.g., Haemophilus influenzae ATCC 49247) with defined MIC and zone diameter ranges.

Technological Characteristics

Paper discs impregnated with 30 mcg Ceftibuten. Principle: Agar diffusion (Bauer-Kirby method). Media: Mueller Hinton Agar, Haemophilus Test Medium, or Mueller Hinton with 5% Sheep Blood. Connectivity: None. Sterilization: Not specified. Software: None.

Indications for Use

Indicated for in vitro agar diffusion susceptibility testing to determine bacterial susceptibility to Ceftibuten. Applicable to gram-positive and gram-negative bacteria, specifically Streptococcus pneumoniae (penicillin-susceptible), Streptococcus pyogenes, Haemophilus influenzae, and Moraxella catarrhalis.

Regulatory Classification

Identification

An antimicrobial susceptibility test disc is a device that consists of antimicrobic-impregnated paper discs used to measure by a disc-agar diffusion technique or a disc-broth elution technique the in vitro susceptibility of most clinically important bacterial pathogens to antimicrobial agents. In the disc-agar diffusion technique, bacterial susceptibility is ascertained by directly measuring the magnitude of a zone of bacterial inhibition around the disc on an agar surface. The disc-broth elution technique is associated with an automated rapid susceptibility test system and employs a fluid medium in which susceptibility is ascertained by photometrically measuring changes in bacterial growth resulting when antimicrobial material is eluted from the disc into the fluid medium. Test results are used to determine the antimicrobial agent of choice in the treatment of bacterial diseases.

Predicate Devices

• Cefixime, 5 mcg, Sensi-Disc®

Submission Summary (Full Text)

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K965159

FEB - 4 1997

Date 12/20/96

# SUMMARY OF SAFETY AND EFFECTIVENESS

## SUBMITTED BY:

Robert E. James, Director
International Regulatory and Quality Development
Becton Dickinson Microbiology Systems
P.O. Box 243
Cockeysville, MD 21030-0243

## NAME OF DEVICE:

**Trade Name:**
Ceftibuten, 30 mcg, Sensi-Discs
Catalog Numbers 4331701, 4331702

**Common Name/Description:**
Antimicrobial Susceptibility Test Discs

**Classification Name:**
Antimicrobial Susceptibility Test Discs

## PREDICATE DEVICE:
Other BBL® Sensi-Discs® such as
Cefixime, 5 mcg, Sensi-Disc®

## DEVICE DESCRIPTION:

### INTENDED USE:

Antimicrobial Susceptibility Test Discs are used for semi-quantitative in vitro susceptibility testing by standardized agar diffusion test procedures. Ceftibuten Sensi-Discs® are intended for use in determining the susceptibility of gram-positive and gram-negative bacteria, including *Streptococcus peuemoniae* (penicillin-susceptible strains only), *Streptococcus pyrogens*, *Haemophilus influenzae*, (including β-lactamase-producing strains) and *Moraxella catarrhalis* (including β-lactamase-producing strains) species to Ceftibuten. Zone sizes used for interpretation of tests, including control organism limits, were determined by the antimicrobic manufacturer, Schering Corporation, and received FDA approval under NDA Nos. 50-685 and 50-686.

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# INDICATIONS FOR USE:

Use of BBL® Ceftibuten Sensi-Discs® for in vitro agar diffusion susceptibility testing is indicated when there is a need to determine the susceptibility of bacteria to Ceftibuten.

# PRODUCT DESCRIPTION:

Ceftibuten Susceptibility Test Discs are prepared by impregnating high quality paper with accurately determined amounts of Ceftibuten supplied by the manufacturer, Schering Corporation, Kenilworth, New Jersey. Each Ceftibuten disc is clearly marked on both sides with the agent and content. Ceftibuten discs are furnished in cartridges of 50 discs each. Ceftibuten cartridges are packed as either a single cartridge in a single box, or in a package containing ten cartridges.

