Cefprozil 500 Mg Oral Tablet
- DESCRIPTION
- CLINICAL PHARMACOLOGY
- Microbiology:
- INDICATIONS AND USAGE
- CONTRAINDICATIONS
- WARNINGS
- PRECAUTIONS
- Information for Patients:
- DRUG INTERACTIONS
- Drug/Laboratory Test Interactions:
- Carcinogenesis, Mutagenesis, Impairment of Fertility:
- Pregnancy:
- Labor and Delivery:
- Nursing Mothers:
- Pediatric Use:
- Geriatric Use:
- ADVERSE REACTIONS
- OVERDOSAGE
- DOSAGE AND ADMINISTRATION
- HOW SUPPLIED
- CLINICAL STUDIES
- REFERENCES
- ASK A DOCTOR
DESCRIPTION
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 tablets are intended for oral administration.
Cefprozil tablets contain cefprozil equivalent to 250 mg or 500 mg of anhydrous cefprozil. In addition, each tablet contains the following inactive ingredients: magnesium stearate, methylcellulose, microcrystalline cellulose, sodium starch glycolate and titanium dioxide. The 250 mg tablet also contains FD and C Yellow No. 6 Aluminum Lake.
CLINICAL PHARMACOLOGY
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 mcg/mL, respectively, and were obtained within 1.5 hours after dosing. Urinary recovery accounted for approximately 60% of the administered dose. (See Table.)
| Dosage (mg) |
|
Mean Plasma Cefprozil Concentrations (mcg/mL)* |
|
8 hour Urinary Excretion (%) |
|
|
Peak appx. 1.5 h | 4 h | 8 h |
|
| 250 mg | 6.1 | 1.7 | 0.2 | 60% |
| 500 mg | 10.5 | 3.2 | 0.4 | 62% |
| 1000 mg | 18.3 | 8.4 | 1.0 | 54% |
* Data represent mean values of 12 healthy volunteers.
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 mcg/mL, 1000 mcg/mL, and 2900 mcg/mL, respectively.
Administration of cefprozil with food did not affect the extent of absorption (AUC) or the peak plasma concentration (Cmax) of cefprozil. However, there was an increase of 0.25 to 0.75 hours in the time to maximum plasma concentration of cefprozil (Tmax).
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 mcg/mL to 20 mcg/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
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% to 60% higher AUC and 40% lower renal clearance values compared with healthy adult volunteers 20 to 40 years of age. The average AUC in young and elderly female subjects was approximately 15% to 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 to 12 years) and adults following oral administration of selected matched doses. The maximum concentrations are achieved at 1 to 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.
|
|
Mean (SD) Plasma Cefprozil | |||||
|
|
Concentrations (mcg/mL) | |||||
| Population | Dose | 1 h | 2 h | 4 h | 6 h | T½ (h) |
| children | 7.5 mg/kg | 4.70 | 3.99 | 0.91 | 0.23 a | 0.94 |
| (n=18) |
|
(1.57) | (1.24) | (0.30) | (0.13) | (0.32) |
| adults | 250 mg | 4.82 | 4.92 | 1.70b | 0.53 | 1.28 |
| (n=12) |
|
(2.13) | (1.13) | (0.53) | (0.17) | (0.34) |
| children | 15 mg/kg | 10.86 | 8.47 | 2.75 | 0.61c | 1.24 |
| (n=19) |
|
(2.55) | (2.03) | (1.07) | (0.27) | (0.43) |
| adults | 500 mg | 8.39 | 9.42 | 3.18d | 1.00d | 1.29 |
| (n=12) |
|
(1.95) | (0.98) | (0.76) | (0.24) | (0.14) |
| children | 30 mg/kg | 16.69 | 17.61 | 8.66 | -- | 2.06 |
| (n=10) |
|
(4.26) | (6.39) | (2.70) |
|
(0.21) |
| adults | 1000 mg | 11.99 | 16.95 | 8.36 | 2.79 | 1.27 |
| (n=12) |
|
(4.67) | (4.07) | (4.13) | (1.77) | (0.12) |
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
Staphylococcus aureus
(including ß-lactamase-producing strains)
NOTE: Cefprozil is inactive against methicillin-resistant staphylococci.
