Cefuroxime Axetil Tablets Cefuroxime Axetil Powder for Oral Suspension

CEFUROXIME AXETIL - cefuroxime axetil tablet, film coated 
Goldline Laboratories, Inc.

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Cefuroxime Axetil Tablets

Cefuroxime Axetil Powder for Oral Suspension

DESCRIPTION

Cefuroxime Axetil Tablets and Cefuroxime Axetil for Oral Suspension contain cefuroxime as cefuroxime axetil. Cefuroxime Axetil is a semisynthetic, broad-spectrum cephalosporin antibiotic for oral administration.

Chemically, cefuroxime axetil, the 1-(acetyloxy) ethyl ester of cefuroxime, is (RS)-1-hydroxyethyl (6R,7R)-7-[2-(2-furyl)glyoxylamido]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, 72-(Z)-(O-methyloxime),1-acetate 3-carbamate. Its molecular formula is C20H22N4O10S, and it has a molecular weight of 510.48.

Cefuroxime axetil is in the amorphous form and has the following structural formula:

Structural formula for Cefuroxime Axetil

Cefuroxime Axetil Tablets are film-coated and contain the equivalent of 250 or 500 mg of cefuroxime as cefuroxime axetil. Cefuroxime Axetil tablets contain the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, hydrogenated vegetable oil, hypromellose, methylparaben, microcrystalline cellulose, propylene glycol, propylparaben, sodium benzoate, sodium lauryl sulfate, and titanium dioxide.

CLINICAL PHARMACOLOGY

Absorption and Metabolism: 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. Cefuroxime is subsequently distributed throughout the extracellular fluids. The axetil moiety is metabolized to acetaldehyde and acetic acid.

Pharmacokinetics:

Approximately 50% of serum cefuroxime is bound to protein. Serum pharmacokinetic parameters for Cefuroxime Axetil Tablets and Cefuroxime Axetil for Oral Suspension are shown in Tables 1 and 2.

Table 1. Postprandial Pharmacokinetics of Cefuroxime Administered as Cefuroxime Axetil Tablets to Adults*

Dose

(Cefuroxime

Equivalent)

Peak Plasma

Concentration

(mcg/mL)

Time of Peak

Plasma

Concentration (hr)

Mean

Elimination

Half-Life (hr)

AUC

(mcg-hr mL)

125 mg

2.1

2.2

1.2

6.7
250 mg4.12.51.212.9
500 mg7.03.01.227.4
1,000 mg13.62.51.350.0

*Mean values of 12 healthy adult volunteers.

Drug administered immediately after a meal.

Table 2. Postprandial Pharmacokinetics of Cefuroxime Administered as Cefuroxime Axetil for Oral Suspension to Pediatric Patients*

Dose

(Cefuroxime

Equivalent)
n

Peak Plasma

Concentration

(mcg/mL)

Time of Peak

Plasma

Concentration (hr)

Mean

Elimination

Half-Life (hr)

AUC

(mcg-hr mL)

10 mg/kg

8

3.3

3.6

1.4

12.4
15 mg/kg125.12.71.922.5
20 mg/kg87.03.11.932.8

*Mean age = 23 months.

Drug administered with milk or milk products.

Comparative Pharmacokinetic Properties: A 250 mg/5 mL-dose of Cefuroxime Axetil Suspension is bioequivalent to 2 times 125 mg/5 mL-dose of Cefuroxime Axetil Suspension when administered with food (see Table 3). Cefuroxime Axetilfor Oral Suspension was not bioequivalent to Cefuroxime Axetil Tablets when tested in healthy adults. The tablet andpowder for 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 had to be established in separate clinical trials.

Table 3. Pharmacokinetics of Cefuroxime Administered as 250 mg/5 mL or 2 x 125 mg/5 mL Cefuroxime Axetil for Oral Suspension to Adults* With Food

Dose

(Cefuroxime

Equivalent)

Peak Plasma

Concentration

(mcg/mL)

Time of Peak

Plasma

Concentration (hr)

Mean

Elimination

Half-Life (hr)

AUC

(mcg-hr mL)

250 mg/5 mL

2.23

3

1.40

8.92
2 x 125 mg/5 mL2.3731.449.75

*Mean values of 18 healthy adult volunteers.

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

All pharmacokinetic and clinical effectiveness and safety studies in pediatric patients 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 patients.

Renal 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 the urine of pediatric patients have not been studied at this time. Until further data are available, the renal pharmacokinetic properties of cefuroxime axetil established in adults should not be extrapolated to pediatric patients.

Because cefuroxime is renally excreted, the serum half-life is prolonged in patients with reduced renal function. In a study of 20 elderly patients (mean age = 83.9 years) having a mean creatinine clearance of 34.9 mL/min, the mean serum elimination half-life was 3.5 hours. Despite the lower elimination of cefuroxime in geriatric patients, dosage adjustment based on age is not necessary (see PRECAUTIONS: Geriatric Use).

