CEFZIL® (cefprozil) 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 (cefprozil) 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, hydroxypropylmethylcellulose, 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 four-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® (cefprozil) 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.
The average AUC observed in elderly subjects (>/= 65 years of age) is approximately 35-60% higher relative to young adults, and the average AUC in females is approximately 15-20% higher than in males. 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.
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 section.
Aerobic gram-positive microorganisms:
Staphylococcus aureus (including (beta)-lactamase-producing strains)
NOTE: Cefprozil is inactive against methicillin-resistant staphylococci.
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 (MIC's) 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:
Streptococci (Groups C, D, F, and G)
viridans group Streptococci
NOTE: Cefprozil is inactive against Enterococcus faecium.
Aerobic gram-negative microorganisms:
Neisseria gonorrhoeae (including (beta)-lactamase-producing strains)
NOTE: Cefprozil is inactive against most strains of Acinetobacter, Enterobacter, Morganella morganii, Proteus vulgaris, Providencia, Pseudomonas, and Serratia .
Prevotella (Bacteroides) melaninogenicus
NOTE: Most strains of the Bacteroides fragilis group are resistant to cefprozil.
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MIC's). These MIC's provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC's 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:
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 section.)
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).
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).
Uncomplicated Skin and Skin-Structure Infections caused by Staphylococcus aureus (including penicillinase-producing strains), and Streptococcus pyogenes. Abscesses usually require surgical drainage.
Culture and susceptiblity testing should be performed when appropriate to determine susceptibility of the causative organism to cefprozil.
CEFZIL (cefprozil) is contraindicated in patients with known allergy to the cephalosporin class of antibiotics.
BEFORE THERAPY WITH CEFZIL IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFZIL, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-SENSITIVITY AMONG (beta)-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO CEFZIL OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY 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 cefprozil, and may range in severity 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 the 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 clinically effective against Clostridium difficile colitis
In patients with known or suspected renal impairment (see DOSAGE AND ADMINISTRATION ), careful clinical observation and appropriate laboratory studies should be done prior to and during therapy. The total daily dose of CEFZIL (cefprozil) should be reduced in these patients because high and/or prolonged plasma antibiotic concentrations can occur in such individuals from usual doses. Cephalosporins, including CEFZIL, should be given with caution to patients receiving concurrent treatment with potent diuretics since these agents are suspected of adversely affecting renal function.
Prolonged use of CEFZIL may result in the overgrowth of nonsusceptible organisms. Careful observation of the patient is essential.
If superinfection occurs during therapy, appropriate measures should be taken.
Cefprozil should be prescribed with caution in individuals with a history of gastrointestinal disease particularly colitis.
Positive direct Coombs' tests have been reported during treatment with cephalosporin antibiotics.
Phenylketonurics: CEFZIL (cefprozil) for oral suspension contains phenylalanine 28 mg per 5 mL (1 teaspoonful) constituted suspension for both the 125 mg/5 mL and 250 mg/5 mL dosage forms.
Nephrotoxicity has been reported following concomitant administration of aminoglycoside antibiotics and cephalosporin antibiotics. Concomitant administration of probenecid doubled the AUC for cefprozil.
The bioavailability of the capsule formulation of cefprozil was not affected when administered 5 minutes following an antacid.
Cephalosporin antibiotics may produce a false positive reaction for glucose in the urine with copper reduction tests (Benedict's or Fehling' solution or with Clinitest® 4 tablets), but not with enzyme-based tests for glycosuria (e.g., Tes-Tape® 5 ). A false negative reaction may occur in the ferricyanide test for blood glucose. The presence of cefprozil in the blood does not interfere with the assay of plasma or urine creatinine by the alkaline picrate method.
Long term in vivo studies have not been performed to evaluate the carcinogenic potential of cefprozil.
Cefprozil was not found to be mutagenic in either the Ames Salmonella or E. coli WP2 urvA reversion assays or the Chinese hamster ovary cell HGPRT forward gene mutation assay and it did not induce chromosomal abnormalities in Chinese hamster ovary cells or unscheduled DNA synthesis in rat hepatocytes in vitro . Chromosomal aberrations were not observed in bone marrow cells from rats dosed orally with over 30 times the highest recommended human dose based upon mg/m 2 .
Impairment of fertility was not observed in male or female rats given oral doses of cefprozil up to 18.5 times the highest recommended human dose based upon mg/m 2 .
Reproduction studies have been performed in rabbits, mice and rats using oral doses of cefprozil of 0.8, 8.5 and 18.5 times the maximum daily human dose (1000 mg) based upon mg/m 2 , and have revealed no harm to the fetus. 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.
Cefprozil has not been studied for use during labor and delivery. Treatment should only be given if clearly needed.
Small amounts of cefprozil (< 0.3% of dose) have been detected in human milk following administration of a single 1 gram dose to lactating women. The average levels over 24 hours ranged from 0.25 to 3.3 µg/mL. Caution should be exercised when CEFZIL is administered to a nursing woman, since the effect of cefprozil on nursing infants is unknown.
Pediatric Use: (See and DOSAGE AND ADMINISTRATION .)