Streptococcus pneumoniae
Streptococcus pyogenes
Aerobic Gram-Negative Microorganisms:Haemophilus influenzae
(including ß-lactamase-producing strains)
Moraxella (Branhamella) catarrhalis
(including ß-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 mcg/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 ß-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:
|
|
|
| ≤8 | Susceptible (S) |
| 16 | Intermediate (I) |
| ≥32 | Resistant (R) |
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:
|
|
|
|
Enterococcus faecalis ATCC 29212 |
4-16 |
|
Escherichia coli ATCC 25922 |
1-4 |
|
Haemophilus influenzae ATCC 49766 |
1-4 |
|
Staphylococcus aureus ATCC 29213 |
0.25-1 |
|
Streptococcus pneumoniae ATCC 49619 |
0.25-1 |
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 mcg cefprozil disk should be interpreted according to the following criteria:
|
|
|
| ≥18 | Susceptible (S) |
| 15-17 | Intermediate (I) |
| ≤14 | Resistant (R) |
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 mcg cefprozil disk should provide the following zone diameters in these laboratory test quality control strains.
|
|
|
|
Escherichia coli ATCC 25922 |
21-27 |
|
Haemophilus influenzae ATCC 49766 |
20-27 |
|
Staphylococcus aureus ATCC 25923 |
27-33 |
|
Streptococcus pneumoniae ATCC 49619 |
25-32 |
INDICATIONS AND USAGE
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.
NOTE: In the treatment of otitis media due to ß-lactamase producing organisms, cefprozil had bacteriologic eradication rates somewhat lower than those observed with a product containing a specific ß-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 ß-lactamase inhibitors.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefprozil tablets and other antibacterial drugs, cefprozil tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and 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.
CONTRAINDICATIONS
Cefprozil is contraindicated in patients with known allergy to the cephalosporin class of antibiotics.WARNINGS
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Cefprozil, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
PRECAUTIONS
In patients with known or suspected renal impairment (see
Prolonged use of cefprozil 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.
Information for Patients:
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 two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
DRUG INTERACTIONS
The bioavailability of the capsule formulation of cefprozil was not affected when administered 5 minutes following an antacid.
Drug/Laboratory Test Interactions:
Cephalosporin antibiotics may produce a false positive reaction for glucose in the urine 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®). 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.Carcinogenesis, Mutagenesis, Impairment of Fertility:
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/m2.
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/m2.
Pregnancy:
Labor and Delivery:
Cefprozil has not been studied for use during labor and delivery. Treatment should only be given if clearly needed.Nursing Mothers:
Small amounts of cefprozil (less than 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 mcg/mL. Caution should be exercised when cefprozil tablets are administered to a nursing woman, since the effect of cefprozil on nursing infants is unknown.Pediatric Use:
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 cefprozil
for the treatment of otitis media is supported by evidence from adequate and
well-controlled studies of cefprozil in pediatric patients. (See
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 cefprozil 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 cefprozil 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.
Geriatric Use:
Cefprozil is known to be substantially excreted by the kidney, and the risk
of toxic reactions to this drug may be greater in patients with impaired renal
function. Because elderly patients are more likely to have decreased renal
function, care should be taken in dose selection and it may be useful to monitor
renal function. See
ADVERSE REACTIONS
The most common adverse effects observed in patients treated with cefprozil are:
The following adverse events, regardless of established causal relationship to cefprozil tablets, 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.
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
OVERDOSAGE
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.