Microbiology: The in vivo bactericidal activity of cefuroxime axetil is due to cefuroxime's binding to essential target proteins and the resultant inhibition of cell-wall synthesis.

Cefuroxime has bactericidal activity against a wide range of common pathogens, including many beta-lactamase-producing strains. Cefuroxime is stable to many bacterial beta-lactamases, especially plasmid-mediated enzymes that are commonly found in enterobacteriaceae.

Cefuroxime has been demonstrated to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section (see INDICATIONS AND USAGE section).

Aerobic Gram-Positive Microorganisms:

Staphylococcus aureus (including beta-lactamase-producing strains)
Streptococcus pneumoniae
Streptococcus pyogenes

Aerobic Gram-Negative Microorganisms:

Escherichia coli
Haemophilus influenzae (including beta-lactamase-producing strains)
Haemophilus parainfluenzae
Klebsiella pneumoniae
Moraxella catarrhalis (including beta-lactamase-producing strains)
Neisseria gonorrhoeae (including beta-lactamase-producing strains)

Spirochetes:

Borrelia burgdorferi

Cefuroxime has been shown to be active in vitro against most strains of the following microorganisms; however, the clinical significance of these findings is unknown.

Cefuroxime exhibits in vitro minimum inhibitory concentrations (MICs) of 4.0 mcg/mL or less (systemic susceptible breakpoint) against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of cefuroxime in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.

Aerobic Gram-Positive Microorganisms:

Staphylococcus epidermidis
Staphylococcus saprophyticus
Streptococcus agalactiae
NOTE: Certain strains of enterococci, e.g., Enterococcus faecalis (formerly Streptococcus faecalis), are resistant to cefuroxime. Methicillin-resistant staphylococci are resistant to cefuroxime.

Aerobic Gram-Negative Microorganisms:

Morganella morganii
Proteus inconstans
Proteus mirabilis
Providencia rettgeri
NOTE: Pseudomonas spp., Campylobacter spp., Acinetobacter calcoaceticus, and most strains of Serratia spp. and Proteus vulgaris are resistant to most first- and second-generation cephalosporins. Some strains of Morganella morganii,Enterobacter cloacae, and Citrobacter spp. have been shown by in vitro tests to be resistant to cefuroxime and other cephalosporins.

Anaerobic Microorganisms:

Peptococcus niger
NOTE: Most strains of Clostridium difficile and Bacteroides fragilis are resistant to cefuroxime.

Susceptibility Tests: Dilution Techniques: Quantitative methods that are used to determine MICs provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standardized dilution method1 (broth, agar, or microdilution) or equivalent with cefuroxime powder. The MIC values obtained should be interpreted according to the following criteria:

MIC (mcg/mL)Interpretation
≤ 4 (S) Susceptible
8-16 (I) Intermediate
≥ 32 (R) Resistant

A report of "Susceptible" indicates that the pathogen, if in the blood, is likely to be inhibited by usually achievable concentrations of the antimicrobial compound in blood. A report of “Intermediate” indicates that inhibitory concentrations of the antibiotic may be achieved if high dosage is used or if the infection is confined to tissues or fluids in which high antibiotic concentrations are attained. 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 usually achievable concentrations of the antimicrobial compound in the blood are unlikely to be inhibitory and that other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms. Standard cefuroxime powder should give the following MIC values:

MicroorganismMIC (mcg/mL)
Escherichia coli ATCC 25922 2-8
Staphylococcus aureus ATCC 29213 0.5-2

Diffusion Techniques: Quantitative methods that require measurement of zone diameters provide estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 that has been recommended (for use with disks) to test the susceptibility of microorganisms to cefuroxime uses the 30-mcg cefuroxime disk. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for cefuroxime.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-mcg cefuroxime disk should be interpreted according to the following criteria:

Zone Diameter (mm)Interpretation
≥ 23 (S) Susceptible
15-22 (I) Intermediate
≤14 (R) Resistant

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

As with standard dilution techniques, diffusion methods require the use of laboratory control microorganisms. The 30-mcg cefuroxime disk provides the following zone diameters in these laboratory test quality control strains:

MicroorganismZone Diameter (mm)
Escherichia coli ATCC 25922 20-26
Staphylococcus aureus ATCC 25923 27-35

INDICATIONS AND USAGE

NOTE: CEFUROXIME AXETIL TABLETS AND CEFUROXIME AXETIL FOR ORAL SUSPENSION ARE NOT BIOEQUIVALENTAND ARE NOT SUBSTITUTABLE ON A MILLIGRAM-PER-MILLIGRAM BASIS (SEE CLINICAL PHARMACOLOGY).