The safety and effectiveness of cefprozil in the treatment of otitis media have been established in the age groups 6 months to 12 years. Use of CEFZIL for the treatment of otitis media is supported by evidence from adequate and well-controlled studies of cefprozil in pediatric patients. (See CLINICAL STUDIES section.)
The safety and effectiveness of cefprozil in the treatment of pharyngitis/ tonsillitis or uncomplicated skin and skin structure infections have been established in the age groups 2 to 12 years. Use of CEFZIL for the treatment of these infections is supported by evidence from adequate and well-controlled studies of cefprozil in pediatric patients.
The safety and effectiveness of cefprozil in the treatment of acute sinusitis have been established in the age groups 6 months to 12 years. Use of CEFZIL in these age groups is supported by evidence from adequate and well-controlled studies of cefprozil in adults.
Safety and effectiveness in pediatric patients below the age of 6 months have not been established for the treatment of otitis media or acute sinusitis or below the age of 2 years for the treatment of pharyngitis/tonsillitis or uncomplicated skin and skin structure infections. However, accumulation of other cephalosporin antibiotics in newborn infants (resulting from prolonged drug half-life in this age group) has been reported.
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 when compared to healthy adult volunteers 20-40 years of age. In clinical studies, when geriatric patients received the usual recommended adult doses, clinical efficacy and safety were acceptable and comparable to results in non-geriatric adult patients.
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 CEFZIL, have been rarely reported during post-marketing surveillance: anaphylaxis, angioedema, colitis (including pseudomembranous colitis), erythema multiforme, fever, serum-sickness like reactions, Stevens-Johnson Syndrome and thrombocytopenia.
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.
Single 5000 mg/kg oral doses of cefprozil caused no mortality or signs of toxicity in adult, weanling, or neonatal rats, or adult mice. A single oral dose of 3000 mg/kg caused diarrhea and loss of appetite in cynomolgus monkeys, but no mortality.
Cefprozil is eliminated primarily by the kidneys. In case of severe overdosage, especially in patients with compromised renal function, hemodialysis will aid in the removal of cefprozil from the body.
CEFZIL (cefprozil) is administered orally.
Cefprozil may be administered to patients with impaired renal function. The following dosage schedule should be used.
No dosage adjustment is necessary for patients with impaired hepatic function.
CEFZIL® (Cefprozil) Tablets
Each light orange film-coated tablet, imprinted with "7720" on one side and "250" on the other, contains the equivalent of 250 mg anhydrous cefprozil.
Bottles of 100 Tablets NDC 0087-7720-60
Cartons of 100 Tablets NDC 0087-7720-66
(10 strips containing 10 tablets on each strip)
Each white film-coated tablet, imprinted with "7721" on one side and "500" on the other, contains the equivalent of 500 mg anhydrous cefprozil.
Bottles of 50 Tablets NDC 0087-7721-50
Bottles of 100 Tablets NDC 0087-7721-60
Cartons of 100 Tablets NDC 0087-7721-66
(10 strips containing 10 tablets on each strip)
Store at controlled room temperature, 59° to 86° F (15° to 30° C).
CEFZIL® (Cefprozil) For Oral Suspension
Each 5 mL of constituted suspension contains the equivalent of 125 mg anhydrous cefprozil.
50 mL Bottle NDC 0087-7718-40
75 mL Bottle NDC 0087-7718-62
100 mL Bottle NDC 0087-7718-64
Each 5 mL of constituted suspension contains the equivalent of 250 mg anhydrous cefprozil.
50 mL Bottle NDC 0087-7719-40
75 mL Bottle NDC 0087-7719-62
100 mL Bottle NDC 0087-7719-64
All powder formulations for oral suspension contain cefprozil in a bubble-gum flavored mixture.
Reconstitution Directions for Oral Suspension
Prepare the suspension at the time of dispensing; for ease in preparation, add water in two portions and shake well after each aliquot.
After mixing, store in a refrigerator and discard unused portion after 14 days.
Store at 59° to 77° F (15° to 25° C) prior to constitution.
U.S. Patent No. 4,520,022
In a controlled clinical study of acute otitis media performed in the United States where significant rates of (beta)-lactamase producing organisms were found, cefprozil was compared to an oral antimicrobial agent that contained a specific (beta)-lactamase inhibitor. In this study, using very strict evaluability criteria and microbiologic and clinical response criteria at the 10-16 days post-therapy follow-up, the following presumptive bacterial eradication/clinical cure outcomes (i.e. clinical success) and safety results were obtained:
In a controlled clinical study of acute otitis media performed in Europe, cefprozil was compared to an oral antimicrobial agent that contained a specific (beta)-lactamase inhibitor. As expected in a European population, this study population had a lower incidence of (beta)-lactamase-producing organisms than usually seen in U.S. trials. In this study, using very strict evaluability criteria and microbiologic and clinical response criteria at the 10-16 days post-therapy follow-up, the following presumptive bacterial eradication/clinical cure outcomes (i.e. clinical success) were obtained:
Revised March 1998
Bristol-Myers Squibb Company
Princeton, New Jersey 08543