DOSAGE AND ADMINISTRATION
Cefprozil tablets are administered orally.| Population/Infection | Dosage (mg) | Duration (days) |
| ADULTS (13 years and older) |
|
|
| UPPER RESPIRATORY TRACT |
|
|
| Pharyngitis/Tonsillitis | 500 q24h | 10 a |
| Acute Sinusitis | 250 q12h or | 10 |
| (For moderate to severe infections, the higher dose should be used) | 500 q12h |
|
| LOWER RESPIRATORY TRACT |
|
|
| Secondary Bacterial Infection of Acute Bronchitis and Acute Bacterial Exacerbation of Chronic Bronchitis |
500 q12h | 10 |
| SKIN AND SKIN STRUCTURE |
|
|
| Uncomplicated Skin and Skin Structure Infections | 250 q12h or | 10 |
|
|
500 q24h or |
|
|
|
500 q12h |
|
| CHILDREN (2 years-12 years) |
|
|
| UPPER RESPIRATORY TRACT b |
|
|
| Pharyngitis/Tonsillitis | 7.5 mg/kg q12h | 10 a |
| SKIN AND SKIN STRUCTURE b |
|
|
| Uncomplicated Skin and Skin Structure Infections | 20 mg/kg q24h | 10 |
| INFANTS and CHILDREN (6 months-12 years) |
|
|
| UPPER RESPIRATORY TRACT b |
|
|
| Otitis Media | 15 mg/kg q12h | 10 |
|
(See
|
|
|
| Acute Sinusitis | 7.5 mg/kg q12h or | 10 |
| (For moderate to severe infections, the higher dose should be used) | 15 mg/kg q12h |
a In the treatment of infections due to Streptococcus pyogenes, cefprozil for oral suspension should be administered for at least 10 days.
b Not to exceed recommended adult doses.
Renal Impairment:
Cefprozil may be administered to patients with impaired renal function. The following dosage schedule should be used.
|
Creatinine Clearance (mL/min) |
Dosage (mg) |
Dosing Interval |
| 30-120 | standard | standard |
| 0-29 |
50% of standard | standard |
Hepatic Impairment:
No dosage adjustment is necessary for patients with impaired hepatic function.
HOW SUPPLIED
Cefprozil tablets USP, 250 mg and 500 mg are available as follows:Each white film-coated, oval tablet debossed with ‘LUPIN’ on one side and ‘500’ on the other side, contains the equivalent of 500 mg anhydrous cefprozil.
Bottles of 20 Tablets NDC 67296-0590-1
Store at 20°-25°C (68°-77°F) [See USP Controlled Room Temperature].
CLINICAL STUDIES
In a controlled clinical study of acute otitis media performed in the United States where significant rates of ßlactamase- producing organisms were found, cefprozil was compared to an oral antimicrobial agent that contained a specific ß-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:
EFFICACY:
|
Pathogen |
% of Cases with Pathogen(n=155) |
Outcome |
|
S. pneumoniae |
48.4% | cefprozil success rate 5% better than control |
|
H. influenzae |
35.5% | cefprozil success rate 17% less than control |
|
M. catarrhalis |
13.5% | cefprozil success rate 12% less than control |
|
S. pyogenes |
2.6% | cefprozil equivalent to control |
| Overall | 100.0% | cefprozil success rate 5% less than control |
SAFETY:
The incidences of adverse events, primarily diarrhea and rash*, were clinically and statistically significantly higher in the control arm versus the cefprozil arm.
|
Age Group |
Cefprozil |
Control |
| 6 months-2 years | 21% | 41% |
| 3-12 years | 10% | 19% |
* The majority of these involved the diaper area in young children.
Study Two:
In a controlled clinical study of acute otitis media performed in Europe, cefprozil was compared to an oral antimicrobial agent that contained a specific ß-lactamase inhibitor. As expected in a European population, this study population had a lower incidence of ß-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:
EFFICACY:
|
Pathogen |
% of Cases with Pathogen(n=47) |
Outcome |
|
S. pneumoniae |
51.0% | cefprozil equivalent to control |
|
H. influenzae |
29.8% | cefprozil equivalent to control |
|
M. catarrhalis |
6.4% | cefprozil equivalent to control |
|
S. pyogenes |
12.8% | cefprozil equivalent to control |
| Overall | 100.0% | cefprozil equivalent to control |
SAFETY:
The incidence of adverse events in the cefprozil arm was comparable to the incidence of adverse events in the control arm (agent that contained a specific ß-lactamase inhibitor).
REFERENCES
- 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.
- 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.
- 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.
Manufactured for: Manufactured by
Lupin Pharmaceuticals, Inc. Lupin Limited
Baltimore, Maryland 21202 Mumbai 400 098
United States INDIA
Revised: December, 2007 ID#: 213043