Agar diffusion methods employing dried filter paper discs impregnated with specific concentrations of antimicrobial agents were developed in the 1940s. In order to eliminate or minimize variability in the testing, Bauer et al. developed a standardized procedure in which Mueller Hinton Agar was selected as the test medium.

Various regulatory agencies and standards-writing organizations subsequently published standardized reference procedures based on the Bauer-Kirby method. Among the earliest and most widely accepted of these standardized procedures were those published by the U.S. Food and Drug Administration (FDA) and the World Health Organization (WHO). The procedure was adopted as a consensus standard by the National Committee for Clinical Laboratory Standards (NCCLS) and is periodically updated. The latest NCCLS documents are M2-A5 (12/93) and M100-S6 (12/95).

Discs containing a wide variety of antimicrobial agents are applied to the surface of Mueller Hinton Agar plates [or Haemophilus Test Medium Agar for H. influenzae or Mueller Hinton Agar with 5% Sheep Blood for S. pneumoniae] inoculated with pure cultures of clinical isolates. Following incubation, the plates are examined and the zones of inhibition surrounding the discs are measured and compared with established zone size ranges for individual antimicrobial agents in order to determine the agent(s) most suitable for use in antimicrobial therapy. The determination as to whether the organism in question is susceptible (S), intermediate (I), or resistant (R) to an antimicrobial agent is made by comparing zone sizes to those found in the respective organism tables

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of National Committee for Clinical Laboratory Standards (NCCLS) Document M2-A5 ("Performance Standards for Antimicrobial Disk Susceptibility tests - Fifth Edition, Approved Standard", 12/93) and of NCCLS Document M100-S6 ("Performance Standards for Antimicrobial Susceptibility Testing", Sixth Informational Supplement, 12/95).

## PERFORMANCE DATA:

See attached Schering Corporation product insert section on Susceptibility testing Diffusion Techniques for CEDAX® (Ceftibuten).

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F-18690801

PROZO INFORMATION

# CEDAX

# (cellibuten capsules)

and

# (cellibuten for oral suspension)

FOR ORAL USE ONLY

# DESCRIPTION

CEDAX (cellibuten capsules) and (cellibuten for oral suspension) contain the active ingredient cellibuten as cellibuten univariate. Cellibuten (involving a 1-symmetrical communication antibody; for oral administration. Chemically, it is (+)-(6R,7R)-7-((2)-2-(2-Amino-4-thiazoyl)-4-carboxypropan-2-2-methyl-6-oxy-4-thiazoyl)-4,2,6a,6,7-oxy-3-carboxamide). It is molecular weight is 446.43 as the univariate.

Cellibuten (involving has the following structural formula:


CEDAX Capsules contain cellibuten univariate equivalent to 400 mg of cellibuten. Inactive ingredients contained in the capsule formulation include: magnesium chloride, methylcytidine cellulose, and sodium starch (glycolate). The capsule shell and/or zone contains gallate, sodium teuryl sulfate, titanium dioxide, and polybromide 80. The capsule shell may also contain trinitrolic acid, sodium propionate, acetate calcium disodium, butylpyridine, propylpyridine, and methylpyridine.

CEDAX Oral Suspension after remanufacture contains cellibuten. Allophane equivalent to either 90 mg of cellibuten per 5 mL or 180 mg of cellibuten per 5 mL. CEDAX Oral Suspension is cherry-havored and contains the inactive ingredients: cherry-havoring, polybromide 80, vitamin dioxide, semisilicone, sodium benzoate, sodium (approximately 1 g/5 mL), titanium dioxide, and vanillin (pH).

# CLOSURES PERMISSIBLE

# Absorption:

# CEDAX CAPSULES

Cellibuten is rapidly absorbed after oral administration of CEDAX Capsules. The plasma concentrations and pharmacokinetic parameters of cellibuten after a single 400-mg dose of CEDAX Capsules to 12 healthy adult male volunteers (20 to 39 years of age) are displayed in the table below. When CEDAX Capsules were administered twice daily for 7 days, the average $C_{\mathrm{max}}$ was 17.9 μg/mL, on day 7. Therefore, cellibuten accumulation in plasma is about 20% at steady state.

