INDICATIONS AND CLINICAL USE

Sandoz Cefprozil (cefprozil) is indicated for treatment of the following infections caused by susceptible strains of the designated microorganisms:

UPPER RESPIRATORY TRACT

Pharyngitis/tonsillitis Streptococcus pyogenes.

caused by group A b-hemolytic (GABHS)

Substantial data establishing the efficacy of cefprozil in the subsequent prevention of rheumatic fever are not available at present, although no case was reported during its evaluation in over 978 pediatric and 831 adult patients in controlled clinical trials.

Otitis media Streptococcus pneumoniae, Haemophilus influenzae, Moraxella (Branhamella) catarrhalis.

caused by

Acute sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae, (beta- lactamase positive and negative strains), and Moraxella (Branhamella) catarrhalis.

SKIN AND SKIN STRUCTURE

Uncomplicated skin and skin-structure infections Staphylococcus aureus

caused by

(including penicillinase-producing strains) and Streptococcus pyogenes.

URINARY TRACT

Uncomplicated urinary tract infections

(including acute cystitis) caused by

Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis.

Cultures and susceptibility studies should be performed when appropriate.

CONTRAINDICATIONS

Patients who are hypersensitive to this drug, to the cephalosporin class of antibiotics, or to any ingredient in the formulations or component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING, COMPOSITION section of the Product Monograph.

WARNINGS AND PRECAUTIONS

Before therapy with cefprozil is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cefprozil, 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 cefprozil 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. 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". Pseudomembranous colitis is associated with the use of broad-spectrum antibiotics (including macrolides, semisynthetic penicillins and cephalosporins) 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. After the diagnosis of pseudomembranous colitis has been established, 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 oral antibacterial drug effective against C. difficile (e.g. metronidazole).

GENERAL

Evaluation of renal status before and during therapy is recommended, especially in seriously ill patients. 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 cefprozil should be reduced in patients with creatinine clearance values <=30 mL/min because high and/or prolonged plasma antibiotic concentrations can occur from usual doses in such individuals. Cephalosporins, including cefprozil, 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 cefprozil may result in the overgrowth of non-susceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken. Positive direct Coombs tests have been reported during treatment with cephalosporin antibiotics.

SPECIAL POPULATIONS

Pregnant Women

Reproduction studies have been performed in mice, rats and rabbits at doses 14, 7 and 0.7 times the maximum human daily dose (1000 mg) based upon mg/m2, and have revealed no evidence of harm to the fetus due to cefprozil. 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 the potential benefit justifies the potential risk.

Nursing Women

Less than 1.0% of a maternal dose is excreted in human milk. Caution should be exercised when cefprozil is administered to a nursing mother. Consideration should be given to temporary discontinuation of nursing and use of formula feeding.

Pediatrics

The use of cefprozil in the treatment of acute sinusitis in these age groups is supported by evidence from adequate and well-controlled studies of cefprozil in adults and from pediatric pharmacokinetic studies. Safety and effectiveness in children below the age of 6 months have not been established. Accumulation of other cephalosporin antibiotics in newborn infants (resulting from prolonged drug half-life in this age group) has been reported.

Geriatrics

Cefprozil has not been studied in the chronically ill or institutionalized elderly subjects. In these subjects, drug clearance by the kidney may be reduced even with normal serum creatinine clearance. Reduction of dose or of frequency of administration may be indicated.

ADVERSE REACTIONS

ADVERSE DRUG REACTION OVERVIEW

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.

CLINICAL TRIAL ADVERSE DRUG REACTIONS

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. The most common adverse events (of probable or unknown relationship to study drug) observed in 4227 patients treated with cefprozil in clinical efficacy trials are:

Gastrointestinal

: Diarrhea (2.7%), nausea (2.3%), vomiting (1.4%) and abdominal pain (0.9%).

Hepatobiliary

: As with some penicillins and some other cephalosporin antibiotics, cholestatic jaundice has been reported rarely.

Hypersensitivity

: Rash (1.2%), erythema (0.1%), pruritus (0.3%) and urticaria (0.07%). 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, hyperactivity, headache, nervousness, insomnia, confusion and drowsiness have been reported rarely (<1%) and causal relationship is uncertain. All were reversible.

Other:

Genital pruritus (0.8%) and vaginitis (0.7%).

