Ceftin®
(cefuroxime axetil)
Tablets, Powder for Oral Suspension
DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED
CLINICAL STUDIES
REFERENCES
DESCRIPTION
CEFTIN Tablets and CEFTIN for Oral Suspension contain cerfuroxime as cerfuroxime axetil. CEFTIN is a semisynthetic, broad-spectrum cephalosporin antibiotic for oral administration.Chemically, cerfuroxime axetil, the 1-(acetyloxy) ethyl ester of cefuroxime, is (RS)-1-hydroxyethyl (6R, 7R)-7-[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:
CEFTIN Tablets are film-coated and contain the equivalent of 125, 250, or 500 mg of cefuroxime as cefuroxime axetil. CEFTIN Tablets contain the inactive ingredients collodial silicon dioxide, croscarmellose sodium, FD&C Blue No.1 (250- and 500-mg tablets only), hydrogenated vegetable oil, hydroxypropyl methycellulose, methylparaben, microcrystalline cellulose, propylene glycol, propylparaben, sodium benzoate (125-mg tablets only), sodium lauryl sulfate, and titanium dioxide.CEFTIN for Oral Suspension, when reconstituted with water, provides the equivalent of 125 mg of cefuroxime (as cefuroxime axetil) per 5 mL of suspension. CEFTIN for Oral Suspension contains the inactive ingredients povidone K30, stearic acid, sucrose, an d tutti-frutti flavoring.
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 distr ibuted throughout the extracellular fluids. The axetil moiety is metabolized to acetaldehyde and acetic acid.Serum Pharmacokinetics: Serum cefuroxime pharmacokinetic parameters for CEFTIN Tablets and CEFTIN for Oral Suspension are shown in the tables below.
Postprandial Pharmacokinetics of Cefuroxime Administered as CEFTIN Tablets to Adults*
Dose+ Peak Plasma Time of Peak Mean A.U.C. (Cefuroxime Concentration Plasma Elimination (mcg-h Equivalent) (mcg/mL) Concentration(h) Half-Life (h) mL)
125 mg 2.1 2.2 1.2 6.7 250 mg 4.1 2.5 1.2 12.9 500 mg 7.0 3.0 1.2 27.4 1,000 mg 13.6 2.5 1.3 50.0
*Mean Values of 12 healthy adult volunteers.
+Drug administered immediately after a meal.
Postprandial Pharmacokinetics of Cerfuroxime Administered as CEFTIN for Oral Suspension to Pediatric Patients* Dose+ Peak Plasma Time of Peak Mean A.U.C. (Cefuroxime Concentration Plasma Elimination (mcg-h Equivalent) n (mcg/mL) Concentration(h) Half-life (h) mL)
10 mg/kg 8 3.3 3.6 1.4 12.4 15 mg/kg 12 5.1 2.7 1.9 22.5 20 mg/kg 8 7.0 3.1 1.9 32.8
*Mean age=23 months.
+Drug administered with milk or milk products.Approximately 50% of serum cefuroxime is bound to protein.
Comparative Pharmacokinetic Properties: CEFTIN for Oral Suspension was not bioequivalent to CEFTIN Tables when tested in healthy adults. The tablet and powder for oral suspension formulations are NOT substitutable on a mg/mg 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 susp ension formulations had to be established in separate clinical trials.Food Effect on Pharmacokinetics: Absorption of the tablet is greater when taken after food (absolute bioabailabiliaty of CEFTIN Tablets increase 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 two 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 stu died 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 (mena age 83.9 years) having a mean creatinine clearance of 34.9 mL/min, the mean serum elimination half-li fe 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 cefuxime 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 enterob acteriaceae.
Cefuroxime has been demonstrated to be active against most strains of the following microorgamisms 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 (beta-lactamase negative strains only)
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 treat ing clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.
- Aerobic Gram-Positive Microorganisms:
Staphylococcus epidermidis
Staphylococcus saprophyticus
Staphylococcus agalactiae
NOTE: Certain strains of enterococci, e.g., Enterococcus faecalis (formerly Streptococcus faecalis), are resistant to cerfuroxime. Methicillin-resistant staphylococci are resistant to cefuoxime.- Aerobic Gram-negative Microorganisms:
Morganella morganii
Neisseria gonorrhoeae (beta-lactamase-producing strains only)
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 Morgane lla 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 cerfuoxime.Susceptibility Tests: Dilution Techniques: Quantitative methods that are used to determine MICs provide reproductible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standar dized dilution method (broth, agar, or microdilution) or equivalent with cefuroxime powder. The MIC values obtained should be interpreted according to the following criteria:
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 an tibiotic 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:
Microorganism MIC (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:
Interpretation should be as stated above for results using dilution techniques.