# CEDAX ORAL SUSPENSION

Cellibuten is rapidly absorbed after oral administration of CEDAX Oral Suspension. The plasma concentrations and pharmacokinetic parameters of cellibuten after a single 9-mg/kg dose of CEDAX Oral Suspension to 32 fasting pediatric patients (6 months to 12 years of age) are displayed in the following table:

| Parameter | Average Plasma Concentration (in μg/mL of cellibuten after a single 400-mg dose) and Derived Pharmacokinetic Parameters (≤ 1 SD) (n = 12 healthy adult males) | Average Plasma Concentration (in μg/mL of cellibuten after a single 9-mg/kg dose) and Derived Pharmacokinetic Parameters (≤ 1 SD) (n = 32 pediatric patients) |
| --- | --- | --- |
| 1.0 h | 6.1 (5.1) | 5.3 (6.3) |
| 1.5 h | 9.8 (5.9) | 8.6 (4.4) |
| 2.0 h | 11.3 (5.2) | 11.2 (4.6) |
| 3.0 h | 13.3 (3.0) | 9.0 (3.4) |
| 4.0 h | 11.2 (2.9) | 6.6 (3.1) |
| 6.0 h | 5.8 (1.8) | 3.5 (2.5) |
| 6.5 h | 3.2 (1.0) | 1.6 (1.3) |
| 12.0 h | 1.1 (0.4) | 0.5 (0.4) |
| $C_{\mathrm{max}}$ μg/mL | 15.0 (3.3) | 13.4 (4.9) |
| $S_{\mathrm{max}}$ h | 2.6 (0.9) | 2.0 (1.0) |
| AUC, μg/mL | 73.7 (16.0) | 56.0 (16.9) |
| Tb, h | 2.4 (0.2) | 2.0 (0.5) |
| Total body clearance (CVF) mL/min/kg | 1.3 (0.3) | 2.9 (0.7) |

The absolute bioavailability of CEDAX Oral Suspension has not been determined. The plasma concentrations of cellibuten in pediatric patients are dose-proportional following single doses of CEDAX Capsules of 200 mg and 400 mg and of CEDAX Oral Suspension between 4.5 mg/kg and 9 mg/kg.

# Distribution:

# CEDAX CAPSULES

The average apparent volume of distribution (V/F) of cellibuten in 6 adult subjects is 0.21 L/kg (≤ 1 SD = 0.03 L/kg).

# CEDAX ORAL SUSPENSION

The average apparent volume of distribution (V/F) of cellibuten in 32 fasting pediatric patients is 0.5 L/kg (≤ 1 SD = 0.2 L/kg).

# Protein Binding:

Cellibuten in 60% bound to plasma proteins. The protein binding is independent of plasma cellibuten concentration.

# Tissue Penetration:

Bronchial secretions: In a study of 15 adults administered a single 400-mg dose of cellibuten and evaluated as undergo bronchoscopy, the mean concentrations in epithelial lining fluid and bronchial mucosa were 15% and 37%, respectively, of the tissue concentrations.

Sputum: Cellibuten sputum levels average approximately 7% of the concomitant plasma cellibuten level. In a study of 24 adults administered cellibuten 200 mg bid or 400 mg qd, the average $C_{\mathrm{max}}$ in sputum (1.5 μg/mL) occurred at 2 hours postdose and the average $C_{\mathrm{max}}$ in plasma (17 μg/mL) occurred at 2 hours postdose.

