Cefzil for oral suspension

CEFZIL is a semi-synthetic broad-spectrum cephalosporin antibiotic.

Cefprozil is a cis and trans isomeric mixture (>/=90% cis). The chemical name for the monohydrate is (6R, 7R)-7-[(R)-2-amino-2-(p-hydroxyphenyl)acetamido]-8-oxo-3-propenyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monohydrate, and the structural formula is:

Cefprozil is a white to yellowish powder with a molecular formula for the monohydrate of C 18 H 19 N 3 O 5 S·H 2 O and a molecular weight of 407.45.

CEFZIL tablets and CEFZIL for oral suspension are intended for oral administration.

CEFZIL tablets contain cefprozil equivalent to 250 mg or 500 mg of anhydrous cefprozil. In addition, each tablet contains the following inactive ingredients: cellulose, hypromellose, magnesium stearate, methylcellulose, simethicone, sodium starch glycolate, polyethylene glycol, polysorbate 80, sorbic acid, and titanium dioxide. The 250 mg tablets also contain FD&C Yellow No. 6.

CEFZIL for oral suspension contains cefprozil equivalent to 125 mg or 250 mg anhydrous cefprozil per 5 mL constituted suspension. In addition, the oral suspension contains the following inactive ingredients: aspartame, cellulose, citric acid, colloidal silicone dioxide, FD&C Red No. 3, flavors (natural and artificial), glycine, polysorbate 80, simethicone, sodium benzoate, sodium carboxymethylcellulose, sodium chloride, and sucrose.

The pharmacokinetic data were derived from the capsule formulation; however, bioequivalence has been demonstrated for the oral solution, capsule, tablet, and suspension formulations under fasting conditions.

Following oral administration of cefprozil to fasting subjects, approximately 95% of the dose was absorbed. The average plasma half-life in normal subjects was 1.3 hours, while the steady-state volume of distribution was estimated to be 0.23 L/kg. The total body clearance and renal clearance rates were approximately 3 mL/min/kg and 2.3 mL/min/kg, respectively.

Average peak plasma concentrations after administration of 250 mg, 500 mg, or 1 g doses of cefprozil to fasting subjects were approximately 6.1, 10.5, and 18.3 µg/mL, respectively, and were obtained within 1.5 hours after dosing. Urinary recovery accounted for approximately 60% of the administered dose. (See Table.)

During the first 4-hour period after drug administration, the average urine concentrations following 250 mg, 500 mg, and 1 g doses were approximately 700 µg/mL, 1000 µg/mL, and 2900 µg/mL, respectively.

Administration of CEFZIL tablet or suspension formulation with food did not affect the extent of absorption (AUC) or the peak plasma concentration (C max ) of cefprozil. However, there was an increase of 0.25 to 0.75 hours in the time to maximum plasma concentration of cefprozil (T max ).

The bioavailability of the capsule formulation of cefprozil was not affected when administered 5 minutes following an antacid.

Plasma protein binding is approximately 36% and is independent of concentration in the range of 2 µg/mL to 20 µg/mL.

There was no evidence of accumulation of cefprozil in the plasma in individuals with normal renal function following multiple oral doses of up to 1000 mg every 8 hours for 10 days.

In patients with reduced renal function, the plasma half-life may be prolonged up to 5.2 hours depending on the degree of the renal dysfunction. In patients with complete absence of renal function, the plasma half-life of cefprozil has been shown to be as long as 5.9 hours. The half-life is shortened during hemodialysis. Excretion pathways in patients with markedly impaired renal function have not been determined. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION .)

In patients with impaired hepatic function, the half-life increases to approximately 2 hours. The magnitude of the changes does not warrant a dosage adjustment for patients with impaired hepatic function.

