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 1).
| TABLE 1 |
| Dosage (mg) |
Mean Plasma Cefprozil*
Concentrations (mcg/ml) |
8-hour Urinary Excretion
(%) |
| |
Peak appx. 1.5 hr |
4 hr |
8 hr |
|
| 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 mg/ml, 1000 mcg/ml,
and 2900 mcg/ml, respectively.
Administration of cefprozil tablet or suspension formulation
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 ceprozil (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 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 (³
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 TABLE 2A and
TABLE 2B.
| TABLE 2A |
| Mean (SD) Plasma
Cefprozil Concentrations (mcg/ml) |
| Population |
Dose |
1 hr |
2 hr |
4 hr |
| Children (n=18) |
7.5 mg/kg |
4.70 (1.57) |
3.99 (1.24) |
0.91 (0.30) |
| Adults (n=12) |
250 mg |
4.82 (2.13) |
4.92 (1.13) |
1.70 † (0.53) |
| Children (n=19) |
15 mg/kg |
10.86 (2.55) |
8.47 (2.03) |
2.75 (1.07) |
| Adults (n=12) |
500 mg |
8.39 (1.95) |
9.42 (0.98) |
3.18 §(0.76) |
| Children (n=10) |
30 mg/kg |
16.69 (4.26) |
17.61 (6.39) |
8.66 (2.70) |
| Adults (n=12) |
1000 mg |
11.99 (4.67) |
16.95 (4.07) |
8.36 (4.13) |
| † n=5
, § n=11 |
| TABLE 2B |
| Mean (SD) Plasma
Cefprozil Concentrations (mcg/ml) |
| Population |
Dose |
6 hr |
T½ (hr) |
| Children (n=18) |
7.5 mg/kg |
0.23 * (0.13) |
0.94 (0.32) |
| Adults (n=12) |
250 mg |
0.53 (0.17) |
1.28 (0.34) |
| Children (n=19) |
15 mg/kg |
0.61 ‡ (0.27) |
1.24 (0.43) |
| Adults (n=12) |
500 mg |
1.00 § (0.24) |
1.29 (0.14) |
| Children (n=10) |
30 mg/kg |
---- |
2.06 (0.21) |
| Adults (n=12) |
1000 mg |
2.79 (1.77) |
1.27 (0.12) |
| * n=11
, ‡ n=9 , § n=11 |
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 INDICATIONS
AND USAGE.
Aerobic Gram-positive Microorganisms
Staphylococcus aureus (including
b-lactamase-producing strains)
Streptococcus pneumoniae
Streptococcus pyogenes
NOTE: Cefprozil is inactive against methicillin-resistant
staphylococci.
Aerobic Gram-negative Microorganisms
Haemophilus influenzae (including b-lactamase-producing
strains)
Moraxella (Brannamella) catarnalis (including b-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 mcg/ml
or less against most (³90%) 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
Listena monocytogenes
Staphylococcus epidermidis
Staphylococcus saprophyticus
Staphylococcus wamen
Streptococcus agaiactiae
Streptococci (Groups C.D.F. and
G)
Viridans group Streptococci
NOTE: Cefprozil is inactive against Enterococcus
taecium.
Aerobic Gram-negative Microorganisms
Citrobacter diversus
Eschenchia coli
Kiebsiella pneumoniae
Neissena gonorrhoeae (including
b-lactamase-producing strains)
Proteus mirabilis
Salmonella spp.
Shigella spp.
Vibrio spp.
NOTE: Cefprozil is inactive against most
strains of Acinetobacter, Enterobacter, Morganella morganii,
Proteus vulgans, Providencia, Pseudomonas, and Serratia.
Anaerobic Microorganisms
Prevotella (Bacteroides) melaninogenicus
Clostridium difficile
Clostridium perfringens
Fusobacterium spp.
Peptostreptococcus spp.
Propionibactenum acnes
NOTE: Most strains of the Bacteroides
tragilis group are resistant to cefprozil.
Susceptibility Tests
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 method1,2 (broth or agar)
or equivalent with standardized inoculum concentrations
and standardized concentrations of cefprozil powder. The
MIC values should be interpreted according to the criteria
found in TABLE 3.
| TABLE 3 |
| MIC (mcg/ml) |
Interpretation |
| £8 |
Susceptible (S) |
| 16 |
Intermediate (I) |
| ³32 |
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 MIC values found in
TABLE 4.
| TABLE 4 |
| Microorganism |
MIC (mcg/ml) |
| 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 |
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 procedure3
requires the use of standardized inoculum concentrations.
This procedure uses paper disks impregnated with 30-mcg
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-mcg cefprozil
disk should be interpreted according to the criteria found
in TABLE 5.
| TABLE 5 |
| Zone diameter (mm) |
Interpretation |
| ³18 |
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
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.
| TABLE 6 |
| Microorganism |
Zone diameter (mm) |
| Escherichia coli ATCC 25922 |
21-27 |
| Haemophilus influenzae
ATCC 49766 |
20-27 |
| Staphylococcus aureus ATCC
25923 |
27-33 |
| Streptococcus pneumoniae
ATCC 49619 |
25-32 |
CLINICAL STUDIES
Study One
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
(see TABLE 7).
| TABLE 7 U.S.
Acute Otitis Media Study |
| Cefprozil
vs beta-lactamase inhibitor-containing control drug |
| 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 incidence of adverse events, primarily diarrhea and
rash*, were clinically and statistically significantly higher
in the control arm versus the cefprozil arm (see TABLE 8).
| TABLE 8 |
| 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 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 (see
TABLE 9)
| TABLE 9 European
Acute Otitis Media Study |
| Cefprozil
vs beta-lactamase inhibitor-containing control drug |
| 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 beta-lactamase
inhibitor).
|
|