Middle-ear fluid (MEF): Cellibuten middle-ear fluid levels average approximately 55% of the concomitant plasma cellibuten level. In a study of 30 children administered 9 mg qd of cellibuten, the average $C_{\mathrm{max}}$ in MEF (2.9 ± 0.9 μg/mL) occurred at 4 hours postdose and the average $C_{\mathrm{max}}$ in plasma (6.7 ± 1.9 μg/mL) occurred at 2 hours postdose.

Tendolar tissue: Data on cellibuten penetration into tonsillar tissue are not available.

Cerebrospinal fluid: Data on cellibuten penetration into cerebrospinal fluid are not available.

# Metabolism and Excretion:

A study with radiolabeled cellibuten administered to 6 healthy adult male volunteers demonstrated that cytocellibuten is the predominant component in both plasma and urine. About 10% of cellibuten is converted to the trans-isomer. The trans-isomer is approximately a as antimicrobial agent as the co-isomer.

Cellibuten is excreted in the urine: 95% of the administered radioactivity was recovered either in urine or feces. In 6 healthy adult male volunteers, approximately 56% of the administered dose of cellibuten.

The results of the study, because renal excretion is a significant pathway of elimination, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment (see DOSAGE AND ADMINISTRATION).

# Food Effect on Absorption:

Food affects the bioavailability of cellibuten from CEDAX Capsules and CEDAX Oral Suspension.

The effect of food on the bioavailability of CEDAX Capsules was evaluated in 26 healthy adult male volunteers who ingested 400 mg of CEDAX Capsules after an overnight fast or immediately after a standardized breakfast. Results showed that food delays the time of $C_{\mathrm{max}}$ by 1.75 hours, decreases the $C_{\mathrm{max}}$ by 18%, and decreases the extent of absorption (AUC) by 8%.

The effect of food on the bioavailability of CEDAX Oral Suspension was evaluated in 18 healthy adult male volunteers who ingested 400 mg of CEDAX Oral Suspension after an overnight fast or immediately after a standardized breakfast. Results obtained demonstrated a decrease in $C_{\mathrm{max}}$ of 26% and an AUC of 17% when CEDAX Oral Suspension was administered with a high-fat breakfast, and a decrease in $C_{\mathrm{max}}$ of 17% and an AUC of 12% when CEDAX Oral Suspension was administered with a low-calorie nonfat breakfast (see PRECAUTIONS).

# Ecoseminence of Dosage Formulations:

A study in 18 healthy adult male volunteers demonstrated that a 400-mg dose of CEDAX Capsules produced equivalent concentrations to a 400-mg dose of CEDAX Oral Suspension. Average $C_{\mathrm{max}}$ values were 15.6 (3.1) μg/mL for the capsule and 17.0 (3.2) μg/mL for the suspension. Average AUC values were 80.1 (14.4) μg/mL for the capsule and 87.0 (12.2) μg/mL for the suspension.

# Special Populations:

Geriatric patients: Cellibuten pharmacokinetics have been investigated in elderly (65 years of age and older) men (n = 8) and women (n = 4). Each volunteer received cellibuten 200-mg capsules twice daily for 24 days. The average $C_{\mathrm{max}}$ was 17.5 (3.7) μg/mL after 24 days of testing compared to 12.9 (2.1) μg/mL after the first dose; cellibuten accumulation in plasma was 48% at steady state. Information regarding the renal function of these volunteers was not available; therefore, the significance of this finding for clinical use of CEDAX Capsules in elderly patients is not clear. Cellibuten dosage adjustment in elderly patients may be necessary (see DOSAGE AND ADMINISTRATION).

