Cefprozil

INDICATIONS AND USAGE Cefprozil for oral suspension 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: Upper Respiratory Tract: 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 ß-lactamase-producing strains), and Moraxella (Branhamella) catarrhalis (including ß-lactamase-producing strains). (See CLINICAL STUDIES .) 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. Acute Sinusitis: Caused by Streptococcus pneumoniae, Haemophilus influenzae (including ß-lactamase producing strains), and Moraxella (Branhamella) catarrhalis (including ß-lactamase-producing strains). Lower Respiratory Tract: Acute Bacterial Exacerbation of Chronic Bronchitis: Caused by Streptococcus pneumoniae , Haemophilus influenzae (including ß-lactamase-producing strains), and Moraxella (Branhamella) catarrhalis (including ß-lactamase-producing strains). Skin And Skin Structure: Uncomplicated Skin and Skin-Structure Infections: Caused by Staphylococcus aureus (including penicillinase-producing strains) and Streptococcus pyogenes . Abscesses usually require surgical drainage. To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefprozil for oral suspension and other antibacterial drugs, cefprozil for oral suspension 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.

DOSAGE AND ADMINISTRATION Cefprozil for oral suspension is administered orally. 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. Header$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 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 to 12 years) UPPER RESPIRATORY TRACT b Pharyngitis/Tonsillitis 7.5 mg/kg q12h 10 a SKIN AND SKIN STRUCTURE Uncomplicated Skin and Skin Structure Infections 20 mg/kg q24h 10 INFANTS & CHILDREN (6 months to 12 years) UPPER RESPIRATORY TRACT b Otitis Media 15 mg/kg q12h 10 (See INDICATIONS AND USAGE and CLINICAL STUDIES ) Acute Sinusitis 7.5 mg/kg q12h or 10 (For moderate to severe infections, the higher dose should be used) 15 mg/kg q12h 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 to 120 standard standard 0 to 29 Cefprozil is in part removed by hemodialysis; therefore, cefprozil should be administered after the completion of hemodialysis. 50% of standard standard Hepatic Impairment: No dosage adjustment is necessary for patients with impaired hepatic function.

WARNINGS 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 β-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. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefprozil tablets, 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.

CONTRAINDICATIONS Cefprozil for oral suspension is contraindicated in patients with known allergy to the cephalosporin class of antibiotics.

Drug Interactions: 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.

ADVERSE REACTIONS 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 cefprozil tablets, have been rarely reported during postmarketing surveillance: anaphylaxis, angioedema, colitis (including pseudomembranous colitis), erythema multiforme, fever, serumsickness like reactions, Stevens-Johnson syndrome, and thrombocytopenia. Cephalosporin Class Paragraph: 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.

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 8 hour Urinary Excretion (%) Concentrations (mcg/mL) Data represent mean values of 12 healthy volunteers. 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 a n=11 b n=5 c n=9 d n=11 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 1.70 b 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 0.61 c 1.24 (n=19) (2.55) (2.03) (1.07) (0.27) (0.43) adults 500 mg 8.39 9.42 3.18 d 1.00 d 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 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: Dilution Techniques: 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 a