Cefuroxime Axetil

Cefuroxime axetil tablets are indicated for the treatment of adult patients and pediatric patients (13 years and older) with mild-to-moderate pharyngitis/tonsillitis caused by susceptible strains of Streptococcus pyogenes.

Limitations of Use

• The efficacy of cefuroxime axetil tablets in the prevention of rheumatic fever was not established in clinical trials.
• The efficacy of cefuroxime axetil tablets in the treatment of penicillin-resistant strains of Streptococcus pyogenes has not been demonstrated in clinical trials.

Cefuroxime axetil tablets are indicated for the treatment of pediatric patients (who can swallow tablets whole) with acute bacterial otitis media caused by susceptible strains of Streptococcus pneumoniae, Haemophilus influenzae (including β-lactamase–producing strains), Moraxella catarrhalis (including β-lactamase–producing strains), or Streptococcus pyogenes.

Cefuroxime axetil tablets are indicated for the treatment of adult and pediatric patients (13 years and older) with mild-to-moderate acute bacterial maxillary sinusitis caused by susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae (non-β-lactamase–producing strains only).

Limitations of Use

The effectiveness of cefuroxime axetil tablets for sinus infections caused by β-lactamase–producing Haemophilus influenzae or Moraxella catarrhalis in patients with acute bacterial maxillary sinusitis was not established due to insufficient numbers of these isolates in the clinical trials [see Clinical Studies (14.1)].

Cefuroxime axetil tablets are indicated for the treatment of adult patients and pediatric patients (aged 13 and older) with mild-to-moderate acute bacterial exacerbations of chronic bronchitis caused by susceptible strains of  Streptococcus pneumoniae, Haemophilus influenzae (β-lactamase–negative strains), or Haemophilus parainfluenzae (β-lactamase–negative strains).

Cefuroxime axetil tablets are indicated for the treatment of adult patients and pediatric patients (aged 13 and older) with uncomplicated skin and skin-structure infections caused by susceptible strains of Staphylococcus aureus (including β-lactamase–producing strains) or Streptococcus pyogenes.

Cefuroxime axetil tablets are indicated for the treatment of adult patients and pediatric patients (aged 13 and older) with uncomplicated urinary tract infections caused by susceptible strains of Escherichia coli or Klebsiella pneumoniae.

Cefuroxime axetil tablets are indicated for the treatment of adult patients and pediatric patients (aged 13 and older) with uncomplicated gonorrhea, urethral and endocervical, caused by penicillinase-producing and non-penicillinase–producing susceptible strains of Neisseria gonorrhoeae and uncomplicated gonorrhea, rectal, in females, caused by non-penicillinase–producing susceptible strains of Neisseria gonorrhoeae.

Cefuroxime axetil tablets are indicated for the treatment of adult patients and pediatric patients (aged 13 and older) with early Lyme disease (erythema migrans) caused by susceptible strains of Borrelia burgdorferi.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefuroxime axetil tablets and other antibacterial drugs, cefuroxime axetil tablets should be used only to treat or prevent infections that are proven or strongly 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.

• Cefuroxime axetil tablets and cefuroxime axetil for oral suspension are not bioequivalent and are therefore not substitutable on a milligram-per-milligram basis [see Clinical Pharmacology (12.3)] .
• Administer cefuroxime axetil tablets as described in the appropriate dosage guidelines [see Dosage and Administration (2.2)].
• Administer cefuroxime axetil tablets with or without food.
• Pediatric patients (aged 13 years and older) who cannot swallow the cefuroxime axetil tablets whole should receive cefuroxime axetil for oral suspension because the tablet has a strong, persistent bitter taste when crushed [see Dosage and Administration (2.2)].

Administer cefuroxime axetil tablets as described in the dosage guidelines table below with or without food.

Table 1. Adult Patients and Pediatric Patients Dosage Guidelines for Cefuroxime Axetil Tablets

^a    The safety and effectiveness of cefuroxime axetil tablets administered for less than 10 days in patients with acute exacerbations of chronic bronchitis have not been established.