Patients with renal insufficiency: Cellibuten pharmacokinetics have been investigated in adult patients with renal dysfunction. The cellibuten plasma half-life increased and apparent total clearance (CVF) decreased proportionately with increasing degree of renal dysfunction. In 6 patients with moderate renal dysfunction (creatinine clearance 30 to 49 mL/min), the baseline half-life of cellibuten increased to 7.1 hours and CVF decreased to 30 mL/min. In 6 patients with severe renal dysfunction (creatinine clearance 0 to 29 mL/min), the half-life increased to 13.4 hours and CVF decreased to 16 mL/min. In 6 functionalized anabolic patients (creatinine clearance <5 mL/min), the half-life increased to 22.3 hours and CVF decreased to 11 mL/min (a 7- to 8-fold change compared to healthy volunteers). Hemodialysis removed 60% of the drug from the blood in 2 to 4 hours. These changes serve as the basis for dosage adjustment recommendations in adult patients with mild to severe renal dysfunction (see DOSAGE AND ADMINISTRATION).

# Microbiology:

Cellibuten exerts its bactericidal action by binding to essential target proteins of the bacterial cell wall. This binding leads to inhibition of cell-wall synthesis.

Cellibuten is stable in the presence of most plasmid-mediated beta-lactamases, but it is not stable in the presence of chromosomal-inhibited cephalosporinases produced in organisms such as Bacteroides, Citrobacter, Enterobacter, Morganella, and Serratia. Late other beta-lactam agents, cellibuten should not be used against strains resistant to beta-lactams due to general mechanisms such as permeability or penicillin-binding protein changes like penicillin-resistant S. pneumoniae.

Cellibuten has been shown to be active against most strains of the following organisms both in vitro and in clinical infections (see INDICATIONS AND USAGE):

# Gram-positive aerobes:

Streptococcus pneumoniae (penicillin-susceptible strains only)

Streptococcus pyogenes

# Gram-negative aerobes:

Haemophilus influenzae (including β-lactamase-producing strains)

Moraxella catarrhalis (including β-lactamase-producing strains)

There are no known organisms which are potential pathogens in the indications approved for cellibuten for which cellibuten exhibits in vitro activity but for which the safety and efficacy of cellibuten in treating clinical infections due to these organisms, none has been established in alloptics and well-controlled trials.

NOTE: Cellibuten is INACTIVE in vitro against Acinetobacter, Bordetella, Campylobacter, Enterobacter, Enterococcus, Flavobacterium, Hafnia, Lactaria, Pseudomonas, Staphylococcus, and Streptococcus (except pneumoniae and pyogenes) species. In addition, it shows little in vitro activity against most anaerobes, including most species of Bacteroides.

# Susceptibility Testing:

Dilution Techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth, agar, or microdilution) or equivalent with standardized inoculum concentrations and standardized concentrations of cellibuten powder. The MIC values should be interpreted according to the following criteria when testing Haemophilus species using Haemophilus Test Media (HTM):

MIC (μg/mL)

Interpretation

(2)

# Susceptible

The current absence of resistant strains precludes defining any categories other than "Susceptible". Strains existing results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing.

A report of "Susceptible" implies that an infection due to the strain may be appropriately treated with the dosage of antimicrobial agent recommended for that type of infection and infecting species, unless otherwise contraindicated.

Cellibuten is indicated for penicillin-susceptible only strains of Streptococcus pneumoniae. A pneumococcal isolate that is susceptible to penicillin (MIC ≤0.06 μg/mL) can be considered susceptible to cellibuten for approved indications. Testing of cellibuten against penicillin-aminobutyric or penicillin-resistant isolates is not recommended. Reliable alternative criteria for cellibuten are not currently available. Physicians should be informed that clinical response rates with cellibuten may be lower in strains that are not penicillin-susceptible.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspect of laboratory procedures. Standard cellibuten powder should provide the following MIC values:

Ontaclism

MIC range (μg/mL)

Haemophilus influenzae

ATCC 49274

0.25-1.0

Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized inoculum requires the use of standardized inoculum concentrations. This procedure uses paper extra impregnated with 30 μg of cellibuten to test the susceptibility of microorganisms to cellibuten.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-μg cellibuten disk should be interpreted according to the following criteria when testing Haemophilus species using Haemophilus Test Media (HTM):

Zone diameter (mm)

Interpretation

(2.5)

(5) Susceptible

The current absence of resistant strains precludes defining any categories other than "Susceptible". Strains existing results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing.