LABORATORY ABNORMALITIES

Transitory abnormalities in clinical laboratory test results of uncertain etiology have been reported during clinical trials as follows:

HepatobiliaryHematopoieticRenal

: Elevations of AST, ALT, alkaline phosphatase, and bilirubin.

: Transiently decreased leukocyte count and eosinophilia.

: Slight elevations in BUN and serum creatinine.

POSTMARKET ADVERSE DRUG REACTIONS

Adverse reactions reported from postmarketing experience and which were not seen in the clinical trials include serum sickness, pseudomembranous colitis, Stevens Johnson syndrome and exfoliative dermatitis. The association between these events and cefprozil administration is unknown.

CEPHALOSPORIN-CLASS ANTIBIOTICS ADVERSE DRUG REACTIONS

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. Anaphylaxis, erythema multiforme, toxic epidermal necrolysis, fever, renal dysfunction, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, prolonged prothrombin time, positive Coombs's tests, elevated LDH, pancytopenia, neutropenia, agranulocytosis, thrombocytopenia. 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.

DRUG INTERACTIONS

Nephrotoxicity has been reported following concomitant administration of aminoglycoside antibiotics and cephalosporin antibiotics. Concomitant administration of probenecid doubled the area under the curve for cefprozil. If an aminoglycoside is used concurrently with cefprozil, especially if high dosages of the former are used or if therapy is prolonged, renal function should be monitored because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics.

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 (glucose oxidase) for glycosuria. 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.

DOSAGE AND ADMINISTRATION

RECOMMENDED DOSE AND DOSAGE ADJUSTMENT

Sandoz Cefprozil (cefprozil) is administered orally (with or without food), in the treatment of infections due to susceptible bacteria in the following doses:

Adults (13 years and older)

Upper respiratory tract (pharyngitis/tonsillitis) 500 mg q24h Acute sinusitis 250 mg or 500 mg q 12h Skin & skin structure 250 mg q12h or 500 mg q24h Uncomplicated urinary tract 500 mg q24h

Children (2 years-12 years)

Ages given are a useful guide only. Correct dosage should be determined by weight.

Infants and children (6 months-12 years)

Ages given are a useful guide only. Correct dosage should be determined by weight.

Skin & skin structure 20 mg/kg q24h
Age * (years)	Weight (kg)	Multidose Bottle
125 mg/5mL	250 mg/5 mL
tsp/dose	mL/dose	tsp/dose	mL/dose
2-3	11-14	2.0	10.0	1.0	5.0
4-6	15-21	3.0	15.0	1.5	7.5
7-8	22-26	---	---	2.0	10.0
9-10	28-31	---	---	2.5	12.5
11	35	---	---	3.0	15.0

Otitis media 15 mg/kg q12h
Age * (years)	Weight (kg)	Multidose Bottle
125 mg/5mL	250 mg/5 mL
tsp/dose	mL/dose	tsp/dose	mL/dose
6 mths-1 yr	7-9	1.0	5.0	0.5	2.5
2	11-12	1.5	7.5	0.75	3.75
3-4	14-15	---	---	1.0	5.0
5-6	17-21	---	---	1.25	6.25
7-8	22-26	---	---	1.5	7.5
9-10	28-31	---	---	1.75	8.75
11-12	35-39	---	---	2.0	10.0

Upper respiratory tract (pharyngitis/tonsillitis) 7.5 mg/kg q12h
Age * (years)	Weight (kg)	Multidose Bottle
125 mg/5mL	250 mg/5 mL
tsp/dose	mL/dose	tsp/dose	mL/dose
6 mths-1 yr	7-9	0.5	2.5	---	---
2-6	11-21	1.0	5.0	0.5	2.5
7-9	22-28	---	---	0.75	3.75
10-11	31-35	---	---	1.0	5.0
12	41	---	---	1.25	6.25

Acute sinusitis 7.5 mg/kg q 12h or 15 mg/kg q 12h Follow dosing instructions as for otitis media and upper respiratory tract presented above. The maximum pediatric daily dose should not exceed the maximum daily dose recommended for adults (i.e. 1 g per day).

ADMINISTRATION

Duration of Therapy

Duration of therapy in the majority of clinical trials was 10 to 15 days. The duration of treatment should be guided by the patient's clinical and bacteriological response. In the treatment of acute uncomplicated cystitis, a 7 day oral therapy is usually sufficient. In the treatment of infections due to Streptococcus pyogenes, a therapeutic dosage of Sandoz Cefprozil should be administered for at least 10 days.