Cefuroxime Axetil Tablets: Cefuroxime Axetil Tablets are indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the designated microorganisms in the conditions listed below:

1. Pharyngitis/Tonsillitis caused by Streptococcus pyogenes.

NOTE: The usual drug of choice in the treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever, is penicillin given by the intramuscular route. Cefuroxime Axetil Tablets are generally effective in the eradication of streptococci from the nasopharynx; however, substantial data establishing the efficacy of cefuroxime in the subsequent prevention of rheumatic fever are not available. Please also note that in all clinical trials, all isolates had to be sensitive to both penicillin and cefuroxime. There are no data from adequate and well-controlled trials to demonstrate the effectiveness of cefuroxime in the treatment of penicillin-resistant strains of Streptococcus pyogenes.

2. Acute Bacterial Otitis Media caused by Streptococcus pneumoniae, Haemophilus influenzae (including beta-lactamase-producing strains), Moraxella catarrhalis (including beta-lactamase-producing strains), or Streptococcus pyogenes.

3. Acute Bacterial Maxillary Sinusitis caused by Streptococcus pneumoniae or Haemophilus influenzae (non-beta-lactamase-producing strains only). (See CLINICAL STUDIES section.)

NOTE: In view of the insufficient numbers of isolates of beta-lactamase-producing strains of Haemophilus influenzae and Moraxella catarrhalis that were obtained from clinical trials with Cefuroxime Axetil Tablets for patients with acute bacterial maxillary sinusitis, it was not possible to adequately evaluate the effectiveness of Cefuroxime Axetil Tablets for sinus infections known, suspected, or considered potentially to be caused by beta-lactamase-producing Haemophilus influenzae or Moraxella catarrhalis.

4. Acute Bacterial Exacerbations of Chronic Bronchitis and Secondary Bacterial Infections of Acute Bronchitis caused by Streptococcus pneumoniae, Haemophilus influenzae (beta-lactamase negative strains), or Haemophilus parainfluenzae (beta-lactamase negative strains). (See DOSAGE AND ADMINISTRATION section and CLINICAL STUDIES section.)

5.Uncomplicated Skin and Skin-Structure Infections caused by Staphylococcus aureus (including beta-lactamase-producing strains) or Streptococcus pyogenes.

6. Uncomplicated Urinary Tract Infections caused by Escherichia coli or Klebsiella pneumoniae.

7. Uncomplicated Gonorrhea, urethral and endocervical, caused by penicillinase-producing and non-penicillinase-producing strains of Neisseria gonorrhoeae and uncomplicated gonorrhea, rectal, in females, caused by non-penicillinase-producing strains of Neisseria gonorrhoeae.

8. Early Lyme Disease (erythema migrans) caused by Borrelia burgdorferi.

Cefuroxime Axetil for Oral Suspension: Cefuroxime Axetil for Oral Suspension is indicated for the treatment of pediatric patients 3 months to 12 years of age with mild to moderate infections caused by susceptible strains of the designated microorganisms in the conditions listed below. The safety and effectiveness of Cefuroxime Axetil for Oral Suspension in the treatment of infections other than those specifically listed below have not been established either by adequate and well-controlled trials or by pharmacokinetic data with which to determine an effective and safe dosing regimen.

1. Pharyngitis/Tonsillitis caused by Streptococcus pyogenes.

NOTE: The usual drug of choice in the treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever, is penicillin given by the intramuscular route. Cefuroxime Axetil for Oral Suspension is generally effective in the eradication of streptococci from the nasopharynx; however, substantial data establishing the efficacy of cefuroxime in the subsequent prevention of rheumatic fever are not available. Please also note that in all clinical trials, all isolates had to be sensitive to both penicillin and cefuroxime. There are no data from adequate and well-controlled trials to demonstrate the effectiveness of cefuroxime in the treatment of penicillin-resistant strains of Streptococcuspyogenes.

2. Acute Bacterial Otitis Media caused by Streptococcus pneumoniae, Haemophilus influenzae (including beta-lactamase-producing strains), Moraxella catarrhalis (including beta-lactamase-producing strains), or Streptococcus pyogenes.

3. Impetigo caused by Staphylococcus aureus (including beta-lactamase-producing strains) or Streptococcus pyogenes.

Culture and susceptibility testing should be performed when appropriate to determine susceptibility of the causative microorganism(s) to cefuroxime. Therapy may be started while awaiting the results of this testing. Antimicrobial therapy should be appropriately adjusted according to the results of such testing.

CONTRAINDICATIONS

Cefuroxime Axetil products are contraindicated in patients with known allergy to the cephalosporin group of antibiotics.

WARNINGS

CEFUROXIME AXETIL TABLETS AND CEFUROXIME AXETIL FOR ORAL SUSPENSION ARE NOT BIOEQUIVALENT ANDARE THEREFORE NOT SUBSTITUTABLE ON A MILLIGRAM-PER-MILLIGRAM BASIS (SEE CLINICAL PHARMACOLOGY).