Interpretation should be as stated above for results using dilution techniques.

Cellibuten is indicated for penicillin-susceptible only strains of Streptococcus pneumoniae.

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Pneumococcal isolates with biocillin zone sizes of ≥20 mm are susceptible to penicillin and can be considered susceptible for approved indications. Reliable data diffusion tests for ceftolupim do not yet exist.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30-μg ceftolupim disk should provide the following zone diameters in these laboratory test quality control strains:

| Organism | Zone diameter (mm) |
| --- | --- |
| Haemophilus influenzae ATCC 49247 | 29-35 |

Cacrolitoponyl-class disks should not be used to test for susceptibility to ceftolupim.

## INDICATIONS AND USAGE:

CEDAX (ceftolupim) is indicated for the treatment of individuals with mild-to-moderate infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below (see INFRAME AND ADMINISTRATION and CLINICAL STUDIES sections).

- Acute Bacterial Exacerbations of Chronic Bronchitis due to Haemophilus influenzae (including β-lactamase-producing strains), Moraxella catarrhalis (including β-lactamase-producing strains), or Streptococcus pneumoniae (penicillin-susceptible strains only).

NOTE: In acute bacterial exacerbations of chronic bronchitis clinical trials where Moraxella catarrhalis was isolated from infected sputum at baseline, ceftolupim clinical efficacy was 22% less than control.

- Acute Bacterial Otitis Media due to Haemophilus influenzae (including β-lactamase-producing strains), Moraxella catarrhalis (including β-lactamase-producing strains), or Streptococcus pyogenes.

NOTE: Although ceftolupim used empirically was equivalent to collaborators in the treatment of clinically and/or microbiologically documented acute otitis media, the efficacy against Streptococcus pneumoniae was 23% less than control. Therefore, ceftolupim should be given empirically only when adequate antimicrobial coverage against Streptococcus pneumoniae has been previously administered.

## Pharyngitis and Tonsillitis due to Streptococcus pyogenes.

NOTE: Only penicillin by the intramuscular route of administration has been shown to be effective in the prophylaxis of rheumatic fever. Ceftriaxone is generally effective in the eradication of Streptococcus pyogenes from the oropharynx; however, data establishing the efficacy of CEDAX for the prophylaxis of suboptimal rheumatic fever are not available.

## CONTRAINDICATIONS:

CEDAX (ceftolupim) is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.

## WARNINGS:

BEFORE TREATY WITH CEDAX IS INSTITUTED, CAREFUL INJURY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PROGRESS INTERPRETIBILITY REACTIONS TO CEDAX, OTHER CEPHALOSPHERES, PENICILLUS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVEN TO PENICILLUS-SENSITIVE PATIENTS, CAREFUL SHOULD BE OBSERVED BECAUSE CROSS EXPERIMENTARY AROUND DETA-LACTAS ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLUS ALLERGY. IF AN ALLERGIC REACTION TO CEDAX OCCURS, SUCCESSIONS THE DOGS, NEEDING ACUTE INTERPRETIBILITY REACTIONS MAY REQUIRE TREATMENT WITH SPINTPHENIC AND OTHER CHEMISSOCIUM BEHAVIORS, INCLUDING OXIDASE, EXTINGUISHING FLUIDS, EXTINGUISHING ANTIBIOTICIDES, CONTROSTENOID, PRESSURE AROUND, AND AIRWAY MANAGEMENT, AS CLINICALLY IMPROVED.

Pseudomembranous colitis has been reported with severe oil antibacterial agents, including ceftriaxone, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of "antibiotic-associated colitis".

After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis closely respond to drug discontinuation cases. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, proton supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile.

