Cefuroxime Axetil (cefuroxime axetil 500 mg) Dailymed

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 indicated.

Prescribing cefuroxime axetil tablets 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.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

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. Patients should be counseled that antibacterial drugs, including cefuroxime axetil tablets, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefuroxime axetil tablet is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cefuroxime axetil tablets or other antibacterial drugs in the future.

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 tablets compared with that of fasting state and tend to cancel the effect of postprandial absorption.

In common with other antibiotics, cefuroxime axetil may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.

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

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 postmarketing 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

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 2. Adverse Reactions-Cefuroxime axetil Tablets Multiple-Dose Dosing Regimens-Clinical Trials

Incidence ≥1%	Diarrhea/loose stools	3.7%
	Nausea/vomiting	3%
	Transient elevation in AST	2%
	Transient elevation in ALT	1.6%
	Eosinophilia	1.1%
	Transient elevation in LDH	1%
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

In clinical trials using cefuroxime axetil tablets 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.

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.

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 United States.

Table 3. 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

POSTMARKETING EXPERIENCE WITH CEFUROXIME AXETIL TABLETS

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 were reported spontaneously. Data are generally insufficient to allow an estimate of incidence or to establish causation.

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

Pseudomembranous colitis (see WARNINGS ).

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

Hepatic impairment including hepatitis and cholestasis, jaundice.

Seizure.

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

Renal dysfunction.

CEPHALOSPORIN-CLASS ADVERSE REACTIONS

In addition to the adverse reactions uled 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 BIOEQUIVALENT AND ARE NOT SUBSTITUTABLE ON A MILLIGRAM-PER-MILLIGRAM BASIS (SEE CLINICAL PHARMACOLOGY)

Table 4. Cefuroxime axetil Tablets (May be administered without regard to meals.)

Population/Infection	Dosage	Duration (days)
Adolescents and Adults (13 years and older)
Pharyngitis/tonsillitis	250 mg b.i.d.	10
Acute bacterial maxillary sinusitis	250 mg b.i.d.	10
Acute bacterial exacerbations of chronic bronchitis	250 or 500 mg b.i.d.	10The safety and effectiveness of cefuroxime axetil administered for less than 10 days in patients with acute exacerbations of chronic bronchitis have not been established.
Secondary bacterial infections of acute bronchitis	250 or 500 mg b.i.d.	5-10
Uncomplicated skin and skin-structure infections	250 or 500 mg b.i.d.	10
Uncomplicated urinary tract infections	250 mg b.i.d.	7-10
Uncomplicated gonorrhea	1,000 mg once	single dose
Early Lyme disease	500 mg b.i.d.	20
Pediatric Patients (who can swallow tablets whole)
Acute otitis media	250 mg b.i.d.	10
Acute bacterial maxillary sinusitis	250 mg b.i.d.	10

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, USP 250 mg: Light blue colored film coated, capsule shaped tablets having “250” on one side and “P125” on the other side. Tablets are supplied as follows:

Bottle of 20 Tablets    NDC 16714-232-01                                                     

Bottle of 60 Tablets     NDC 16714-232-02

Cefuroxime axetil tablets, USP 500 mg: Dark blue colored film coated, capsule shaped tablets having “500” on one side and “P126” on the other side. Tablets are supplied as follows:

Bottle of 20 Tablets      NDC 16714-233-01                                                     

Bottle of 60 Tablets      NDC 16714-233-02               

Store at 20° to 25°C (68° to 77°F); [see USP Controlled Room Temperature]. Replace cap securely after each opening.

Clinical Studies

Cefuroxime axetil tablets

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 5. Clinical Effectiveness of Cefuroxime axetil Tablets Compared to Beta-Lactamase Inhibitor-Containing Control Drug in the Treatment of Acute Bacterial Maxillary Sinusitis

	US Patients95% Confidence interval around the success difference [-0.08, +0.32].		South American Patients95% Confidence interval around the success difference [-0.10, +0.16].
	Cefuroximeaxetil tablet (n = 49)	Control (n = 43)	Cefuroxime axetil tablet (n = 87)	Control (n = 89)
Clinical success (cure + improvement)	65%	53%	77%	74%
Clinical cure	53%	44%	72%	64%
Clinical improvement	12%	9%	5%	10%

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.

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).

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 6. Clinical Effectiveness of Cefuroxime axetil Tablets Compared to Doxycycline in the Treatment of Early Lyme Disease

	Part I (1 Month Posttreatment)95% confidence interval around the satisfactory difference for Part I (-0.08, +0.05).		Part II (1 Year Posttreatment)95% confidence interval around the satisfactory difference for Part II (-0.13, +0.07).
	Cefuroxime axetil tablet (n = 125)	Doxycycline (n = 108)	Cefuroxime axetil tablet (n = 105n’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]).)	Doxycycline (n = 83 )
Satisfactory clinical outcomeSatisfactory clinical outcome includes cure + improvement (Part I) and success + improvement (Part II).	91%	93%	84%	87%
Clinical cure/success	72%	73%	73%	73%
Clinical improvement	19%	19%	10%	13%

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

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).

Four randomized, controlled clinical studies were performed comparing 5 days versus 10 days of cefuroxime axetil tablets 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 tablets 250 mg twice daily for 5 days, cefuroxime axetil tablets 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 tablets 250 mg twice daily for 5 days, cefuroxime axetil tablets 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 7. 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-51795% Confidence interval around the success difference [-0.164, +0.029].		CAEA4001 and CAEA400295% Confidence interval around the success difference [-0.061, +0.103].
	5 Day	10 Day	5 Day	10 Day
	(n = 127)	(n = 139)	(n = 173)	(n = 192)
Clinical success (cure + improvement)	80%	87%	84%	82%
Clinical cure	61%	70%	73%	72%
Clinical improvement	19%	17%	11%	10%

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

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 for Bacteria 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 Susceptibility Tests. 4th ed. Approved Standard NCCLS Document M2-A4, Vol. 10, No. 7. Villanova, Pa: NCCLS; 1990.

CLINITEST and CLINISTIX are registered trademarks of Ames Division, Miles Laboratories, Inc.

AUGMENTIN^® and CECLOR^® are registered trademarks of GlaxoSmithKline.

Manufactured for: Northstar Rx LLC

Memphis, TN 38141

Toll free number: 1 800 206 7821

Manufactured by: Hospira Healthcare India Pvt. Ltd.,

At Irungattukottai - 602 105, India

On behalf of: Orchid Healthcare

(A Division of Orchid Chemicals & Pharmaceuticals Ltd.)

At Irungattukottai - 602 105, India

Revised: 04/10

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