BEFORE THERAPY WITH CEFUROXIME AXETIL PRODUCTS IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADETO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFUROXIMEAXETIL PRODUCTS, OTHER CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVENTO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-HYPERSENSITIVITYAMONG BETA-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OFPATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF A CLINICALLY SIGNIFICANT ALLERGIC REACTION TOCEFUROXIME AXETIL PRODUCTS OCCURS, DISCONTINUE THE DRUG AND INSTITUTE APPROPRIATE THERAPY.SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHEREMERGENCY MEASURES, INCLUDING OXYGEN, INTRAVENOUS FLUIDS, INTRAVENOUS ANTIHISTAMINES, CORTICOSTEROIDS,PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including cefuroxime, and mayrange from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present withdiarrhea 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 usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug effective against Clostridium difficile.

PRECAUTIONS

General:

As with other broad-spectrum antibiotics, prolonged administration of cefuroxime axetil may result in overgrowth of nonsusceptible microorganisms. If superinfection occurs during therapy, appropriate measures should be taken.

Cephalosporins, including cefuroxime axetil, should be given with caution to patients receiving concurrent treatment with potent diuretics because these diuretics are suspected of adversely affecting renal function.

Cefuroxime axetil, as with other broad-spectrum antibiotics, should be prescribed with caution in individuals with a history of colitis. The safety and effectiveness of cefuroxime axetil have not been established in patients with gastrointestinal malabsorption. Patients with gastrointestinal malabsorption were excluded from participating in clinical trials of cefuroxime axetil.

Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous Vitamin K administered as indicted.

Information for Patients/Caregivers (Pediatric):

1. During clinical trials, the tablet was tolerated by pediatric patients old enough to swallow the cefuroxime axetil tablet whole. The crushed tablet has a strong, persistent, bitter taste and should not be administered to pediatric patients in this manner. Pediatric patients who cannot swallow the tablet whole should receive the oral suspension.

2. Discontinuation of therapy due to taste and/or problems of administering this drug occurred in 1.4% of pediatric patients given the oral suspension. Complaints about taste (which may impair compliance) occurred in 5% of pediatric patients.

Drug/Laboratory Test Interactions:

A false-positive reaction for glucose in the urine may occur with copper reduction tests (Benedict's or Fehling's solution or with CLINITEST® tablets), but not with enzyme-based tests for glycosuria (e.g., CLINISTIX®). 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.

Drug/Drug Interactions:

Concomitant administration of probenecid with cefuroxime axetil tablets increases the area under the serum concentration versus time curve by 50%. The peak serum cefuroxime concentration after a 1.5-g single dose is greater when taken with 1 g of probenecid (mean = 14.8 mcg/mL) than without probenecid (mean = 12.2 mcg/mL).

Drugs that reduce gastric acidity may result in a lower bioavailability of Cefuroxime Axetil compared with that of fasting state and tend to cancel the effect of postprandial absorption.

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. Reproduction studies in rats at doses up to 1,000 mg/kg/day (9 times the recommended maximum human dose based on mg/m2) have revealed no impairment of fertility.

Pregnancy:

Teratogenic Effects:

Pregnancy Category B. 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 mg/m2) and in rats at doses up to 1,000 mg/kg/day (9 times the recommended maximum human dose based on mg/m2) and have revealed no evidence of impaired fertility or harm to the fetus due to cefuroxime axetil. There are, however, 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:

Cefuroxime axetil has not been studied for use during labor and delivery.

Nursing Mothers:

Because cefuroxime is excreted in human milk, consideration should be given to discontinuing nursing temporarily during treatment with cefuroxime axetil.

Pediatric Use:

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 studies 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 post-marketing adverse events surveillance (see CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE, ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION, and CLINICAL STUDIES).

Geriatric Use:

Of the total number of subjects who received cefuroxime axetil in 20 clinical studies of cefuroxime axetil, 375 were 65 and over while 151 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger adult subjects. The geriatric patients reported somewhat fewer gastrointestinal events and less frequent vaginal candidiasis compared with patients aged 12 to 64 years old; however, no clinically significant differences were reported between the elderly and younger adult patients. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients.

ADVERSE REACTIONS

CEFUROXIME AXETIL TABLETS IN CLINICAL TRIALS: Multiple-Dose Dosing Regimens: 7 to 10 Days Dosing: Using multiple doses of cefuroxime axetil tablets, 912 patients were treated with cefuroxime axetil (125 to 500 mg twice daily). There were no deaths or permanent disabilities thought related to drug toxicity. Twenty (2.2%) patients discontinued medication due to adverse events thought by the investigators to be possibly, probably, or almost certainly related to drug toxicity. Seventeen (85%) of the 20 patients who discontinued therapy did so because of gastrointestinal disturbances, including diarrhea, nausea, vomiting, and abdominal pain. The percentage of cefuroxime axetil tablet-treated patients who discontinued study drug because of adverse events was very 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 events increased with the higher recommended doses.

The following adverse events were thought by the investigators to be possibly, probably, or almost certainly related to cefuroxime axetil tablets in multiple-dose clinical trials (n = 912 cefuroxime axetil-treated patients).