## PRECAUTIONS:

### General:

As with other broad-spectrum antibiotics, prolonged treatment may result in the possible emergence and overgrowth of resistant organisms. Cordial observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

The dose of ceftriaxone may require adjustment to patients with varying degrees of renal insufficiency, particularly in patients with creatinine clearance less than 50 mL/min or undergoing hemodialysis (see INFRAME AND ADMINISTRATION). Ceftriaxone is readily dialysable. Dialysis patients should be monitored carefully, and administration of ceftriaxone should occur immediately following dialysis.

Ceftriaxone should be prescribed with caution to individuals with a history of gastrointestinal disease, particularly colitis.

### Information to Patients:

Patients should be informed that:

- If the patient is diabetic, he/she should be informed that CEDAX Oral Suspension contains 1 gram sparrow per specimen of suspension.
- CEDAX Oral Suspension should be taken at least 2 hours before a meal or at least 1 hour after a meal (see CLINICAL PHARMACOLOGY, Food Effort on Atmosphere).

### Drug Interactions:

Preoperative Twelve healthy male volunteers were administered one 200-mg ceftolupim capsule twice daily for 6 days. With the morning dose of ceftolupim on day 6, each volunteer received a single intravenous infusion of theophylline (4 mg/kg). The pharmacokinetics of theophylline were not altered. The effect of ceftolupim on the pharmacokinetics of theophylline administration orally has not been investigated.

Analysis of H₂-receptor antagonists: The effect of increased plasma pH on the bioavailability of ceftolupim was evaluated in 18 healthy adult volunteers. Each volunteer was administered one 400-mg ceftolupim capsule. A single dose of liquid ethanol did not affect the Cmax or AUC of ceftolupim; however, 150 mg of ranitidine (12h for 3 days increased the ceftolupim Cmax by 23% and ceftolupim AUC by 16%. The clinical relevance of these increases is not known.

### Drug Laboratory Test Interactions:

There have been no chemical or laboratory test interactions with ceftolupim noted to date. False-positive direct Coombs tests have been reported during treatment with other cephalosporins. Therefore, it should be recognized that a positive Coombs test could be due to the drug. The results of assays using red cells from healthy subjects to determine whether ceftolupim would cause direct Coombs reactions in vitro showed no positive reaction at ceftolupim concentrations as high as 40 μg/mL.

### Carcinogenesis, Intergenesis, Impairment of Fertility:

Lung-term animal studies have not been performed to evaluate the carcinogenic potential of ceftolupim. No mutagenic effects were seen in the following studies; in vitro chromosome assay in human lymphocytes. In vivo chromosome assay in mouse bone marrow cells. Clonidia hamster Ovary (CVD) cell point mutation assay at the hyos admitane-quinone endosymbiontial membrane (HGPRT) locus, and in a bacterial reversion point mutation test (Ames). No impairment of fertility occurred when rats were administered ceftolupim orally up to 2000 mg/kg/day (approximately 43 times the human dose based on mg/m²/day).

### Pregnancy: Teratogenic effects: Pregnancy Category II:

Ceftolupim was not teratogenic in the pregnant rat at oral doses up to 400 mg/kg/day (approximately 8.6 times the human dose based on mg/m²/day). Ceftolupim was not teratogenic in the pregnant rabbit at oral doses up to 40 mg/kg/day (approximately 1.5 times the human dose based on mg/m²/day) and has revealed no evidence of harm to the fetus. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

### Labor and Delivery:

Ceftolupim has not been studied for use during labor and delivery. Its use during such clinical situations should be weighed in terms of potential risk and benefit to both mother and fetus.

## Nursing Mothers:

It is not known whether ceftolupim (at recommended dosages) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ceftolupim is administered to a nursing woman.

## Pediatric Use:

The safety and efficacy of ceftolupim in infants less than 6 months of age has not been established.

## Geriatric Patients:

The usual adult dosage recommendation may be followed for patients in this age group. However, these patients should be monitored closely, particularly their renal function, as dosage adjustment may be required.

