Cefuroxime Axetil (Page 4 of 6)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Cefuroxime axetil is an antibacterial drug [see Microbiology (12.4)].

12.3 Pharmacokinetics

Absorption

After oral administration, cefuroxime axetil is absorbed from the gastrointestinal tract and rapidly hydrolyzed by nonspecific esterases in the intestinal mucosa and blood to cefuroxime. Serum pharmacokinetic parameters for cefuroxime following administration of cefuroxime axetil tablets to adults are shown in Table 8.

Table 8. Pharmacokinetics of Cefuroxime Administered in the Postprandial State as Cefuroxime Axetil Tablets to Adultsa

Doseb (Cefuroxime Equivalent) Peak Plasma Concentration (mcg/mL) Time of Peak Plasma Concentration (h) Mean Elimination Half-life (h) AUC (mcg•h/mL)
125 mg 2.1 2.2 1.2 6.7
250 mg 4.1 2.5 1.2 12.9
500 mg 7 3 1.2 27.4
1,000 mg 13.6 2.5 1.3 50

a Mean values of 12 healthy adult volunteers.

b Drug administered immediately after a meal.

Effect of Food: Absorption of the tablet is greater when taken after food (absolute bioavailability increases from 37% to 52%). Despite this difference in absorption, the clinical and bacteriologic responses of subjects were independent of food intake at the time of tablet administration in 2 trials where this was assessed.

All pharmacokinetic and clinical effectiveness and safety trials in pediatric subjects using the suspension formulation were conducted in the fed state. No data are available on the absorption kinetics of the suspension formulation when administered to fasted pediatric subjects.

Lack of Bioequivalence : Oral suspension was not bioequivalent to tablets when tested in healthy adults. The tablet and oral suspension formulations are NOT substitutable on a milligram-per-milligram basis. The area under the curve for the suspension averaged 91% of that for the tablet, and the peak plasma concentration for the suspension averaged 71% of the peak plasma concentration of the tablets. Therefore, the safety and effectiveness of both the tablet and oral suspension formulations were established in separate clinical trials.

Distribution

Cefuroxime is distributed throughout the extracellular fluids. Approximately 50% of serum cefuroxime is bound to protein.

Metabolism

The axetil moiety is metabolized to acetaldehyde and acetic acid.

Excretion

Cefuroxime is excreted unchanged in the urine; in adults, approximately 50% of the administered dose is recovered in the urine within 12 hours. The pharmacokinetics of cefuroxime in pediatric subjects have not been studied. Until further data are available, the renal elimination of cefuroxime axetil established in adults should not be extrapolated to pediatric subjects.

Specific Populations

Patients with Renal Impairment: In a trial of 28 adults with normal renal function or severe renal impairment (creatinine clearance <30 mL/min), the elimination half-life was prolonged in relation to severity of renal impairment. Prolongation of the dosage interval is recommended in adult patients with creatinine clearance <30 mL/min [see Dosage and Administration ( 2.5)].

Geriatric Patients : In a trial of 20 elderly subjects (mean age = 83.9 years) having a mean creatinine clearance of 34.9 mL/min, the mean serum elimination half-life was prolonged to 3.5 hours; however, despite the lower elimination of cefuroxime in geriatric patients, dosage adjustment based on age is not necessary [see Use in Specific Populations ( 8.5)].

Drug Interaction Studies

Concomitant administration of probenecid with cefuroxime axetil tablets increases the cefuroxime area under the serum concentration versus time curve and maximum serum concentration by 50% and 21%, respectively. [see Drug Interactins( 7.2)].

12.4 Microbiology

Mechanism of Action

Cefuroxime axetil is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Cefuroxime axetil has activity in the presence of some β-lactamases, both penicillinases and cephalosporinases, of gram-negative and gram-positive bacteria.

Resistance

Resistance to cefuroxime axetil is primarily through hydrolysis by β-lactamase, alteration of penicillin-binding proteins (PBPs), decreased permeability, and the presence of bacterial efflux pumps.

Susceptibility to cefuroxime axetil will vary with geography and time; local susceptibility data should be consulted, if available. Beta-lactamase negative, ampicillin-resistant (BLNAR) isolates of H. influenzae should be considered resistant to cefuroxime axetil.

Antimicrobial Activity

Cefuroxime axetil has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1)]:

Aerobic Bacteria:

Gram-positive bacteria
• Staphylococcus aureus (methicillin-susceptible isolates only)
• Streptococcus pneumoniae
• Streptococcus pyogenes

Gram-negative bacteria
• Escherichia colia
• Klebsiella pneumoniaea
• Haemophilus influenzae
• Haemophilus parainfluenzae
• Moraxella catarrhalis
• Neisseria gonorrhoeae
a Most extended spectrum β-lactamase (ESBL)-producing and carbapenemase-producing isolates are resistant to cefuroxime axetil.

Spirochetes
• Borrelia burgdorferi
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefuroxime against isolates of similar genus or organism group. However, the efficacy of cefuroxime axetil in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.

Aerobic Bacteria:

Gram-positive bacteria
• Staphylococcus epidermidis (methicillin-susceptible isolates only)
• Staphylococcus saprophyticus (methicillin-susceptible isolates only)
• Streptococcus agalactiae
Gram-negative bacteria
• Morganella morganii
• Proteus inconstans
• Proteus mirabilis
• Providencia rettgeri
Anaerobic Bacteria :
Gram-positive bacteria
• Peptococcus niger

Susceptibility Testing
For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Although lifetime studies in animals have not been performed to evaluate carcinogenic potential, no mutagenic activity was found for cefuroxime axetil in a battery of bacterial mutation tests. Positive results were obtained in an in vitro chromosome aberration assay; however, negative results were found in an in vivo micronucleus test at doses up to 1.5 g/kg. Fertility studies in rats (males dosed for 70 days prior to and through mating; females dosed 21 days prior to mating through lactation) at doses up to 1,000 mg/kg/day (9 times the MRHD based on body surface area) have revealed no adverse effects on fertility.

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