^b    When crushed, the tablet has a strong, persistent bitter taste. Therefore, patients who cannot swallow the tablet whole should receive the oral suspension.

A dosage interval adjustment is required for patients whose creatinine clearance is <30 mL/min, as listed in Table 4 below, because cefuroxime is eliminated primarily by the kidney [see Clinical Pharmacology (12.3)].

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on β-lactam antibacterials. These reactions are more likely to occur in individuals with a history of β-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Cefuroxime axetil is contraindicated in patients with a known hypersensitivity to cefuroxime axetil or other β-lactam antibacterial drugs [see Contraindications (4)].  Before initiating therapy with cefuroxime axetil, inquire about previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, discontinue cefuroxime axetil and institute appropriate therapy.

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefuroxime axetil, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy.

Prescribing cefuroxime axetil either in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

A false-positive result for glucose in the urine may occur with copper reduction tests, and a false-negative result for blood/plasma glucose may occur with ferricyanide tests in subjects receiving cefuroxime axetil [see Drug Interactions (7.4)].

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

Tablets

Multiple-Dose Dosing Regimens with 7 to 10 Days’ Duration: In multiple-dose clinical trials, 912 subjects were treated with cefuroxime axetil (125 to 500 mg twice daily). It is noted that 125 mg twice daily is not an approved dosage. Twenty (2.2%) subjects discontinued medication due to adverse reactions. Seventeen (85%) of the 20 subjects who discontinued therapy did so because of gastrointestinal disturbances, including diarrhea, nausea, vomiting, and abdominal pain. The percentage of subjects treated with cefuroxime axetil who discontinued study drug because of adverse reactions was similar at daily doses of 1,000, 500, and 250 mg (2.3%, 2.1%, and 2.2%, respectively). However, the incidence of gastrointestinal adverse reactions increased with the higher recommended doses.

The adverse reactions in Table 5 are for subjects (n = 912) treated with cefuroxime axetil in multiple-dose clinical trials.

The following adverse reactions occurred in less than 1% but greater than 0.1% of subjects   (n = 912) treated with cefuroxime axetil in multiple-dose clinical trials.

    Immune System Disorders: Hives, swollen tongue.

    Metabolism and Nutrition Disorders: Anorexia.

    Nervous System Disorders: Headache.

    Cardiac Disorders: Chest pain.

    Respiratory Disorders: Shortness of breath.

    Gastrointestinal Disorders: Abdominal pain, abdominal cramps, flatulence, indigestion, mouth ulcers.

    Skin and Subcutaneous Tissue Disorders: Rash, itch.

    Renal and Urinary Disorders: Dysuria.

    Reproductive System and Breast Disorders: Vaginitis, vulvar itch.

    General Disorders and Administration Site Conditions: Chills, sleepiness, thirst.

    Investigations: Positive Coombs’ test.

Early Lyme Disease with 20-Day Regimen: Two multicenter trials assessed cefuroxime axetil 500 mg twice daily for 20 days. The most common drug-related adverse experiences were diarrhea (10.6%), Jarisch-Herxheimer reaction (5.6%), and vaginitis (5.4%). Other adverse experiences occurred with frequencies comparable to those reported with 7 to 10 days’ dosing.

Single-Dose Regimen for Uncomplicated Gonorrhea: In clinical trials using a single 1,000 mg dose of cefuroxime axetil, 1,061 subjects were treated for uncomplicated gonorrhea.

The adverse reactions in Table 6 were for subjects treated with a single dose of 1,000 mg cefuroxime axetil in U.S. clinical trials.

The following adverse reactions occurred in less than 1% but greater than 0.1% of subjects (n = 1,061) treated with a single dose of cefuroxime axetil 1,000 mg for uncomplicated gonorrhea in U.S. clinical trials.

    Infections and Infestations: Vaginal candidiasis.

    Nervous System Disorders: Headache, dizziness, somnolence.

    Cardiac Disorders: Tightness/pain in chest, tachycardia.

    Gastrointestinal Disorders: Abdominal pain, dyspepsia.

    Skin and Subcutaneous Tissue Disorders: Erythema, rash, pruritus.