As with standard dilution techniques, diffusion methods require the use of laboratory control microoranisms. The 30 mcg cefuroxime disk provides the following zone diameters in these laboratory test quality control strains:
INDICATIONS AND USAGE
NOTE: CEFTIN TABLETS AND CEFTIN FOR ORAL SUSPENSION ARE NOT BIOEQUIVALENT AND ARE NOT SUBSTITUTABLE ON A MG/MG BASIS (SEE CLINICAL PHARMACOLOGY).
CEFTIN Tablets: CEFTIN 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. Pharynigitis/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. CEFTIN Tablets are generally effective in the eradication of strepto cocci from the nasopharynx; however, substantial data establishing the effiicacy 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 penic illin 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 pneumonia 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 CEFTIN Tablets for patients with acute bacterial maxil lary sinusitis, it was not possible to adequately evaluate the effectiveness of CEFTIN Tablets for sinus infections known, suspected, or considered potentially to be caused by beta-lactamase-producing Haemophilus influenzae or Moraxella catarrha lis.4. Acute Bacterial Exacebations 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).
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 endocevical) caused by non-penicillinase-producing strains of Neisseria gonorrhoeae.
CEFTIN for Oral Suspension: CEFTIN 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 conditi ons listed below. The safety and effectiveness for CEFTIN 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 wi th which to determine an effective and safe dosing regimen.
1. Pharynigitis/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. CEFTIN for Oral Suspension is generally effective in the eradicatio n 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 t o 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, Hemophilus influenzae (including beta-lactamase producing strains). Moraxella catarrhalis (including beta-lactamase-producing strains) or Streptococcus pyogenes< /I>.
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 must be started while awaiting the results of this testing. Antimicrobial therapy should be appropriately adjusted according to the results of such testing.
CONTRAINDICATONS
CEFTIN products are contraindicated in patients with known allergy to the cephalosporin group of antibiotics.
WARNINGS
CEFTIN TABLETS AND CEFTIN FOR ORAL SUSPENSION ARE NOT BIOEQUIVALENT AND ARE THEREFORE NOT SUBSTITUTABLE ON A MG/MG BASIS (SEE CLINICAL PHARMACOLOGY).BEFORE THERAPY WITH CEFTIN PRODUCTS IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PERVIOUS HYPERSENSITIVITY REACTIONS TO CEFTIN PRODUCTS, OTHER CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO B E GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-HYPERSENSITIVITY AMONG BETA-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF A CLINICALLY SI GNIFICANT ALLERGIC REACTION TO CEFTIN PRODUCTS OCCURS, DISCONTINUE THE DRUG AND INSTITUTE APPROPRIATE THERAPY, SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, INTRAVENOUS FLUI DS, INTRAVENOUS ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including cefuroxime, and may range from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostriduim difficle 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 nonusceptible 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 gastroinestinal malabsor ption. Patients with gastrointestinal malabsorption were excluded from participating in clinical trials of cefuroxime axetil.
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 sh ould 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., Cl inistix®, Tes-Tape®). 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. T he presence of cefuroxime does not interfere with the assay of serum and urine creatine 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 ceuroxime concentration after a 1.5-g single dose is greater when taken with 1 g of probencid (mean=14.8 mcg/mL) than without probencid (mean=12.2 mcg/mL).
Drugs that reduce gastric acidity may result in a lower bioavailabilitly of CEFTIN 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 potential was found for cefuroxime axetil in the micronucleus test and a battery of bacterial mutation tests. Reproduction studies in rats at doses up to 1,000 mg/kg/day ( nine times the recommended maximum human dose based on mg/m2) have revealed no evidence of impaired fertility.
Pregnancy: Teratogenic Effects: Pregnancy Category B: Reproduction studies have been performed in rats and mice at doses up to 3,200 mg/kg/day (23 times the recommended maximum human dose based on mg/m2) and have revealed no evid ene of harm to the fetus due to cefuroxime axetil. There are however, no edequate and well-controlled studies in pregnant women. Because animal reporduction studies are not always predictive of human response, this drug should be used during pregnancy o nly 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: In controlled clinical trials, cefuroxime axetil has been administered to pediatric patients ranging in the age from 3 months to 12 years (see INDICATIONS AND USAGE AND DOSAGE AND ADMINISTRATION sections).