Healthy geriatric volunteers (>/=65 years old) who received a single 1-g dose of cefprozil had 35-60% higher AUC and 40% lower renal clearance values compared with healthy adult volunteers 20-40 years of age. The average AUC in young and elderly female subjects was approximately 15-20% higher than in young and elderly male subjects. The magnitude of these age- and gender-related changes in the pharmacokinetics of cefprozil is not sufficient to necessitate dosage adjustments.

Adequate data on CSF levels of cefprozil are not available.

Comparable pharmacokinetic parameters of cefprozil are observed between pediatric patients (6 months-12 years) and adults following oral administration of selected matched doses. The maximum concentrations are achieved at 1-2 hours after dosing. The plasma elimination half-life is approximately 1.5 hours. In general, the observed plasma concentrations of cefprozil in pediatric patients at the 7.5, 15, and 30 mg/kg doses are similar to those observed within the same time frame in normal adult subjects at the 250, 500 and 1000 mg doses, respectively. The comparative plasma concentrations of cefprozil in pediatric patients and adult subjects at the equivalent dose level are presented in the table below.

Microbiology

Cefprozil has in vitro activity against a broad range of gram-positive and gram-negative bacteria. The bactericidal action of cefprozil results from inhibition of cell-wall synthesis. Cefprozil has been shown 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.

Aerobic gram-positive microorganisms:

Staphylococcus aureus (including (beta)-lactamase-producing strains)

NOTE:   Cefprozil is inactive against methicillin-resistant staphylococci.

Streptococcus pneumoniae

Streptococcus pyogenes

Aerobic gram-negative microorganisms:

Haemophilus influenzae (including (beta)-lactamase-producing strains)

Moraxella (Branhamella) catarrhalis (including (beta)-lactamase-producing strains)

The following in vitro data are available; however, their clinical significance is unknown. Cefprozil exhibits in vitro minimum inhibitory concentrations (MICs) of 8 µg/mL or less against most (>/=90%) strains of the following microorganisms; however, the safety and effectiveness of cefprozil in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-positive microorganisms:

Enterococcus durans

Enterococcus faecalis

Listeria monocytogenes

Staphylococcus epidermidis

Staphylococcus saprophyticus

Staphylococcus warneri

Streptococcus agalactiae

Streptococci (Groups C, D, F, and G)

viridans group Streptococci

NOTE:   Cefprozil is inactive against Enterococcus faecium.

Aerobic gram-negative microorganisms:

Citrobacter diversus

Escherichia coli

Klebsiella pneumoniae

Neisseria gonorrhoeae (including (beta)-lactamase-producing strains)

Proteus mirabilis

Salmonella spp.

Shigella spp.

Vibrio spp.

NOTE:   Cefprozil is inactive against most strains of Acinetobacter, Enterobacter, Morganella morganii, Proteus vulgaris, Providencia, Pseudomonas, and Serratia .

Anaerobic microorganisms:

Prevotella (Bacteroides) melaninogenicus

Clostridium difficile

Clostridium perfringens

Fusobacterium spp.

Peptostreptococcus spp.

Propionibacterium acnes

NOTE:   Most strains of the Bacteroides fragilis group are resistant to cefprozil.

Susceptibility Tests

Dilution Techniques:   Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method 1,2 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of cefprozil powder. The MIC values should be interpreted according to the following criteria:

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard cefprozil powder should provide the following MIC values:

Diffusion Techniques:   Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure 3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 µg cefprozil to test the susceptibility of microorganisms to cefprozil.

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

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for cefprozil.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30 µg cefprozil disk should provide the following zone diameters in these laboratory test quality control strains.

CEFZIL (cefprozil) is indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the designated microorganisms in the conditions listed below:

UPPER RESPIRATORY TRACT

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. Cefprozil is generally effective in the eradication of Streptococcus pyogenes from the nasopharynx; however, substantial data establishing the efficacy of cefprozil in the subsequent prevention of rheumatic fever are not available at present.

Otitis Media caused by Streptococcus pneumoniae, Haemophilus influenzae (including (beta)-lactamase-producing strains), and Moraxella (Branhamella) catarrhalis (including (beta)-lactamase-producing strains). (See CLINICAL STUDIES .)

