Cefprozil (cefprozil 250 mg) Dailymed

To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefprozil and other antibacterial drugs, cefprozil should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Description

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 C₁₈H₁₉N₃O₅S•H₂O and a molecular weight of 407.44.

Cefprozil Tablets and Cefprozil for Oral Suspension are intended for oral administration.

Each cefprozil tablet contains cefprozil equivalent to 250 mg or 500 mg of anhydrous cefprozil. In addition each tablet contains the following inactive ingredients: hypromellose, magnesium stearate, methylcellulose, microcrystalline cellulose, polyethylene glycol 400, polysorbate 80, sodium starch glycolate and titanium dioxide. The 500 mg tablets also contain ferric oxide.

Cefprozil 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, carboxymethylcellulose sodium, citric acid anhydrous, colloidal silicon dioxide, FD & C Yellow No. 6, glycine, microcrystalline cellulose and carboxymethylcellulose sodium, polysorbate 80, simethicone, sodium benzoate, sodium chloride, sucrose, and Tutti-Frutti flavor.

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) Data represent mean values of 12 healthy volunteers.			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%

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 (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 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.

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	T1/2(h)
children	7.5 mg/kg	4.70	3.99	0.91	0.23n=11;	0.94
(n=18)		(1.57)	(1.24)	(0.30)	(0.13)	(0.32)
adults	250 mg	4.82	4.92	1.70n=5;	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	0.61n=9;	1.24
(n=19)		(2.55)	(2.03)	(1.07)	(0.27)	(0.43)
adults	500 mg	8.39	9.42	3.18n=11.	1.00	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 INDICATIONS AND USAGE section.

Aerobic Gram-Positive Microorganisms

Staphylococcus aureus

(including β-lactamase-producing strains)

NOTE: Cefprozil is inactive against methicillin-resistant staphylococci.

Streptococcus pneumoniae

Streptococcus pyogenes

Aerobic Gram-Negative Microorganisms

Haemophilus influenzae

(including β-lactamase-producing strains)

Moraxella (Branhamella) catarrhalis

(including β-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 β-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

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:

MIC (mcg/mL)	Interpretation
≤ 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:

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

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 following criteria:

Zone diameter (mm)	Interpretation
≥ 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.

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