## ADVERSE EVENTS:

### Clinical Trials:

CEDAX CAPSULES (adult patients)

In clinical trials, 1728 adult patients (1092 US and 636 international) were treated with the recommended dose of ceftolupim capsules (400 mg per day). There were no deaths or permanent disposition thought due to drug toxicity in any of the patients in these studies. Thirty-six of 1728 (2%) patients discontinued medication due to adverse events thought by the investigators to be possibly, probably, or almost certainly related to drug toxicity. The discontinuations were primarily for gastrointestinal disturbances, usually diarrhea, vomiting, or nausea. Six of 1728 (0.3%) patients were discontinued due to rash or pruritus thought related to ceftolupim administration.

In the US trials, the following adverse events were thought by the investigators to be possibly, probably, or almost certainly related to ceftolupim capsules in multiple-dose clinical trials (n = 1092 ceftolupim-treated patients).

| ADVERSE REACTIONS
CETTOLUPIN CAPSULES
US CLINICAL TRIALS IN ADULT PATIENTS (n = 1092) | | |
| --- | --- | --- |
| Incidence equal to or greater than 1% | Rauins
Headache
Dizziness
Dyspepsia
Dizziness
Abdominal pain
Vomiting | 4%
3%
3%
2%
1%
1%
1% |
| Incidence less than 1% but greater than 0.1% | Anorexia
Constipation
Dry mouth
Dyspnea
Dysuria
Erythema
Fungus
Fibrosence
Loose stools
Moutment
Nasal congestion
Paresthesia
Pruritus
Rash
Somnolence
Taste prevention
Urticaria
Vaginitis | |
| LABORATORY VALUE CHANGES
CETTOLUPIN CAPSULES
US CLINICAL TRIALS IN ADULT PATIENTS | | |
| --- | --- | --- |
| Incidence equal to or greater than 1% | T BUN
T Eosinophilia
T Hemoglobin
T ALT (SGPT)
T Bilirubin | 4%
3%
2%
1%
1% |
| Incidence less than 1% but greater than 0.1% | T Alk phosphatase
T Creatinine
T Platelets
L Platelets
L Leukocytes
T AST (SGOT) | |

*Changes in laboratory values with possible clinical significance regardless of whether or not the investigator thought that the change was due to drug toxicity.

CEDAX ORAL SUSPENSION (patients' patients)

In clinical trials, 1152 pediatric patients (772 US and 390 international), 57% of whom were younger than 12 years of age, were treated with the recommended dose of ceftolupim (9 mg/kg once daily up to a maximum dose of 400 mg per day) for 18 days. There were no deaths, life-threatening adverse events, or permanent residences in any of the patients in these studies. Eight of 1152 (<1%) patients discontinued medication due to adverse events thought by the investigators to be possibly, probably, or almost certainly related to drug toxicity. The discontinuations were primarily (7 out of 8) for gastrointestinal disturbances, usually diarrhea or vomiting. One patient was discontinued due to a class-ness with thought between related to ceftolupim administration.

In the US trials, the following adverse events were thought by the investigators to be possibly, probably, or almost certainly related to ceftolupim oral suspension in multiple-dose clinical trials (n = 772 ceftolupim-treated patients).

| ADVERSE REACTIONS
CETTOLUPIN ORAL SUSPENSION
US CLINICAL TRIALS IN PEDIATRIC PATIENTS (n = 772) | | |
| --- | --- | --- |
| Incidence equal to or greater than 1% | Diarrhea
Vomiting
Abdominal pain
Loose stools | 4%
2%
2%
2% |
| Incidence less than 1% but greater than 0.1% | Agitation
Anorexia
Dehydration
Diaple dermatitis
Dizziness
Dyspepsia
Fever
Headache
Hematuria
Hyperthermia
Insomnia
Irritability
Nausea
Pruritus
Rash
Rigors
Urticaria | |

*NOTE: The incidence of diarrhea in children ≤2 years old was 8% (23/301) compared with 2% (9/471) in children >2 years old.