    Musculoskeletal and Connective Tissue Disorders: Muscle cramps, muscle stiffness, muscle spasm of neck, lockjaw-type reaction.

    Renal and Urinary Disorders: Bleeding/pain in urethra, kidney pain.

    Reproductive System and Breast Disorders: Vaginal itch, vaginal discharge.

The following adverse reactions have been identified during post-approval use of cefuroxime axetil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders

Hemolytic anemia, leukopenia, pancytopenia, thrombocytopenia.

Gastrointestinal Disorders

Pseudomembranous colitis [see Warnings and Precautions (5.2)].

Hepatobiliary Disorders

Hepatic impairment including hepatitis and cholestasis, jaundice.

Immune System Disorders

Anaphylaxis, serum sickness-like reaction.

Investigations

Increased prothrombin time.

Nervous System Disorders

Seizure, encephalopathy.

Renal and Urinary Disorders

Renal dysfunction.

Skin and Subcutaneous Tissue Disorders

Angioedema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.

Cefuroxime axetil may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives. Counsel patients to consider alternate supplementary (non-hormonal) contraceptive measures during treatment.

Drugs that reduce gastric acidity may result in a lower bioavailability of cefuroxime axetil compared with administration in the fasting state. Administration of drugs that reduce gastric acidity may negate the food effect of increased absorption of cefuroxime axetil when administered in the postprandial state. Administer cefuroxime axetil at least 1 hour before or 2 hours after administration of short-acting antacids. Histamine-2 (H₂) antagonists and proton pump inhibitors should be avoided.

Concomitant administration of probenecid with cefuroxime axetil tablets increases serum concentrations of cefuroxime [see Clinical Pharmacology (12.3)]. Coadministration of probenecid with cefuroxime axetil is not recommended.

A false-positive reaction for glucose in the urine may occur with copper reduction tests (e.g., Benedict's or Fehling's solution), but not with enzyme-based tests for glycosuria. As a false-negative result may occur in the ferricyanide test, it is recommended that either the glucose oxidase or hexokinase method be used to determine blood/plasma glucose levels in patients receiving cefuroxime axetil. The presence of cefuroxime does not interfere with the assay of serum and urine creatinine by the alkaline picrate method.

Teratogenic Effects

Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, cefuroxime axetil should be used during pregnancy only if clearly needed.

Reproduction studies have been performed in mice at doses up to 3,200 mg/kg/day (14 times the recommended maximum human dose based on body surface area) and in rats at doses up to 1,000 mg/kg/day (9 times the recommended maximum human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to cefuroxime axetil.

Because cefuroxime is excreted in human milk, caution should be exercised when cefuroxime axetil is administered to a nursing woman.

The safety and effectiveness of cefuroxime axetil have been established for pediatric patients aged 3 months to 12 years for acute bacterial maxillary sinusitis based upon its approval in adults. Use of cefuroxime axetil in pediatric patients is supported by pharmacokinetic and safety data in adults and pediatric patients, and by clinical and microbiological data from adequate and well-controlled trials of the treatment of acute bacterial maxillary sinusitis in adults and of acute otitis media with effusion in pediatric patients. It is also supported by postmarketing adverse events surveillance [see Indications and Usage (1), Dosage and Administration (2), Adverse Reactions (6), Clinical Pharmacology (12.3)].

Of the total number of subjects who received cefuroxime axetil in 20 clinical trials, 375 were aged 65 and older while 151 were aged 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger adult subjects. Reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

Cefuroxime is substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Reducing the dosage of cefuroxime axetil is recommended for adult patients with severe renal impairment (creatinine clearance <30 mL/min) [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

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

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.

Food Effect: 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.

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 

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 Interactions

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.

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.

Mechanism of 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.