Geriatric Use: In clinical triasl when 12 to 64 year old patients and geriatric patients (65 years of age or older) were treated with usual recommended dosages (i.e., 125 to 500 mg b.i.d., depending on type of infections, no overall differenes in effectiveness were observed between the two age-groups. The geratric patients reported somewhat fewer gastrointestinal events and less frequent vaginal candidiasis compared with patients aged 12 to 64 years old; however, no clinically significant diff erenes were reported between the two age-groups. Therefore, no adjustment of the usual adult dose is necessary based on age alone.
ADVERSE REACTIONS
CEFTIN TABLETS (MULTIPLE-DOSE REGIMENS): In clinical Trials: In clinical trials using multiple doses of cefuroxime axetil tablets. 912 patients were treated with the recommended doses of cefuroxime axetil (125 to 500 mg twice a day). There were n o deaths or permanent disabilities thought 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 treted patients who discontinued study drug because of adverse events was very similar at daily doses of 1000, 500 and 250 mg (2.3%, 2.1% and 2.2% respectively). However, the incidence of gastrointestinal adverse events increase d 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).
Adverse Reactions CEFTIN Tablets Multiple-Dose Dosing Regimens- Clinical Trials
Incidence >/=1% Diarrhea/loose stools 3.7% Transient elevation in ALT 1.6% Nausea/Vomiting 3.0% Eosinophila 1.1% Transient elevation in AST 2.0% Transient elevation in LDH 1.0%
Incidence Abdominal Pain Rash Mouth ulcers < 1% but > 0.1% Abdominal cramps Hives Swollen tongue Flatulence Itch Sleepiness Indigesion Dysuria Thirst Headache Chills Anorexia Vaginitis Chest Pain Positive Coombs' test Vulvar itch Shortness of breath
In Postmarketing Experience: In addition to the events reported during clinical trials with CEFTIN Tablets, the following adverse experiences have been reported from domestic foreign sources during worldwide postmarketing surveilance: hypersensitivity reactions, including Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, serum sickness-like reactions, anaphylaxis, and angioedema. Jaundice has been reported very rarely. Onset of pseudomembranous colitis sympt oms may occur during or after treatment (see WARNINGS).
CEFTIN TABLETS (SINGLE-DOSE FOR UNCOMPLICATED GONORRHEA): In Clinical Trials: In clinical trials using a single dose of cefuroxime axetil tablets, 644 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 cond ucted in the US.
Adverse Reactions CEFTIN Tablets 1-g Single-Dose Regimen for Uncomplicated Gonorrhea-Clinical Trials
Incidence >/=1% Nausea/Vomiting 6.7% Diarrhea 4.7
Incidence Abdominal pain Vaginal discharge Muscle spasm of neck < 1% but >0.1% Dyspepsia Headache Tightness/pain in chest Erythema Dizziness Bleeding/Pain in urethra Rash Somnolence Kidney pain Pruritus Muscle cramps Tachycardia Vaginal candidiasis Muscle stiffness Lockjaw-type reaction Vaginal itch
CEFTIN FOR ORAL SUSPENSION (MULTIPLE-DOSE DOSING REGIMENS): 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 per day divided twice a day up to a maximum dose of 500 or 1000 mg per 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 clincal 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 US.
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).
Adverse Reactions CEFTIN for Oral Suspension Multiple-Dose Dosing Regimens-Clinical Trials
Incidence >/=1% Diarrhea/loose stools 8.6% Diaper rash 3.4% Dislike of taste 5.0% Nausea/vomiting 2.6%
Incidence < 1% but >0.1% Abdominal pain Irritable behavior Cough Flatulence Eosinophilia Urinary tract infection Gastrointestinal infection Positive direct Coombs' test Joint swelling Candidasis Elivated liver enzymes Arthralgia Vaginal irritation Viral illness Fever Rash Upper respiratory infection Ptyalsim Hyperactivity Sinusitis
In Postmarketing Experience: In addition to the events reported during clinical trials with CEFTIN for Oral Suspencion, the following adverse experiences have been reported in postmarketing surveillance: hypersensitivity reactions (includi ng rash, pruitus, uticaria, and anaphylaxis).
CEPHALOSPORIN-CLASS ADVERSE REACTIONS: In addition to the adverse reeactions listed above that have been observed in patients treated with cefuroxime axetil, the following adverse reactions and altered laboratory tests have been reported for cepha losporin-class antibiotics: renal dysfunction, toxic nephropathy, hepatic cholestasis, aplastic anemia, hemolytic anemia, hemorrhage, increased prothrombin time, increased BUN, increased creatinine, false-positive test for urinary glucose, increased alka line phosphatase, neutropenia, thrombocytopenia, leukopenia, elevated bilirubin, pancytopenia, and agaranulocytosis.