Renal Impairment

Cefprozil may be administered to patients with impaired renal function. No dosage adjustment is necessary for patients with creatinine clearance values >30 mL/min. For those with creatinine clearance values <=30 mL/min, 50% of the standard dose should be given at the standard dosing interval. Cefprozil is in part removed by hemodialysis; therefore, cefprozil should be administered after the completion of hemodialysis.

RECONSTITUTION OF SANDOZ CEFPROZIL FOR ORAL SUSPENSION

Prior to dispensing, the pharmacist must constitute the dry powder with water as follows:
Sandoz Cefprozil for oral suspension	Bottle size (mL)	Diluent (water) added to bottle (mL)	Approximate available volume (mL)	Final concentration
125 mg/5 mL	75	54	75	l25 mg/5 mL
100	72	100	l25 mg/5 mL
250 mg/5 mL	75	54	75	250mg/5 mL
100	72	100	250 mg/5 mL

For ease in preparation, the water can be added in two portions. Shake well after each addition and prior to use.

OVERDOSAGE

Since no case of overdosage has been reported to date, no specific information on symptoms or treatment of overdosage is available. In animal toxicology studies, single doses as high as 5000 mg/kg were without serious or lethal consequences. 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.

ACTION AND CLINICAL PHARMACOLOGY

MECHANISM OF ACTION

Cefprozil is a semisynthetic broad-spectrum cephalosporin antibiotic intended for oral administration. It 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.

PHARMACOKINETICS

Absorption:

Cefprozil is well absorbed following oral administration in both fasting and non-fasting subjects. The oral bioavailability of cefprozil is about 90%. The pharmacokinetics of cefprozil are not altered when administered with meals, or when coadministered with antacid. Average plasma concentrations after administration of cefprozil to fasting subjects are shown in the following table. The average plasma half- life in normal subjects is 1.3 hours.

Distribution:

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

Excretion:

Urinary recovery accounts for 60% of the administered dose. During the first four-hour period after drug administration, the average urine concentrations following the 250 mg, 500 mg, and 1 g doses were approximately 170 mcg/mL, 450 mcg/mL and 600 mcg/mL, respectively. There is no evidence of accumulation of cefprozil in the plasma in individuals with normal renal function following multiple oral doses of up to 1 g every 8 hours for 10 days.

SPECIAL POPULATIONS AND CONDITIONS

Pediatrics:

Comparable pharmacokinetic parameters of cefprozil are observed between pediatric patients (6 months-12 years) and adults following oral administration. The maximum plasma concentrations are achieved at 1-2 hours after dosing. The plasma elimination half-life is approximately 1.5 hours. The AUC of cefprozil to pediatric patients after 7.5, 15 and 30 mg/kg doses is similar to that observed in normal adult subjects after 250, 500 and 1000 mg doses, respectively.

Geriatrics:

Following administration of a single 1 g dose of cefprozil, the average AUC observed in healthy elderly subjects (>=65 years of age) was approximately 35-60% higher than that of healthy young adults and the average AUC in females was approximately 15- 20% higher than in males. The magnitude of these age and gender-related variations in the pharmacokinetics of cefprozil are not sufficient to necessitate dosage adjustments.

Hepatic Insufficiency:

In patients with impaired hepatic function, no differences in pharmacokinetic parameters were observed, when compared to normal control subjects.

Renal Insufficiency:

In patients with reduced renal function, the plasma half-life prolongation is related to the degree of the renal dysfunction and may be prolonged up to

5.2 hours. In patients with complete absence of renal function, the plasma half-life of cefprozil averaged 5.9 hours. The half-life is shortened during hemodialysis to 2.1 hours. Excretion pathways in patients with markedly impaired renal function have not been determined. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.)

STORAGE AND STABILITY

Sandoz Cefprozil for oral suspension must be stored between 15 and 30oC. The constituted Sandoz Cefprozil oral suspension must be refrigerated between 2 and 8degC for up to 14 days. Keep container tightly closed. Discard unused portion after 14 days.