NOTE: In the treatment of otitis media due to (beta)-lactamase producing organisms, cefprozil had bacteriologic eradication rates somewhat lower than those observed with a product containing a specific (beta)-lactamase inhibitor. In considering the use of cefprozil, lower overall eradication rates should be balanced against the susceptibility patterns of the common microbes in a given geographic area and the increased potential for toxicity with products containing (beta)-lactamase inhibitors.

Acute Sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae (including (beta)-lactamase-producing strains), and Moraxella (Branhamella) catarrhalis (including (beta)-lactamase-producing strains).

LOWER RESPIRATORY TRACT

Secondary Bacterial Infection of Acute Bronchitis and Acute Bacterial Exacerbation of Chronic Bronchitis caused by Streptococcus pneumoniae, Haemophilus influenzae (including (beta)-lactamase-producing strains), and Moraxella (Branhamella) catarrhalis (including (beta)-lactamase-producing strains).

SKIN AND SKIN STRUCTURE

Uncomplicated Skin and Skin-Structure Infections caused by Staphylococcus aureus (including penicillinase-producing strains) and Streptococcus pyogenes. Abscesses usually require surgical drainage.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of CEFZIL and other antibacterial drugs, CEFZIL should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

CEFZIL (cefprozil) is contraindicated in patients with known allergy to the cephalosporin class of antibiotics.

The adverse reactions to cefprozil are similar to those observed with other orally administered cephalosporins. Cefprozil was usually well tolerated in controlled clinical trials. Approximately 2% of patients discontinued cefprozil therapy due to adverse events.

The most common adverse effects observed in patients treated with cefprozil are:

Gastrointestinal:   Diarrhea (2.9%), nausea (3.5%), vomiting (1%), and abdominal pain (1%).

Hepatobiliary:    Elevations of AST (SGOT) (2%), ALT (SGPT) (2%), alkaline phosphatase (0.2%), and bilirubin values (<0.1%). As with some penicillins and some other cephalosporin antibiotics, cholestatic jaundice has been reported rarely.

Hypersensitivity:   Rash (0.9%), urticaria (0.1%). Such reactions have been reported more frequently in children than in adults. Signs and symptoms usually occur a few days after initiation of therapy and subside within a few days after cessation of therapy.

CNS:   Dizziness (1%). Hyperactivity, headache, nervousness, insomnia, confusion, and somnolence have been reported rarely (<1%). All were reversible.

Hematopoietic:   Decreased leukocyte count (0.2%), eosinophilia (2.3%).

Renal:   Elevated BUN (0.1%), serum creatinine (0.1%).

Other:    Diaper rash and superinfection (1.5%), genital pruritus and vaginitis (1.6%).

The following adverse events, regardless of established causal relationship to (cefprozil), have been rarely reported during postmarketing surveillance: anaphylaxis, angioedema, colitis (including pseudomembranous colitis), erythema multiforme, fever, serum-sickness like reactions, Stevens-Johnson syndrome, and thrombocytopenia.

Cephalosporin class paragraph

In addition to the adverse reactions listed above which have been observed in patients treated with cefprozil, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics:

Aplastic anemia, hemolytic anemia, hemorrhage, renal dysfunction, toxic epidermal necrolysis, toxic nephropathy, prolonged prothrombin time, positive Coombs' test, elevated LDH, pancytopenia, neutropenia, 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.

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically --Third Edition. Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25, NCCLS, Villanova, PA, December 1993.
2. National Committee for Clinical Laboratory Standards. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria --Third Edition. Approved Standard NCCLS Document M11-A3, Vol. 13, No. 26, NCCLS, Villanova, PA, December 1993.
3. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests --Fifth Edition. Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, December 1993.

E2-B0001-12-03           7718DIM-14

Revised December 2003

Bristol-Myers Squibb Company

Princeton, NJ 08543 U.S.A.

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