Several cephalosporins have been implicated in triggering seizures, partially in patients with renal impairment when the dosage was not reduced (see DOSAGE AND ADMINISTRATION and OVERDOSAGE). If seizurs 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: CEFTIN® TABLETS AND CEFTIN® FOR ORAL SUSPENSION ARE NOT BIOEQUIVALENT AND ARE NOT SUBSTITUTABLE ON A MG/MG BASIS (SEE CLINICAL PHARMACOLOGY).CEFTIN 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 and secondary bacterial infetions of acute bronchitis 250 or 500 mg b.i.d. 10 Uncomplicated skin and skin structure infections 250 or 500 mg b.i.d. 10 Uncomplicated urinary tract infections 125 or 250 mg b.i.d. 7-10 Uncomplicated gonorrhea 1000 mg once Single dose
Children (who can swallow tablets whole) Pharyngitis/tonsillitis 125 mg b.i.d. 10 Acute otitis media 250 mg b.i.d. 10
CEFTIN for Oral Suspension: CEFTIN for Oral Suspension may be administered to infants and children ranging in age from 3 months to 12 years, according to dosages in the following table:
CEFTIN for Oral Suspension (Must be administered with food. Shake well each time before using.)
Population/Infection Dosage Daily Maximum Dose Duration(days) Infants and children (3 months to 12 years) Pharyngitis/tonsillitis 20 mg/kg/day divided b.i.d. 500 mg 10 Acute otitis media 30 mg/kg/day divided b.i.d. 1000 mg 10 Impetigo 30 mg/kg/day divided b.i.d. 1000 mg 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 elimated, its half-life wil be prolonged in patients with renal failure.
Directions for Mixing CEFTIN for Oral Suspension: Prepare a suspension at the time of dispensing as follows:
1. Shake the bottle to loosen the powder
2. Remove the cap
3. Invert the bottle and vigorously rock the bottle from side to side so that water rises through the powder.
5. Once the sound of the powder against the bottle disappears, turn the bottle upright and vigorously shake it in a diagonal direction.
Bottle Size Amount of Water Required for Reconstitution
50 mL 20 mL 100 mL 37 mL 200 mL 74 mL
Each teaspoonful (5 mL) will contain the equivalent of 125 mg of cefuroxime as cefuroxime axetil.
NOTE: SHAKE THE ORAL SUSPENSION WELL BEFORE EACH USE. Replace cap securley after each opening. Reconstituted suspension should be stored between 2o and 25oC (36o and 77oF) (either in the refrigerator or at room temperature). DISCARD AFTER 10 DAYS.
HOW SUPPLIED
CEFTIN Tablets: CEFTIN Tablets, 125 mg of cefuroxime (as cefuroxime axetil), are white, capsule-shaped, film-coated tablets engraved with “395” on one side and “Glaxo” on the other side as follows:20 Tablets/Bottle NDC 0173-0395-00 60 Tablets/Bottle NDC 0173-0395-01 Unit Dose Packs of 100 NDC 0173-0395-02CEFTIN Tablets, 250 mg of cefuroxime (as cefuroxime axetil), are light blue, capsule-shaped, film coated tablets engraved with “387” on one side and “Glaxo” on the other side as follows:
20 Tablets/Bottle NDC 0173-0387-00 60 Tablets/Bottle NDC 0173-0387-42 Unit Dose Packs of 100 NDC 0173-0387-01CEFTIN Tablets, 500 mg of cefuroxime (as cefuroxime axetil), are dark blue, capsule-shaped, film-coated tablets engraved with “394” on one side and “Glaxo” on the other side as follows:
20 Tablets/Bottle NDC 0173-0394-00 60 Tablets/Bottle NDC 0173-0394-42 Unit Dose Packs of 50 NDC 0173-0394-01Store the tablets between 15o and 30oC (59o and 86oF). Replace cap securely after each opening. Protect unit dose packs from excessive moisture.
CEFTIN for Oral Suspension: CEFTIN for Oral Suspension is provided as dry, white to pale yellow, tutti-frutti-flavored powder. When reconstituted as directed, CEFTIN for Oral Suspension provides the equivalent of 125 mg of cefuroxime (as cefuroxi me axetil) per 5 mL of suspension. It is supplied in amber glass bottles as follows:
50-mL Suspension NDC 0173-0406-01 100-mL Suspension NDC 0173-0406-00 200-mL Suspension NDC 0173-0406-04Before reconstitution, store dry powder between 2o and 30oC (36o and 86oF).
After reconstitution, store suspension between 2o and 25oC(36o and 77oF) in a refrigerator or room temperature. DICARD AFTER 10 DAYS.
CLINICAL STUDIES
CEFTIN 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 s inus 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 effecti veness of CEFTIN 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 CEFT IN Talets in treating acute bacterial maxillary sinusitis due only to Streptococcus pneumoniae or non-beta-lactamase-producing Haemophilus influenzae. An insufficient number or beta-lactamase-producing Haemophilus influenzae and M oraxella catarrhalis isolates were obtained in this trial to adequately evaluate the effectiveness of CEFTIN Tablets in the treatment of acute bacterial maxillary sinusitis due to these two 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 b.i.d. or an oral antimicrobial agent that conatined a specific beta-lactamas e inhibitor. An intent-to-treat analysis of the submitted clinical data yielded the following results:
Clinical Effectiveness of CEFTIN Tablets Compared to Beta-Lactamase Inhibitor-Containing Control Drug in the Treatment of Acute Bacterial Maxillary Sinusitis
U.S Patients* South American Patietns** CEFTIN Control CEFTIN Control n=49 n=43 n=87 n=89 Clinical success (cure + improvement) 65% 53% 77% 74% Clinical cure 53% 44% 72% 64% Clinical improvement 12% 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-produc ing 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 speific beta-lactamase inhibitor) versus the cefuroxime axetil arm (12% versus 1%, respectively; p< 0.001), particularly drug-related diarrhea (8% versus 1%, respectively; p= 0.001).
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. Vilanova, 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.GlaxoWellcome
Glaxo Wellcome Inc.
Research Triange Park, NC 27709CEFTIN is registered trademark of Glaxo Wellcome.
CLINITEST and CLINISTIX are registered trademarks of Ames Division, Miles Laboratories, Inc.
TES-TAPE is a registed trademark of Eli Lilly and Company.U.S. Patents 4,267,320; 4,562,181; 4,865,851; and 4,897,270.
© Copyright 1996, Glaxo Wellcome Inc. All rights reserved.
March 1996 RL-294
RERERENCES
1. Musher DM. Streptococus pneumoniae. In: Mandell GL, Bennet JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 4th ed. New York, NY: Churchill Livingstone Inc; 1995:1811-1826.2. Jones RN, Fuchs PC, Gavan TL, Gerlache EH, Barry AL, Thornsberrry C. Cefuroxime, a new parenteral cephalosporin: collaborative in vitro susceptibility comparison with cephalothin against 5,887 clinical bacterial isolates. Antimicrob Agent s Chemother. July 1977; 12:47-50.
3. Forsgren A, Walder M. Branhamella catarrhalis, Haemophilus Influenzae, pneumoccocci, Group A streptococci and Staphylococcus aureus: sensitivity of outpatients strains to comonly prescribed antibiotics 1980 and 1983. In: Proceedings of the 13 th International Congress of Chemotherapy; 1983 Vienna, Austria. Abstract SE 7.27/1-0, part 73:34-37.
4. Knapp CC, Washington JA II. In vitro activities of LY163892, cefaclor, and cefuroxime. Antimicrob Agents Chemother. January 1988;32:131-133.
5. Jorgensen JH, Doern GV, Maher LA, Howell AW, Redding JS. Antimicrobial resistance among respiratory isolates of Haemophilus influenza, Moraxella catarrhalis, and Streptococus pneumoniae in the United States. Antimicrob Agents Chemother. November 1990; 34;2075-2080.
6. Arguedas AG, Arrieta AC, Stutman HR, Akaniro JC, Marks MI. In-vitro activity of cefprozil (BMY 28100) and loracaref (LY 163892) against pathogens obtained from middle ear fluid. J Antimicrob Chmeother 1991;27:311-318.
7. Thornsberry C, Brown SD, Yee YC, Bouchillon SK, Marler JK, Rich T. Increasing penicillin resistance in Streptococcus pneumonia in the U.S.: effect on susceptibility to oral cephalosporins. Infections in Medicine. December 1993; 10 (suppl D): 15-24.
8. Data on file, Glaxo Wellcome Inc.
9. National Committee for Clinical Laboratory Standars. Minimum Inhibitory Concentration (MIC) Interpretive Standards (ug/mL) for Streptococcus pneumoniae. Villanova, Pa: Naional Committee for Clinical Laboratory Standards; 1994;14(16). Approved standard M7-A3.
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