DOSAGE FORMS, COMPOSITION AND PACKAGING

DOSAGE FORMS

Sandoz Cefprozil for oral suspension contains cefprozil, in an orange-flavoured mixture, equivalent to 125 mg or 250 mg cefprozil per 5 mL of constituted solution.

COMPOSITION

In addition to the active ingredient cefprozil, Sandoz Cefprozil for oral suspension also contains: aspartame, citric acid, colloidal silicone dioxide, flavours (natural and artificial), FD&C Yellow no. 6, microcrystalline cellulose, sodium benzoate, sodium carboxymethylcellulose, sodium chloride, simethicone, sucrose, polysorbate 80 and glycine.

PACKAGING

Sandoz Cefprozil for oral suspension 125 mg/5mL and 250 mg/5 mL are available in bottles of 75 mL and 100 mL. PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE

Proper Name

Chemical Name: (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 Empirical Formula: C18H19N3O5S *H2O Molecular Mass: 407.45 Structural Formula:

Physicochemical Properties:

Cefprozil is a cis and trans isomeric mixture in a 9:1 ratio. It is a white to yellowish powder.

CLINICAL TRIALS

The following solubilities of Cefprozil milled were found:
Solvent	Results of Analysis
Methanol	Slightly soluble
Water	Slightly soluble
Acetone	Practically insoluble
Dichloromethane	Practically insoluble

A single dose, randomised, 2-way crossover bioequivalence study of Sandoz's Cefprozil versus Bristol-Myers Squibb's Cefzil, each administered as 10 mL x 125 mg/5mL (total dose of 250 mg) oral suspension, was conducted on a total of 18 healthy male and female volunteers (10 males and 8 females, aged 18-55 years) under fasting conditions

Summary Table of the Comparative Bioavailability Data

+ Cefzil(r) 125 mg/5mL (cefprozil) Powder for Oral Suspension (Bristol-Myers Squibb Canada Inc),

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 is more stable than cefaclor to beta lactamase hydrolysis by plasmid-encoded penicillinases including TEM and S. aureus enzymes as well as class Ia, Ib, Ic and Id enzymes. The in vitro activity of cefprozil against clinical isolates is shown below:

Cefprozil is inactive against methicillin resistant Staphylococci, Enterococcus faecium, most strains of Acinetobacter, Enterobacter, Morganella morganii, Proteus vulgaris, Providencia, Pseudomonas and Serratia.

SUSCEPTIBILITY TESTS

Diffusion Techniques

Quantitative methods that require measurement of zone diameters give the most precise estimate of the susceptibility of bacteria to antimicrobial agents. Interpretation involves correlation of the diameter obtained in the disk test with the minimum inhibitory concentration (MIC) for cefprozil. The class disk for cephalosporin susceptibility testing (the cephalothin disk) is not appropriate because of spectrum differences with cefprozil. The 30 mcg cefprozil disk should be used for all in vitro testing of isolates and should be interpreted according to the following criteria:

A report of "Susceptible" indicates that the pathogen is likely to be inhibited by generally achievable blood concentrations. A report of "Moderately Susceptible" indicates that the organism would be susceptible if high dosage is used or if the infection is confined to tissues and fluids (e.g. urine) in which high antibiotic levels are attained. A report of "Resistant" indicates that the achievable concentration of the antibiotic is unlikely to be inhibitory. Standardized procedures require the use of laboratory control organisms. The 30 mcg cefprozil disk should give the following zone diameters:

Dilution Techniques

Use a standardized dilution method (broth, agar, microdilution) or equivalent with cefprozil powder. The MIC values obtained should be interpreted according to the following criteria:

As with standard diffusion techniques, dilution techniques require the use of laboratory control organisms. Standard cefprozil powder should give the following MIC values:

TOXICOLOGY

ACUTE TOXICITY

No deaths occurred. The only sign of toxicity in mice was a decreased body weight gain in males given cefprozil by oral gavage. There were no signs of toxicity in neonatal (5 days of age), weanling (23 days of age) or adult (7 weeks) rats following administration of cefprozil 5000 mg/kg by oral gavage. Signs of toxicity in monkeys included soft or liquid stools and sporadically disturbed appetite.