Table 4. Adverse Reactions — Cefuroxime Axetil Tablets Multiple-Dose Dosing Regimens — Clinical Trials

Incidence ≥1%

Diarrhea/loose stools 3.7%
Nausea/vomiting 3.0%
Transient elevation in AST 2.0%
Transient elevation in ALT 1.6%
Eosinophilia 1.1%
Transient elevation in LDH 1.0%

Incidence <1% but >0.1%

Abdominal pain
Abdominal cramps
Flatulence
Indigestion
Headache
Vaginitis
Vulvar itch
Rash
Hives
Itch
Dysuria
Chills
Chest Pain
Shortness of breath
Mouth ulcers
Swollen tongue
Sleepiness
Thirst
Anorexia
Positive Coombs test

5-Day Experience (see CLINICAL STUDIES section): In clinical trials using Cefuroxime Axetil in a dose of 250 mg twice daily in the treatment of secondary bacterial infections of acute bronchitis, 399 patients were treated for 5 days and 402 patients were treated for 10 days. No difference in the occurrence of adverse events was found between the 2 regimens.

In Clinical Trials for Early Lyme Disease With 20 Days Dosing: Two multicenter trials assessed cefuroxime axetil tablets 500 mg twice a day for 20 days. The most common drug-related adverse experiences were diarrhea (10.6% of patients), 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 dose of cefuroxime axetil tablets, 1,061 patients were treated with the recommended dosage of cefuroxime axetil (1,000 mg) for the treatment of uncomplicated gonorrhea. There were no deaths or permanent disabilities thought related to drug toxicity in these studies.

The following adverse events were thought by the investigators to be possibly, probably, or almost certainly related to cefuroxime axetil in 1,000-mg single-dose clinical trials of cefuroxime axetil tablets in the treatment of uncomplicated gonorrhea conducted in the US.

Table 5. Adverse Reactions—Cefuroxime Axetil Tablets 1-g Single-Dose Regimen for Uncomplicated Gonorrhea—Clinical Trials

Incidence ≥1%

Nausea/vomiting 6.8%
Diarrhea 4.2%

Incidence <1% but >0.1%

Abdominal pain
Dyspepsia
Erythema
Rash
Pruritus
Vaginal candidiasis
Vaginal itch
Vaginal discharge
Headache
Dizziness
Somnolence
Muscle cramps
Muscle stiffness
Muscle spasm of neck
Tightness/pain in chest
Bleeding/pain in urethra
Kidney pain
Tachycardia
Lockjaw-type reaction

CEFUROXIME AXETIL FOR ORAL SUSPENSION IN CLINICAL TRIALS

In clinical trials using multiple doses of cefuroxime axetil powder for oral suspension, pediatric patients (96.7% of whom were younger than 12 years of age) were treated with the recommended dosages of cefuroxime axetil (20 to 30 mg/kg/day divided twice a day up to a maximum dose of 500 or 1,000 mg/day, respectively). There were no deaths or permanent disabilities in any of the patients in these studies. Eleven US patients (1.2%) 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 or vomiting. During clinical trials, discontinuation of therapy due to the taste and/or problems with administering this drug occurred in 13 (1.4%) pediatric patients enrolled at centers in the United States.

The following adverse events were thought by the investigators to be possibly, probably, or almost certainly related to cefuroxime axetil for oral suspension in multiple-dose clinical trials (n = 931 cefuroxime axetil-treated US patients).

Table 6. Adverse Reactions—Cefuroxime Axetil for Oral Suspension Multiple-Dose Dosing Regimens—Clinical Trials

Incidence ≥1%

Diarrhea/loose stools 8.6%
Dislike of taste 5.0%
Diaper rash 3.4%
Nausea/vomiting 2.6%

Incidence <1% but >0.1%

Abdominal pain
Flatulence
Gastrointestinal infection
Candidiasis
Vaginal irritation
Rash
Hyperactivity
Irritable behavior
Eosinophilia
Positive direct Coombs test
Elevated liver enzymes
Viral illness
Upper respiratory infection
Sinusitis
Cough
Urinary tract infection
Joint swelling
Arthralgia
Fever
Ptyalism

POSTMARKETING EXPERIENCE WITH CEFUROXIME AXETIL PRODUCTS

In addition to adverse events reported during clinical trials, the following events have been identified during clinical practice in patients treated with Cefuroxime Axetil Tablets or with Cefuroxime Axetil for Oral Suspension and were reported spontaneously. Data are generally insufficient to allow an estimate of incidence or to establish causation.

General: The following hypersensitivity reactions have been reported: anaphylaxis, angioedema, pruritus, rash, serum sickness-like reaction, urticaria.

Gastrointestinal: Pseudomembranous colitis (see WARNINGS).

Hematologic: Hemolytic anemia, leukopenia, pancytopenia, thrombocytopenia, and increased prothrombin time.

Hepatic: Hepatic impairment including hepatitis and cholestasis, jaundice.

Neurologic: Seizure.

Skin: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Urologic: Renal dysfunction.

CEPHALOSPORIN-CLASS ADVERSE REACTIONS

In addition to the adverse reactions listed above that have been observed in patients treated with cefuroxime axetil, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics: toxic nephropathy, aplastic anemia, hemorrhage, increased BUN, increased creatinine, false-positive test for urinary glucose, increased alkaline phosphatase, neutropenia, elevated bilirubin, and agranulocytosis.

Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced (see DOSAGE AND ADMINISTRATION and OVERDOSAGE). If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.

OVERDOSAGE

Overdosage of cephalosporins can cause cerebral irritation leading to convulsions. Serum levels of cefuroxime can be reduced by hemodialysis and peritoneal dialysis.

DOSAGE AND ADMINISTRATION

NOTE: CEFUROXIME AXETIL TABLETS AND CEFUROXIME AXETIL FOR ORAL SUSPENSION ARE NOT BIOEQUIVALENTAND ARE NOT SUBSTITUTABLE ON A MILLIGRAM-PER-MILLIGRAM BASIS (SEE CLINICAL PHARMACOLOGY).

Table 7. Cefuroxime Axetil Tablets (May be administered without regard to meals.)

Population/Infection

Dosage

Duration (days)
Adolescents and Adults (13 years and older)

Pharyngitis/tonsillitis
Acute bacterial maxillary sinusitis
Acute bacterial exacerbations of chronic bronchitis
Secondary bacterial infections of acute bronchitis
Uncomplicated skin and skin-structure infections
Uncomplicated urinary tract infections
Uncomplicated gonorrhea
Early Lyme disease

250 mg b.i.d.
250 mg b.i.d.
250 or 500 mg b.i.d.
250 or 500 mg b.i.d.
250 or 500 mg b.i.d.
250 mg b.i.d.
1,000 mg once

500 mg b.i.d.

10
10
10*
5-10
10
7-10
single dose

20
Pediatric Patients (who can swallow tablets whole)

Acute otitis media

Acute bacterial maxillary sinusitis

250 mg b.i.d.

250 mg b.i.d.

10

10

*The safety and effectiveness of Cefuroxime Axetil administered for less than 10 days in patients with acute exacerbations of chronic bronchitis have not been established.

Patients With Renal Failure:

The safety and efficacy of cefuroxime axetil in patients with renal failure have not been established. Since cefuroxime is renally eliminated, its half-life will be prolonged in patients with renal failure.

HOW SUPPLIED

Cefuroxime Axetil Tablets:

Cefuroxime Axetil Tablets, 250 mg of cefuroxime (as cefuroxime axetil), are white, capsule-shaped, film-coated tablets, engraved “GX ES7” on one side:

20 Tablets/Bottle NDC 0182-2689-15

60 Tablets/Bottle NDC 0182-2689-26

Cefuroxime Axetil Tablets, 500 mg of cefuroxime (as cefuroxime axetil),are white, capsule-shaped, film-coated tablets, engraved “GX EG2” on one side:

20 Tablets/Bottle NDC 0182-2690-15

60 Tablets/Bottle NDC 0182-2690-26

Store the tablets between 15° and 30°C (59° and 86°F). Replace cap securely after each opening.

Cefuroxime Axetil for Oral Suspension:

Cefuroxime Axetil for Oral Suspension is not available under the national drug code series 0182.

CLINICAL STUDIES

Cefuroxime Axetil Tablets: Acute Bacterial Maxillary Sinusitis: One adequate and well-controlled study was performed in patients with acute bacterial maxillary sinusitis. In this study each patient had a maxillary sinus aspirate collected by sinus puncture before treatment was initiated for presumptive acute bacterial sinusitis. All patients had to have radiographic and clinical evidence of acute maxillary sinusitis. As shown in the following summary of the study, the general clinical effectiveness of Cefuroxime Axetil Tablets was comparable to an oral antimicrobial agent that contained a specific beta-lactamase inhibitor in treating acute maxillary sinusitis. However, sufficient microbiology data were obtained to demonstrate the effectiveness of Cefuroxime Axetil Tablets in treating acute bacterial maxillary sinusitis due only to Streptococcus pneumoniae or non-beta-lactamase-producing Haemophilus influenzae. An insufficient number of beta-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis isolates were obtained in this trial to adequately evaluate the effectiveness of Cefuroxime Axetil Tablets in the treatment of acute bacterial maxillary sinusitis due to these 2 organisms.

This study enrolled 317 adult patients, 132 patients in the United States and 185 patients in South America. Patients were randomized in a 1:1 ratio to cefuroxime axetil 250 mg twice daily or an oral antimicrobial agent that contained a specific beta-lactamase inhibitor. An intent-to-treat analysis of the submitted clinical data yielded the following results:

Table 8. Clinical Effectiveness of Cefuroxime Axetil Tablets Compared to Beta-Lactamase Inhibitor-Containing Control Drug in the Treatment of Acute Bacterial Maxillary Sinusitis
US Patients*South American Patients
Cefuroxime Axetil (n = 49)Control (n = 43)Cefuroxime Axetil (n = 87)Control
(n = 89)
Clinical success
(cure + improvement)
65%53%77%74%
Clinical cure53%44%72%64%
Clinical improvement12%9%5%10%

* 95% Confidence interval around the success difference [-0.08, +0.32].

95% Confidence interval around the success difference [-0.10, +0.16].

In this trial and in a supporting maxillary puncture trial, 15 evaluable patients had non-beta-lactamase-producing Haemophilus influenzae as the identified pathogen. Ten (10) of these 15 patients (67%) had their pathogen (non-beta-lactamase-producing Haemophilus influenzae) eradicated. Eighteen (18) evaluable patients had Streptococcus pneumoniae as the identified pathogen. Fifteen (15) of these 18 patients (83%) had their pathogen (Streptococcus pneumoniae) eradicated.

Safety: The incidence of drug-related gastrointestinal adverse events was statistically significantly higher in the control arm (an oral antimicrobial agent that contained a specific beta-lactamase inhibitor) versus the cefuroxime axetil arm (12% versus 1%, respectively; P<.001), particularly drug-related diarrhea (8% versus 1%, respectively; P = .001).

Early Lyme Disease: Two adequate and well-controlled studies were performed in patients with early Lyme disease. In these studies all patients had to present with physician-documented erythema migrans, with or without systemic manifestations of infection. Patients were randomized in a 1:1 ratio to a 20-day course of treatment with cefuroxime axetil 500 mg twice daily or doxycycline 100 mg 3 times daily. Patients 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 patients (181 treated with cefuroxime axetil and 174 treated with doxycycline) were enrolled in the 2 studies. In order to objectively validate the clinical diagnosis of early Lyme disease in these patients, 2 approaches were used: 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. By these procedures, it was possible to confirm the physician diagnosis of early Lyme disease in 281 (79%) of the 355 study patients. The efficacy data summarized below are specific to this “validated” patient subset, while the safety data summarized below reflect the entire patient population for the 2 studies.

Analysis of the submitted clinical data for evaluable patients in the “validated” patient subset yielded the following results:

Table 9. Clinical Effectiveness of Cefuroxime Axetil Tablets Compared to Doxycycline in the Treatment of Early Lyme Disease

Part I

(1 Month Posttreatment)*

Part II

(1 Year Posttreatment)
Cefuroxime Axetil
(n = 125)
Doxycycline (n = 108)Cefuroxime
Axetil
(n = 105 )
Doxycycline
(n = 83 )
Satisfactory clinical outcome§91%93%84%87%
Clinical
cure/success
72%73%73%73%
Clinical
improvement
19%19%10%13%

* 95% confidence interval around the satisfactory difference for Part I (-0.08, +0.05).

95% confidence interval around the satisfactory difference for Part II (-0.13, +0.07).

n’s include patients assessed as unsatisfactory clinical outcomes (failure + recurrence) in Part I (Cefuroxime Axetil - 11 [5 failure, 6 recurrence]; doxycycline - 8 [6 failure, 2 recurrence]).

§ Satisfactory clinical outcome includes cure + improvement (Part I) and success + improvement (Part II).

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

Safety: Drug-related adverse events affecting the skin were reported significantly more frequently by patients treated with doxycycline than by patients treated with cefuroxime axetil (12% versus 3%, respectively; P = .002), primarily reflecting the statistically significantly higher incidence of drug-related photosensitivity reactions in the doxycycline arm versus the cefuroxime axetil arm (9% versus 0%, respectively; P<.001). While the incidence of drug-related gastrointestinal adverse events was similar in the 2 treatment groups (cefuroxime axetil - 13%; doxycycline - 11%), the incidence of drug-related diarrhea was statistically significantly higher in the cefuroxime axetil arm versus the doxycycline arm (11% versus 3%, respectively; P = .005).

Secondary Bacterial Infections of Acute Bronchitis: Four randomized, controlled clinical studies were performed comparing 5 days versus 10 days of Cefuroxime Axetil for the treatment of patients with secondary bacterial infections of acute bronchitis. These studies enrolled a total of 1,253 patients (CAE-516 n = 360; CAE-517 n = 177; CAEA4001 n = 362; CAEA4002 n = 354). The protocols for CAE-516 and CAE-517 were identical and compared Cefuroxime Axetil 250 mg twice daily for 5 days, Cefuroxime Axetil 250 mg twice daily for 10 days, and AUGMENTIN® 500 mg 3 times daily for 10 days. These 2 studies were conducted simultaneously. CAEA4001 and CAEA4002 compared Cefuroxime Axetil 250 mg twice daily for 5 days, Cefuroxime Axetil 250 mg twice daily for 10 days, and CECLOR® 250 mg 3 times daily for 10 days. They were otherwise identical to CAE-516 and CAE-517 and were conducted over the following 2 years. Patients were required to have polymorphonuclear cells present on the Gram stain of their screening sputum specimen, but isolation of a bacterial pathogen from the sputum culture was not required for inclusion. The following table demonstrates the results of the clinical outcome analysis of the pooled studies CAE-516/CAE-517 and CAEA4001/CAEA4002, respectively:

Table 10. Clinical Effectiveness of Cefuroxime Axetil Tablets 250 mg Twice Daily in Secondary Bacterial Infections of Acute Bronchitis: Comparison of 5 Versus 10 Days' Treatment Duration
CAE-516 and CAE-517*CAEA4001 and CAEA4002

5 Day

(n = 127)

10 Day

(n = 139)

5 Day

(n = 173)

10 Day

(n = 192)
Clinical success
(cure + improvement)
80%87%84%82%
Clinical cure61%70%73%72%
Clinical improvement19%17%11%10%

* 95% Confidence interval around the success difference [-0.164, +0.029].

95% Confidence interval around the success difference [-0.061, +0.103].

The response rates for patients who were both clinically and bacteriologically evaluable were consistent with those reported for the clinically evaluable patients.

Safety: In these clinical trials, 399 patients were treated with Cefuroxime Axetil for 5 days and 402 patients with Cefuroxime Axetil for 10 days. No difference in the occurrence of adverse events was observed between the 2 regimens.

REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests forBacteria that Grow Aerobically. 3rd ed. Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25. Villanova, Pa: NCCLS; 1993.

2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk SusceptibilityTests. 4th ed. Approved Standard NCCLS Document M2-A4, Vol. 10, No. 7. Villanova, Pa: NCCLS; 1990.

CLINTEST®  AND CLINISTIX® are registered trademarks of Ames Division, Miles Laboratories, Inc.

AUGMENTIN®  is a registered trademark of GlaxoSmithKline.

CECLOR®  is a registered trademark of Eli Lilly and Company.

Distributed by:
GOLDLINE LABORATORIES, INC.
a subsidiary of IVAX Pharmaceuticals, Inc.
Miami, FL 33137-3227

Made by Penn Laboratories, UK
Barnard Castle, DL12 8DT UK

Made in England March 2003

0303ISS RL-1191 Ivax

PRINCIPAL DISPLAY PANEL

Image of 250 mg - 20 Tablets Label

250 mg - 20 Tablets Label Text

NDC 0182-2689-15

CEFUROXIME

AXETIL

TABLETS

250 mg

Rx only

20 TABLETS

IVAX Pharmaceuticals, Inc.

PRINCIPAL DISPLAY PANEL

Image of 500 mg - 20 Tablets Label

500 mg - 20 Tablets Label Text

NDC 0182-2690-15

CEFUROXIME

AXETIL

TABLETS

500 mg

Rx only

20 TABLETS

IVAX Pharmaceuticals, Inc.


CEFUROXIME AXETIL 
cefuroxime axetil   tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)0182-2689
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
CEFUROXIME AXETIL (CEFUROXIME) CEFUROXIME250 mg
Inactive Ingredients
Ingredient NameStrength
COLLOIDAL SILICON DIOXIDE 
CROSCARMELLOSE SODIUM 
HYPROMELLOSE 
METHYLPARABEN 
CELLULOSE, MICROCRYSTALLINE 
PROPYLENE GLYCOL 
PROPYLPARABEN 
SODIUM BENZOATE 
SODIUM LAURYL SULFATE 
TITANIUM DIOXIDE 
Product Characteristics
ColorWHITEScore no score
ShapeOVAL (capsule-shaped) Size15mm
FlavorImprint Code GX;ES7
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
10182-2689-1520 TABLET In 1 BOTTLENone
20182-2689-2660 TABLET In 1 BOTTLENone

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA05060512/31/200801/01/2009

CEFUROXIME AXETIL 
cefuroxime axetil   tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)0182-2690
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
CEFUROXIME AXETIL (CEFUROXIME) CEFUROXIME500 mg
Inactive Ingredients
Ingredient NameStrength
COLLOIDAL SILICON DIOXIDE 
CROSCARMELLOSE SODIUM 
HYPROMELLOSE 
METHYLPARABEN 
CELLULOSE, MICROCRYSTALLINE 
PROPYLENE GLYCOL 
PROPYLPARABEN 
SODIUM BENZOATE 
SODIUM LAURYL SULFATE 
TITANIUM DIOXIDE 
Product Characteristics
ColorWHITEScore no score
ShapeOVAL (capsule-shaped) Size20mm
FlavorImprint Code GX;ES2
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
10182-2690-1520 TABLET In 1 BOTTLENone
20182-2690-2660 TABLET In 1 BOTTLENone

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA05060512/31/200801/01/2009

Labeler - Goldline Laboratories, Inc. (032349292)
Revised: 04/2010Goldline Laboratories, Inc.