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)]:

• Gram-positive bacteria

Staphylococcus aureus (methicillin-susceptible isolates only)

Streptococcus pneumoniae

Streptococcus pyogenes

• Gram-negative bacteria

Escherichia coli^a

Klebsiella pneumoniae^a

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 microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefuroxime axetil of 1 mcg/mL. However, the efficacy of cefuroxime axetil in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

• 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

Peptococcus niger

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility tests for antimicrobial drug products used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

Dilution Techniques: Quantitative methods are used to determine antimicrobial MICs. These MICs provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth or agar).^1,2 The MIC values should be interpreted according to criteria provided in Table 10.^2,3

Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.⁴ This procedure uses paper disks impregnated with 30 mcg cefuroxime axetil to test the susceptibility of microorganisms to cefuroxime axetil. The disk diffusion interpretive criteria are provided in Table 10.³

Susceptibility of staphylococci to cefuroxime may be deduced from testing only penicillin and either cefoxitin or oxacillin.

Susceptibility of Streptococcus pyogenes may be deduced from testing penicillin.³

A report of “Susceptible” indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. 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 the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control: Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test.^1,2,4 The QC ranges for MIC and disk diffusion testing using the 30 mcg disk are provided in Table 11.³

           ATCC = American Type Culture Collection.

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. Reproduction studies in rats at doses up to 1,000 mg/kg/day (9 times the recommended maximum human dose based on body surface area) have revealed no impairment of fertility.

One adequate and well-controlled trial was performed in subjects with acute bacterial maxillary sinusitis. In this trial, each subject had a maxillary sinus aspirate collected by sinus puncture before treatment was initiated for presumptive acute bacterial sinusitis. All subjects had radiographic and clinical evidence of acute maxillary sinusitis. In the trial, the clinical effectiveness of cefuroxime axetil in treating acute maxillary sinusitis was comparable to an oral antimicrobial agent containing a specific β-lactamase inhibitor. However, microbiology data demonstrated cefuroxime axetil to be effective in treating acute bacterial maxillary sinusitis due only to Streptococcus pneumoniae or non-β-lactamase–producing Haemophilus influenzae. Insufficient numbers of β-lactamase–producing Haemophilus influenzae and Moraxella catarrhalis isolates were obtained in this trial to adequately evaluate the effectiveness of cefuroxime axetil in treating acute bacterial maxillary sinusitis due to these 2 organisms.

This trial randomized 317 adult subjects, 132 subjects in the U.S. and 185 subjects in South America. Table 12 shows the results of the intent-to-treat analysis.

In this trial and in a supporting maxillary puncture trial, 15 evaluable subjects had non-β-lactamase–producing Haemophilus influenzae as the identified pathogen. Of these, 67% (10/15) had this pathogen eradicated. Eighteen (18) evaluable subjects had Streptococcus pneumoniae as the identified pathogen. Of these, 83% (15/18) had this pathogen eradicated.

Two adequate and well-controlled trials were performed in subjects with early Lyme disease. All subjects presented with physician-documented erythema migrans, with or without systemic manifestations of infection. Subjects were assessed at 1 month posttreatment for success in treating early Lyme disease (Part I) and at 1 year posttreatment for success in preventing the progression to the sequelae of late Lyme disease (Part II).

A total of 355 adult subjects (181 treated with cefuroxime axetil and 174 treated with doxycycline) were randomized in the 2 trials, with diagnosis of early Lyme disease confirmed in 79% (281/355). The clinical diagnosis of early Lyme disease in these subjects was validated by 1) blinded expert reading of photographs, when available, of the pretreatment erythema migrans skin lesion, and 2) serologic confirmation (using enzyme-linked immunosorbent assay [ELISA] and immunoblot assay [“Western” blot]) of the presence of antibodies specific to Borrelia burgdorferi, the etiologic agent of Lyme disease. The efficacy data in Table 14 are specific to this “validated” patient subset, while the safety data below reflect the entire patient population for the 2 trials. Clinical data for evaluable subjects in the “validated” patient subset are shown in Table 13.

Cefuroxime axetil and doxycycline were effective in prevention of the development of sequelae of late Lyme disease.

While the incidence of drug-related gastrointestinal adverse reactions was similar in the 2 treatment groups (cefuroxime axetil - 13%; doxycycline - 11%), the incidence of drug-related diarrhea was higher in the cefuroxime axetil arm versus the doxycycline arm (11% versus 3%, respectively).