BACUTE TOXICITY

CHRONIC TOXICITY

REPRODUCTION AND TERATOLOGY

REPRODUCTION AND TERATOLOGY (cont'd)

SPECIAL STUDIES

There were no testicular changes noted in special screening studies conducted with cefprozil. No evidence of nephrotoxicity or systemic toxicity was apparent in rabbits given cefprozil by oral gavage with single doses up to 1000 mg/kg. Cefprozil administered orally at doses up to 500 mg/kg/day to neonatal male rats on postnatal days 6 through 11 resulted in neither testicular toxicity nor systemic toxicity. In rats given either cefprozil (cis/trans isomers in a 9:1 ratio), the cis isomer or the trans isomer at 1500 mg/kg/day by oral gavage for one month, alopecia, salivation, reduced body weight in males, decreased litter weight and increased kidney weight were observed. No clinical pathology or gross or microscopic pathology was observed. There were no remarkable differences in the toxicity of the cis isomer, the trans isomer or cefprozil (the isomeric mixture) in rats given 1500 mg/kg/day by oral gavage for one month.

MUTAGENICITY AND GENOTOXICITY

Cefprozil (cis isomer) was not mutagenic in the Ames Microbial mutagen test with

S. thyphimurium and the microbial reverse mutation assay using E. coli. Cefprozil (cis/trans isomers) was also not mutagenic in the forward gene mutation assay using Chinese Hamster ovary cells. Unscheduled DNA synthesis in rat hepatocytes in vitro and clastogenicity in Chinese Hamster ovary cells in vitro or in rat bone marrow cells in vivo were unaffected by cefprozil (cis/trans isomers).

REFERENCES

Antimicrobiol. Agents Chemother. 34:2152-2155, 1990 Scribner RK, Marks MI and Finkhouse BD. In Vitro Activity of BMY 28100 Against Common Isolates from Pediatric Infections. Antimicrobiol. Agents Chemother. 31:630- 631, 1987 Wilber RB, Hamilton H et al. Cefprozil vs Cefaclor in the Treatment of Lower Respiratory Tract. Infections in Medicine. Supplement C:44-55, January 1992 World Almanac(r) and Book of Facts 1994, Mahwab, N.J. IMPORTANT: PLEASE READ

Route of Administration	Dosage Form/ Strength	Clinically Relevant Nonmedicinal Ingredients
Oral	Oral Suspension/ 125 mg/5 mL and 250 mg/5mL	Aspartame, Sucrose For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section.

Dosage	Mean Plasma Cefprozil * Concentrations (mcg/mL)			8-hour Urinary Excretion
Dosage	Peak ~ 1.5 hr	4 hr	8 hr	8-hour Urinary Excretion
250 mg	6.1	1.7	0.2	60%
500 mg	10.5	3.2	0.4	62%
1 g	18.3	8.4	1.0	54%

Total Cefprozil in Plasma (Dose 10 mL of 125 mg/5 mL cefprozil as oral suspensio From measured data (total cefprozil) uncorrected for potency Geometric Mean Arithmetic Mean (CV %)					n)
Parameter	Sandoz Cefprozil *	Cefzil(tm) +	% Ratio of Geometric Means	90% Confidence Interval
AUC T	13580.57	14468.01	93.87	91.82-95.96
(ng . h/mL)	13785.72	14674.27
	(18.34)	(17.69)
AUC I	13872.45	14735.18	94.15	92.21-96.12
(ng . h/mL)	14077.21	14940.43
	(18.17)	(17.46)
C max	5703.71	6058.30	94.15	90.75-97.67
(ng/mL)	5814.29	6178.08
	(20.32)	(21.28)
T max (h)	1.03 (20.25)	1.04 (16.97)

T 1/2 (h)	1.33 (20.28)	1.30 (13.78)

Organism	Number of Isolates	Low MIC	High MIC	MIC 50 (ug/mL)	MIC 90 (ug/mL)
Corynebacterium sp.	13	<= 0.008	4.000	<0.008	0.104
S. faecalis	77	0.500	16.000	5.369	8.211
Strep. (Group A)	309	<= 0.008	1.000	0.015	0.088
Strep. (Beta hemolytic)	1	0.016	0.016
S. agalactiae	1	0.250	0.250
S. intermedius	1	0.125	0.125
Strep. (Group G)	32	<= 0.008	0.500	0.025	0.150
Strep. (Group C)	28	0.016	0.500	0.018	0.339
Enterococcus	2	8.000	8.000
Strep. (Group F)	8	0.064	1.000	0.157
S. salivarius	1	0.064	0.064
Strep. (Group B)	48	0.016	0.500	0.084	0.287
S. mitis	13	<= 0.008	2.000	0.117	0.451
S. constellatus	1	0.500	0.500
S. sanguis	17	0.064	2.000	0.149	1.110
S. aureus	344	0.064	8.000	0.863	2.109
S. epidermidis	145	0.016	32.000	0.341	3.123
S. saprophyticus	21	0.500	4.000	0.728	1.653
S. hominis	21	0.032	>128.000	0.375	1.932
S. capitis	9	0.016	0.125	0.025
S. simulans	6	0.032	0.500	0.125
S. haemolyticus	15	0.032	>128.000	0.445	3.364
S. colinii	3	0.250	1.000
S. warneri	8	0.016	0.500	0.091
S. xylosus	2	0.250	0.500
Micrococcus sp.	2	0.032	0.250
AErococcus sp.	1	1.000	1.000
S. pneumoniae	126	<= 0.008	1.000	0.042	0.316
P. aeruginosa	35	>128.000	>128.000	>128.000	>128.000
P. maltophilia	9	>128.000	>128.000	>128.000
P. fluorescens	2	>128.000	>128.000
P. paucimobilis	1	2.000	2.000
P. vesicularis	1	32.000	32.000
P. putida	5	>128.000	>128.000	>128.000
P. cepacia	1	>128.000	>128.000
Pseudomonas Sp. VE-2	1	>128.000	>128.000
P. mendocina	1	> 128.000	>128.000
P. acidovorans	1	> 128.000	>128.000
E. coli	551	0.064	>128.000	1.223	4.948
C. freundii	14	0.500	>128.000	11.314	>78.793
C. diversus	9	0.500	8.000	0.749
K. pneumoniae	68	0.032	32.000	0.660	1.711
K. ozaenae	1	4.000	4.000
K. oxytoca	11	0.125	32.000	1.122	7.464
E. cloacae	38	8.000	>128.000	38.055	>128.000
E. aerogenes	15	16.000	>128.000	24.675	>76.109
E. sakazakii	1	8.000	8.000
E. geroviae	2	2.000	8.000
H. alvei	1	16.000	16.000
S. marcescens	10	4.000	>128.000	>128.000	>128.000
P. mirabilis	66	0.250	8.000	3.143	6.662
P. vulgaris	3	>128.000	>128.000
M. morganii	7	4.000	>128.000	>128.000
P. stuartii	1	16.000	16.000
E. agglomerans	8	0.500	>128.000	2.000
H. infuenzae	11	0.125	8.000	0.771	3.864
H. infuenzae (P+)	14	1.000	16.000	2.692	6.964
H. infuenzae (P-)	77	0.250	32.000	0.887	4.550
H. parainfuenzae	9	0.016	1.000	0.223
H. parainfuenzae (P+)	1	1.000	1.000
Flavobacterium Sp.	1	1.000	1.000
A. anitratus	22	4.000	>128.000	84.449	>128.000
A. lwoffi	17	1.000	>128.000	8.980	>95.339
A. haemolyticus	1	64.000	64.000
M. catarrhalis	9	0.500	4.000	0.917
M. catarrhalis (P+)	32	0.064	4.000	0.707	2.297
M. catarrhalis (P-)	4	0.032	2.000	0.045
A. hydrophilia	1	1.000	1.000

Zone Diameter (mm)	Interpretation
>= 18	(S) Susceptible
15-17	(MS) Moderately Susceptible
<= 14	(R) Resistant

Organism	Zone Diameter (mm)
Escherichia coli ATCC 25922	21-27
Staphylococcus aureus ATCC 25923	27-33

MIC (mcg/mL)	Interpretation
<= 8	(S) Susceptible
16	(MS) Moderately Susceptible
>= 32	(R) Resistant

Organism	MIC (mcg/mL)
Enterococcus faecalis ATCC 29212	4-16
Escherichia coli ATCC 25922	1-4
Pseudomonas aeruginosa ATCC 27853	>32
Staphylococcus aureus ATCC 29213	0.25-1

Species/Strain	Sex (N)	Route	Estimated LD 50 (mg/kg)
Mouse Swiss-Webster	M (5) F (5)	Oral gavage (200 mg/mL suspension)	>5000
Rat Sprague-Dawley	M (5) F (5)	Oral gavage (200 mg/mL suspension)	>5000
Rat Sprague-Dawley	M (15) * * F (15) * *	Oral gavage (250 mg/mL suspension) * CMC 0.5%	>5000
Monkey Cynomolgus	M (1) F (1)	Oral gavage (200 mg/mL suspension)	>3000
Mouse Swiss-Webster	M (5) F (5)	IP	>5000
Mouse Swiss-Webster	M (5) F (5)	Subcutaneous	>5000

Species/Strain	Sex	N/Group	Cefprozil Dosage (mg/kg/day)	Route	Duration	Effects
Rat (CD/Charles River)	M F	10 10	0, 250, 750, 1500 ( *CMC 0.5%)	Oral gavage	4 weeks	Slight increase in kidney weight with reduction in serum creatinine and BUN but no corresponding urinalysis or microscopic pathology in (M) given 750 or 1500 mg/kg. Minimal focal erosion of gastric mucosa for 3 of 20 rats at 1500 mg/kg. Transient soft stools during second week and gross and microscopic dilatation of colon and cecum attributed to enteral antibiotic effect.
Monkey (Cynomolgus)	M F	2 2	0, 50, 200, 600	Oral gavage	1 month	Salivation after dosing at 600 mg/kg/day. No consistent pathologic changes. Dose- related incidence of soft or liquid stools attributed to enteral antibiotic effect.
Rat (CD/Charles River)	M F	20 20	0, 250, 750, 1500 (CMC 0.5%)	Oral gavage	3 months + 1 month recovery	Reversible slight increases in serum creatine kinase and alanine transaminase and in kidney weights at 750 and 1500 mg/kg. No morphologic gross or microscopic pathology.
Monkey (Cynomolgus)	M F	3 or 4 3 or 4	0, 50, 150, 600 (CMC 0.5%)	Oral gavage	3 months + 1 month recovery	No consistent toxicologic change. Transient body weight loss for 2 males at 600 mg/kg dose level. No pathologic changes. Dose-related incidence of diarrhea (reversible and attributed to enteral antibiotic effect).
Monkey (Cynomolgus)	M F	2 2	0, 25, 50 (0.9% sodium chloride)	IV	2 weeks	No consistent toxicologic change. No morphologic gross or microscopic pathology. Transient mild to moderate discolouration was noted at injection sites across all treated and control groups.

Species/Strain	No. of Animals and Sex/Dose	Cefprozil Doses and Frequency	Route	Results
SEGMENT I
Rat (Sprague - Dawley)	20 M 35 F	0, 250, 750 or 1500 mg/kg as follows: M: at least 70 days before mating and during mating. F: 14 days before mating through Day 21 pregnancy or Day 21 postpartum	Oral gavage *	Gestation and parturition unaffected. Copulation index slightly lower than controls for treated rats but with no dose relationship. Minor decreases in food consumption before mating, during gestation and in body weight during lactation. No signs of teratogenicity. Higher postnatal mortality in treated groups. Slight growth inhibition in pups (M) during lactation and postweaning. No adverse effect on F 1 generation reproductive performance.
Rat (Crl: CoBS CD(SD)Br)	30 F	0, 100, 250 and 500 mg/kg as follows: F: 15 days prior to mating with untreated M through Day 20 of gestation or Day 21 postpartum	Oral gavage *	No effect on reproduction of F and their offspring. Incidence of alopecia was increased at 500 mg/kg dose level. Maternal body weight gain during gestation diminished at 250 and 500 dose levels.
SEGMENT II
Mouse (Crl: CD(ICR) Br)	43 F	0, 250, 750 and 1500 mg/kg from Day 6 through Day 15 of gestation	Oral gavage *	No evidence of teratogenicity or embryotoxicity.
Rat (Sprague - Dawley)	35 F	0, 250, 750 and 1500 mg/kg from Day 7 through Day 17 of gestation	Oral gavage	No teratogenic or embryotoxic effects. Reduced implantation with increasing dose. No effects on fetuses, on offspring and on development of pups during lactation and post-weaning.

Control Number: 105676

PART I: HEALTH PROFESSIONAL INFORMATION 3

PART II: SCIENTIFIC INFORMATION 12

PART III: CONSUMER INFORMATION 27

SANDOZ CEFPROZIL

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION