cefprozil 250 mg/5 ml susp

Uses

Cefprozil is used orally for the treatment of mild to moderate respiratory tract infections (i.e., acute sinusitis, secondary bacterial infections of acute bronchitis, acute exacerbations of chronic bronchitis, community-acquired pneumonia) caused by susceptible bacteria. The drug also is used orally for the treatment of acute otitis media caused by susceptible bacteria, pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A β-hemolytic streptococci), and mild to moderate uncomplicated skin and skin structure infections caused by susceptible bacteria.

Acute Otitis Media

Oral cefprozil is used in children 6 months through 12 years of age for the treatment of acute otitis media (AOM) caused by Streptococcus pneumoniae, Haemophilus influenzae (including β-lactamase-producing strains), or Moraxella catarrhalis (including β-lactamase-producing strains).

When anti-infective therapy is indicated for the treatment of AOM, the American Academy of Pediatrics (AAP) recommends high-dose amoxicillin or amoxicillin and clavulanate potassium as the drugs of first choice for initial treatment. These experts recommend certain cephalosporins (cefdinir, cefpodoxime, cefuroxime, ceftriaxone) as alternatives for initial treatment in penicillin-allergic patients who do not have a history of severe and/or recent penicillin-allergic reactions.

Results of controlled clinical studies in children 6 months to 17 years of age with clinically and/or microbiologically confirmed AOM indicate that a 10-day regimen of oral cefprozil generally is as effective as a 10-day regimen of oral cefaclor, oral cefixime, oral amoxicillin and clavulanate potassium, or oral ceftibuten. In published studies, the overall clinical response rate to a 10-day regimen of oral cefprozil in pediatric patients with AOM has been 83-97% and the bacteriologic eradication rate has been 84-95%. Although the clinical and bacteriologic response rates to oral cefprozil in pediatric patients with AOM generally have been similar to those reported with oral amoxicillin and clavulanate potassium, the manufacturer cautions that, in patients with otitis media caused by β-lactamase-producing bacteria, cefprozil therapy may be associated with a slightly lower bacteriologic eradication rate than therapy with an anti-infective agent that contains a specific β-lactamase inhibitor (i.e., amoxicillin and clavulanate potassium) and that the possibility of reduced overall efficacy should be weighed carefully against local susceptibility patterns for common pathogens encountered in this infection when considering use of cefprozil for the treatment of otitis media.

In one study in children 6 months to 12 years of age with AOM with middle ear effusion, including patients with recurrent otitis media (i.e., 4 or more prior episodes of AOM within the last 12 months or 3 or more prior episodes within the last 6 months) or persistent AOM (i.e., symptoms of otalgia and signs of middle ear inflammation despite the fact that anti-infective agent therapy was given within the last 7 days), the overall clinical response rate to 10 days of oral cefprozil therapy (30 mg/kg daily) was 78%. When results of children with AOM caused by a single identified pathogen were stratified according to the causative organism, the clinical response rate to cefprozil was 91% in those with otitis media caused by M. catarrhalis, 77-81% in those with otitis media caused by S. pneumoniae or H. influenzae, and 71% in those with otitis media caused by S. pyogenes.

Cefprozil has been effective for the treatment of AOM in pediatric patients when administered in a 5-day regimen, and there is some evidence that the 5-day regimen may be as effective as the usually recommended 10-day regimen for the treatment of AOM in certain pediatric patients without a history of recurrent infections. In one controlled study in children 3 months to 14 years of age with AOM who were randomized to receive 5 or 10 days of oral cefprozil (30 mg/kg daily given in 2 divided doses), a satisfactory clinical response (cure or improvement) was attained in 94.4% of those who received the 5-day regimen and 96.4% of those who received the 10-day regimen. However, in the subgroup of patients with a history of 3 or more prior episodes of AOM, the clinical response rate was 100% in those who received the 10-day regimen versus 70% in those who received the 5-day regimen. Further study is needed to evaluate use of a 5-day regimen of oral cefprozil for the treatment of AOM. The AAP states that oral anti-infective regimens of less than 10 days' duration are not recommended for the treatment of AOM in children younger than 2 years of age or in patients with severe symptoms.

For additional information regarding treatment of AOM, including information on diagnosis and management strategies, anti-infectives for initial treatment, duration of initial treatment, and anti-infectives after initial treatment failure, .

Pharyngitis and Tonsillitis

Oral cefprozil is used in adults and children 2 years of age or older for the treatment of pharyngitis and tonsillitis caused by susceptible S. pyogenes (group A β-hemolytic streptococci). Although cefprozil usually is effective in eradicating S. pyogenes from the nasopharynx, substantial data to establish efficacy of the drug for prophylaxis of subsequent rheumatic fever are not available to date.

Selection of an anti-infective for the treatment of S. pyogenes pharyngitis and tonsillitis should be based on the drug's spectrum of activity, bacteriologic and clinical efficacy, potential adverse effects, ease of administration, patient compliance, and cost. No regimen has been found to date that effectively eradicates group A β-hemolytic streptococci in 100% of patients.

Because the drugs have a narrow spectrum of activity, are inexpensive, and generally are effective with a low frequency of adverse effects, AAP, Infectious Diseases Society of America (IDSA), American Heart Association (AHA), and others recommend a penicillin regimen (i.e., 10 days of oral penicillin V or oral amoxicillin or a single dose of IM penicillin G benzathine) as the treatment of choice for S. pyogenes pharyngitis and tonsillitis and prevention of initial attacks (primary prevention) of rheumatic fever. Other anti-infectives (e.g., oral cephalosporins, oral macrolides, oral clindamycin) are recommended as alternatives in penicillin-allergic individuals.

If an oral cephalosporin is used for the treatment of S. pyogenes pharyngitis and tonsillitis, a 10-day regimen of a first generation cephalosporin (cefadroxil, cephalexin) is preferred instead of other cephalosporins with broader spectrums of activity (e.g., cefaclor, cefdinir, cefixime, cefpodoxime, cefuroxime).

Although there is some evidence that a shorter duration of therapy with certain oral cephalosporins (e.g., a 5-day regimen of cefadroxil, cefdinir, cefixime, or cefpodoxime proxetil or a 4- or 5-day regimen of cefuroxime axetil) achieves bacteriologic and clinical cure rates equal to or greater than those achieved with the traditional 10-day oral penicillin V regimen, the IDSA and AHA state that use of cephalosporin regimens administered for 5 days or less for the treatment of S. pyogenes pharyngitis and tonsillitis cannot be recommended at this time.

Results of randomized, multicenter studies in pediatric patients with streptococcal pharyngitis or tonsillitis indicate that a 10-day regimen of oral cefprozil is more effective than a 10-day regimen of oral penicillin V. In one study in children 3-18 years of age with streptococcal pharyngitis or tonsillitis randomized to receive 10 days of oral cefprozil (7.5 mg/kg twice daily) or 10 days of oral penicillin V (16.25 mg/kg 3 times daily), the clinical response rate (cure or improvement) was 95.3% in those who received cefprozil versus 88.1% in those who received penicillin V; the bacteriologic eradication rates were 89 or 84.2%, respectively. A 10-day regimen of oral cefprozil has been used effectively to eradicate S. pyogenes in pediatric patients who failed to respond to a 10-day regimen of oral penicillin V.

In an open, randomized study in adults and adolescents 12 years of age or older with acute streptococcal pharyngitis, a 10-day regimen of oral cefprozil (500 mg once daily) was at least as effective as a 10-day regimen of oral cefaclor (250 mg 3 times daily); the clinical response rate was 85% for both drugs and the bacteriologic eradication rate was 91% in those who received cefprozil and 95% in those who received cefaclor. In another study in adults and children 2 years of age or older randomized to receive oral cefprozil or oral cefaclor, the overall clinical response rate was 80% in those who received cefprozil and 72% in those who received cefaclor; the bacteriologic eradication rates were 83 and 76%, respectively.

Respiratory Tract Infections

Acute Sinusitis

Oral cefprozil is used in adults and children 6 months of age or older for the treatment of acute sinusitis caused by S. pneumoniae, H. influenzae (including β-lactamase-producing strains), or M. catarrhalis (including β-lactamase-producing strains). In an open-label, multicenter study in adults and children 13 years of age or older with acute maxillary sinusitis, the overall clinical response rate was 80-83% in those who received cefprozil and 78% in those who received amoxicillin and clavulanate potassium.

When anti-infective therapy is indicated for the treatment of acute bacterial sinusitis, the IDSA recommends amoxicillin and clavulanate potassium and the AAP recommends either amoxicillin or amoxicillin and clavulanate potassium as the drug of choice for initial empiric treatment. Because of variable activity against S. pneumoniae and H. influenzae, the IDSA no longer recommends second or third generation oral cephalosporins for empiric monotherapy of sinusitis in adults or children. If an oral cephalosporin is used as an alternative for empiric treatment of acute bacterial sinusitis in children (e.g., in penicillin-allergic individuals), the IDSA and AAP recommend a combination regimen that includes a third generation cephalosporin (cefixime or cefpodoxime) and clindamycin (or linezolid).

Acute and Chronic Bronchitis

Oral cefprozil is used in adults and children 13 years of age or older for the treatment of secondary bacterial infections of acute bronchitis and acute bacterial exacerbations of chronic bronchitis caused by susceptible S. pneumoniae, H. influenzae (including β-lactamase-producing strains), or M. catarrhalis (including β-lactamase-producing strains). Safety and efficacy of the drug for the treatment of these infections in children 12 years of age or younger have not been established to date.

Results of a multicenter, open-label randomized study in adults with bronchitis indicate that oral cefprozil (500 mg every 12 hours) may be slightly more effective than oral cefuroxime axetil (500 mg every 12 hours) for these infections. The overall clinical response rate was 96% in those who received cefprozil and 82.5% in those who received cefuroxime; the bacteriologic eradication rate was 100% and 91.7%, respectively.

Community-Acquired Pneumonia

Cefprozil is used in the treatment of mild to moderate community-acquired pneumonia (CAP).

If an oral cephalosporin is used as an alternative to penicillin G or amoxicillin for treatment of CAP caused by penicillin-susceptible S. pneumoniae, the American Thoracic Society (ATS) and IDSA recommend cefpodoxime, cefprozil, cefuroxime, cefdinir, or cefditoren.

For additional information on treatment of CAP,

Skin and Skin Structure Infections

Oral cefprozil is used in adults and children 2 years of age or older for the treatment of uncomplicated skin and skin structure infections caused by Staphylococcus aureus (including penicillinase-producing strains) and S. pyogenes. The drug also has been effective when used in a limited number of patients for the treatment of uncomplicated skin and skin structure infections caused by S. epidermidis, S. saprophyticus, group B or G streptococci, Escherichia coli, or Klebsiella pneumoniae. Abscesses should be surgically drained if indicated.

Results of multicenter, randomized studies in adults and children 2 years of age or older with mild to moderate bacterial skin and skin structure infections (e.g., carbuncle, cellulitis, folliculitis, furuncle, impetigo, infected dermatitis, paronychia, pyoderma, superficial abscess, wound infection) indicate that 5-10 days of therapy with oral cefprozil (250 mg twice daily or 500 mg once daily in adults; 20 mg/kg once daily in children) is at least as effective as 5-10 days of therapy with oral cefaclor (250 mg 3 times daily in adults or 20 mg/kg daily in 3 doses). A satisfactory clinical response was attained in 93-95% of patients who received cefprozil and in 78-92% of patients who received cefaclor; the bacteriologic eradication rates were 86-91% and 74-89%, respectively.

Dosage and Administration

Reconstitution and Administration

Cefprozil is administered orally.

Administration of cefprozil tablets or oral suspension with food does not affect the extent of absorption or peak plasma concentrations of the drug, but may increase the time to peak concentrations.(See Pharmacokinetics: Absorption.)

Reconstitution

Cefprozil powder for oral suspension should be reconstituted at the time of dispensing by adding the amount of water specified on the container to provide a suspension containing 125 or 250 mg of cefprozil per 5 mL. The water should be added in 2 equal portions and the bottle shaken after each addition.

The oral suspension should be shaken well prior to administration of each dose.

Dosage

Cefprozil is commercially available as the monohydrate; dosage is expressed in terms of anhydrous cefprozil.

Adult Dosage

Pharyngitis and Tonsillitis

The usual dosage of cefprozil for the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A β-hemolytic streptococci) in adults and adolescents 13 years of age or older is 500 mg once daily for at least 10 days.

Respiratory Tract Infections

For the treatment of acute sinusitis in adults and adolescents 13 years of age or older, the usual dosage of cefprozil is 250 or 500 mg every 12 hours for 10 days; the higher dosage should be used to treat moderate to severe sinusitis.

For the treatment of secondary bacterial infections of acute bronchitis and acute bacterial exacerbations of chronic bronchitis, the usual dosage of cefprozil for adults and adolescents 13 years of age or older is 500 mg every 12 hours for 10 days.

Skin and Skin Structure Infections

For the treatment of uncomplicated skin and skin structure infections in adults and adolescents 13 years of age or older, the usual dosage of cefprozil is 250 or 500 mg every 12 hours or 500 mg once daily for 10 days.

Pediatric Dosage

Children 13 years of age or older may receive the usual adult dosage of cefprozil.

General Pediatric Dosage

The American Academy of Pediatrics (AAP) recommends that pediatric patients beyond the neonatal period receive cefprozil in a dosage of 15-30 mg/kg daily in 2 equally divided doses for the treatment of mild or moderate infections. The AAP states that the drug is inappropriate for the treatment of severe infections.

Acute Otitis Media

For the treatment of acute otitis media in children 6 months through 12 years of age, the usual dosage of cefprozil is 15 mg/kg every 12 hours for 10 days.

Pharyngitis and Tonsillitis

The usual dosage of cefprozil for the treatment of pharyngitis and tonsillitis caused by S. pyogenes (group A β-hemolytic streptococci) in children 2-12 years of age is 7.5 mg/kg every 12 hours for at least 10 days.

Respiratory Tract Infections

For the treatment of acute sinusitis in children 6 months through 12 years of age, the usual dosage of cefprozil is 7.5 or 15 mg/kg every 12 hours for 10 days; the higher dosage should be used to treat moderate to severe infections.

Skin and Skin Structure Infections

For the treatment of uncomplicated skin and skin structure infections in children 2-12 years of age, the usual dosage of cefprozil is 20 mg/kg once daily for 10 days.

Dosage in Renal and Hepatic Impairment

In patients with creatinine clearances less than 30 mL/minute, dose but not frequency of administration of cefprozil should be modified; such patients should receive 50% of the usual cefprozil dose using the usual dosing period. Because the drug is partially removed by hemodialysis, cefprozil should be administered to patients undergoing hemodialysis after the end of the dialysis period.

Modification of usual dosage of cefprozil is not necessary in patients with hepatic impairment.

Cautions

Adverse effects reported with cefprozil are similar to those reported with other cephalosporins. Cefprozil generally is well tolerated; most adverse effects are transient and mild to moderate in severity. Adverse effects have been severe enough to require discontinuance in about 2% of patients. The most frequent adverse effects of cefprozil involve the GI tract. In young children, diarrhea, vomiting, and rash (principally in the diaper area) appear to be most common, while in adults, diarrhea and nausea appear to be most common.

GI Effects

Nausea is one of the most common adverse effects of cefprozil, occurring in 3.5% of patients receiving the drug. Diarrhea or loose stools have occurred in 2.9% of patients receiving cefprozil. The incidence of diarrhea with cefprozil appears to be comparable to that with cefaclor but less than that with amoxicillin and clavulanate potassium, and possibly some other oral cephalosporins. Vomiting and abdominal pain or discomfort each have occurred in 1% of patients. Dyspepsia, flatulence, glossitis, and mouth pain have been reported rarely in patients receiving cefprozil; a causal relationship to the drug has not been established. Adverse GI effects may be severe enough to result in discontinuance of cefprozil.

Clostridium difficile-associated Diarrhea and Colitis

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile.

C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) have been reported with nearly all anti-infectives, including cefprozil, and may range in severity from mild diarrhea to fatal colitis.C. difficile produces toxins A and B which contribute to development of CDAD; hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.

CDAD should be considered in the differential diagnosis in patients who develop diarrhea during or after anti-infective therapy. Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.

If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile should be discontinued whenever possible. Patients should be managed with appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.(See Superinfection/Clostridium difficile-associated Diarrhea and Colitis under Cautions: Precautions and Contraindications.)

Dermatologic and Sensitivity Reactions

Rash occurred in 0.9% of patients receiving cefprozil in clinical studies. In young children, rash associated with cefprozil therapy most commonly is a diaper rash rather than a sensitivity reaction. Urticaria and pruritus have been reported rarely. Anaphylaxis, serum-sickness-like reactions, erythema, exanthema, erythema multiforme, erythema nodosum, and Stevens-Johnson syndrome also have been reported rarely; however, a causal relationship with cefprozil has not been established. Sensitivity reactions (e.g., rash, urticaria) have been reported more frequently in children than in adults. Such reactions usually occur within a few days after initiation of therapy and subside within a few days after discontinuance of the drug. Toxic epidermal necrolysis has been reported with cephalosporins. If a severe hypersensitivity reaction occurs during cefprozil therapy, the drug should be discontinued and the patient given appropriate treatment (e.g., epinephrine, corticosteroids, maintenance of an adequate airway, oxygen) as indicated.

Nervous System Effects

Dizziness has been reported in 1% of patients receiving cefprozil. Hyperactivity, headache, nervousness, insomnia, confusion, and somnolence each have been reported in less than 1% of patients receiving the drug. Lightheadedness has been reported rarely.

Although seizures have not been reported in patients receiving cefprozil, several cephalosporins have been implicated in precipitating seizures, particularly in patients with renal impairment in whom the dosage was not reduced. If seizures associated with cefprozil therapy occur, the drug should be discontinued and anticonvulsant therapy administered if clinically indicated.

Hepatic Effects

Increases in serum AST (SGOT) and ALT (SGPT) concentrations have been reported in 2% of patients receiving cefprozil. Elevations in serum alkaline phosphatase and bilirubin concentrations also have been reported in 0.2% and less than 0.1%, respectively, of patients receiving the drug. Cholestatic jaundice has been reported rarely in patients receiving cefprozil. Increases in serum LDH concentrations have been reported in patients receiving cephalosporins.

Hematologic Effects

Eosinophilia has been reported in 2.3% of patients receiving cefprozil. Decreased leukocyte count has been reported in 0.2% of patients receiving the drug. Although a causal relationship has not been established, neutropenia, thrombocytopenia, prolonged partial thromboplastin time, thrombocytosis,prolonged prothrombin time, prolonged prothrombin ratio, and decreased hematocrit have been reported rarely in patients receiving cefprozil.

Other adverse hematologic effects reported in patients receiving cephalosporins include positive antiglobulin (Coombs') test results, agranulocytosis, aplastic anemia, pancytopenia, hemolytic anemia, and hemorrhage.

Renal Effects

Elevated BUN and serum creatinine concentrations each have been reported in 0.1% of patients receiving cefprozil. Adverse renal effects reported in patients receiving cephalosporins include renal dysfunction and toxic nephropathy.

Other Adverse Effects

Vaginitis and genital pruritus have been reported in 1.6% of patients receiving cefprozil. Leukorrhea and vaginal candidiasis have been reported infrequently. Diaper rash and superinfection have been reported in 1.5% of patients receiving the drug. Although a causal relationship to cefprozil has not been established, fever, chills, sweating, tinnitus, visual field defects, generalized pain, back pain, leg pain, angioedema, and crying have been reported rarely.

Precautions and Contraindications

Cefprozil shares the toxic potentials of the cephalosporins, and the usual precautions of cephalosporin therapy should be observed.

Sensitivity Reactions

Prior to initiation of cefprozil therapy, careful inquiry should be made concerning previous hypersensitivity reactions to cefprozil, other cephalosporins, penicillins, or other drugs. There is clinical and laboratory evidence of partial cross-allergenicity among β-lactam antibiotics including penicillins, cephalosporins, and cephamycins.

Cefprozil is contraindicated in patients with known hypersensitivity to cephalosporins and should be used with caution in patients with a history of hypersensitivity to penicillins. Use of cephalosporins should be avoided in patients who have had an immediate-type (anaphylactic) hypersensitivity reaction to penicillins.

If a hypersensitivity reaction occurs during cefprozil therapy, the drug should be discontinued and the patient treated with appropriate therapy (e.g., epinephrine, corticosteroids, and maintenance of an adequate airway and oxygen as indicated.

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of cefprozil and other antibacterials, the drug should be used only for the treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria. When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used. In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy.

Patients should be advised that antibacterials (including cefprozil) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold). Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with cefprozil or other antibacterials in the future.

Superinfection/Clostridium difficile-associated Diarrhea and Colitis

As with other anti-infective agents, prolonged use of cefprozil may result in overgrowth of nonsusceptible organisms. Careful observation of the patient during cefprozil therapy is essential. If superinfection occurs, appropriate therapy should be initiated.

Because CDI and C. difficile-associated diarrhea and colitis have been reported with the use of cefprozil or other cephalosporins, it should be considered in the differential diagnosis of patients who develop diarrhea during or following cefprozil therapy.

Patients should be advised that diarrhea is a common problem caused by anti-infectives and usually resolves when the drug is discontinued; however, they should contact a clinician if severe watery or bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.

Cefprozil should be used with caution in patients with a history of GI disease, especially colitis.

Other Precautions and Contraindications

In patients with known or suspected renal impairment, careful observation and appropriate laboratory studies should be performed prior to and during cefprozil therapy. Because plasma concentrations of cefprozil may be higher and more prolonged in these patients, doses and/or frequency of administration should be decreased.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.) The manufacturer states that cephalosporins, including cefprozil, should be used with caution in patients receiving potent diuretics (e.g., furosemide), since concomitant use of these drugs may adversely affect renal function.

Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that oral suspensions of cefprozil contains aspartame (NutraSweet) which is metabolized to phenylalanine in the GI tract following oral administration.

Positive direct antiglobulin (Coombs') test results have been reported in patients receiving a cephalosporin. Patients receiving a cephalosporin, including cefprozil, may show a false-positive result in urine glucose determinations using cupric sulfate (e.g., Benedict's solution, Fehling's solution, Clinitest).

Urinary glucose determinations using glucose oxidase methods (e.g., Clinistix, Tes-Tape) are unaffected by the drugs. A false-negative result may occur in the ferricyanide test for blood glucose. Cefprozil does not interfere with the alkaline picrate method used to determine plasma or urinary creatinine concentrations.

Pediatric Precautions

Safety and efficacy of cefprozil for the treatment of acute otitis media or acute sinusitis in children younger than 6 months of age or the treatment of pharyngitis and tonsillitis or uncomplicated skin and skin structure infections in children younger than 2 years of age have not been established. The manufacturers caution that drug accumulation secondary to prolonged elimination has been reported in neonates receiving other cephalosporins.

Sensitivity reactions (e.g., rash, urticaria) have been reported more frequently in children than in adults. The most common adverse effects occurring in children receiving cefprozil are similar to those seen in adults and include diarrhea, nausea, vomiting, and rash.

Geriatric Precautions

Of the more than 4500 adults who received cefprozil in clinical studies, 14% were 65 years of age or older, while 5% were 75 years of age and older. Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out. Cefprozil is known to be substantially excreted by the kidney, and the risk of cefprozil-induced toxicity may be greater in patients with renal impairment. Because geriatric patients may have decreased renal function, initial dosage should be selected carefully and it may be useful to monitor renal function.

Mutagenicity and Carcinogenicity

Mutagenesis studies performed in appropriate prokaryotic and eukaryotic cells in vitro or in vivo have not shown cefprozil to be mutagenic. Long-term in vivo studies have not been performed to date to evaluate the carcinogenic potential of the drug.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in mice, rats, or rabbits using oral cefprozil in dosages 0.8, 8.5, or 18.5 times, respectively, the maximum daily human dose (1 g) based upon mg/m have not revealed evidence of harm to the fetus. There are no adequate and well-controlled studies to date using cefprozil in pregnant women or during labor and delivery, and the drug should be used during pregnancy or labor and delivery only when clearly needed.

Fertility

Reproduction studies in male or female rats receiving oral cefprozil in dosages up to 18.5 times the maximum recommended human dosage have not revealed evidence of impaired fertility.

Lactation

Because trace concentrations of cefprozil (less than 0.3% of a dose) are distributed into milk, the drug should be used with caution in nursing women.

Pharmacokinetics

Some of the pharmacokinetic data described in the Pharmacokinetics section were derived from studies that involved cefprozil capsules (not commercially available in the US); however, these capsules, cefprozil oral solution (not commercially available in the US), commercially available cefprozil film-coated tablets, and commercially available cefprozil oral suspension have been shown to be bioequivalent when administered under fasting conditions. Results of high-pressure liquid chromatographic (HPLC) assays that distinguish between the cis- and trans-isomers of cefprozil indicate that the pharmacokinetics of the isomers are identical and the proportions of cis- and trans-cefprozil in plasma and urine are similar to those contained in commercially available preparations of the drug (i.e., approximately a 9:1 ratio).

In adults with normal renal function, peak plasma concentrations and area under the plasma concentration-time curve (AUC) of cefprozil increase in proportion to the dose over the dosage range of 250 mg to 1 g, and there is no evidence that the drug accumulates in plasma following multiple oral doses (up to 1 g every 8 hours for 8-10 days). Results of pharmacokinetic studies indicate that the AUC of cefprozil reported in healthy geriatric adults (i.e., adults 65 years of age or older) is 35-60% higher than that reported in younger healthy adults (20-40 years of age) and that the average AUC in adult females is 15-20% higher than that reported in adult males. Studies in adults with impaired renal function indicate that the pharmacokinetics of cefprozil are affected by the degree of renal impairment and that plasma half-life of the drug increases with decreasing renal impairment. The plasma half-life of cefprozil is increased slightly in patients with hepatic impairment, but this does not necessitate a change in dosage of the drug.

Absorption

Following oral administration of cefprozil in fasting adults, bioavailability of the drug is approximately 90-95%. Studies using commercially available cefprozil tablets or oral suspension indicate that presence of food in the GI tract does not affect the extent of absorption or peak plasma concentrations of the drug; however, compared with administration in the fasting state, the time to peak plasma concentrations may be prolonged by 15-45 minutes when the drug is administered with food. Results of a crossover study using cefprozil capsules (not commercially available in the US) indicate that bioavailability of the drug is not affected by concomitant administration of an antacid containing magnesium hydroxide and aluminum hydroxide.

In healthy, fasting adults who receive a single 250-mg, 500-mg, or 1-g oral dose of cefprozil as capsules, peak plasma concentrations are attained within 1.5 hours and average 6.1, 10.5, or 18.3 mcg/mL, respectively; plasma concentrations 8 hours after the dose average 0.2, 0.4, or 1 mcg/mL, respectively.

In pediatric patients 8 months to 8 years of age who received a single 15- or 30-mg/kg oral dose of cefprozil as the oral suspension, peak plasma concentrations were attained within 1.2-1.4 hours and averaged 11.2 or 15.9 mcg/mL, respectively. In pediatric patients 6 months to 12 years of age who received a single 7.5-, 15-, or 30-mg/kg oral dose of the drug as the oral suspension, peak plasma concentrations were attained within 1-2 hours; plasma concentrations averaged 3.99, 8.47, or 17.61 mcg/mL, respectively, 2 hours after the dose and 0.91, 2.75, or 8.66 mcg/mL, respectively, 4 hours after the dose.

Distribution

The steady-state volume of distribution of cefprozil is estimated to be 0.23 L/kg in healthy adults with normal renal function.

Following oral administration, cefprozil is distributed into various body tissues and fluids including blister fluid, middle ear fluid, and tonsillar and adenoidal tissue.

In pediatric patients with chronic otitis media with effusion who received a single 15- or 20-mg/kg oral dose of cefprozil as the oral suspension, concentrations of the drug in middle ear fluid collected within 6 hours of the dose ranged from 0.06-4.4 or 0.17-8.67 mcg/mL, respectively; concurrent plasma concentrations ranged from 0.38-15.97 or 1.28-21.47 mcg/mL, respectively.

In children 2-14 years of age undergoing elective tonsillectomy and/or adenoidectomy who received a single 7.5- or 20-mg/kg dose of cefprozil as the oral suspension, concentrations of the drug in tonsillar or adenoidal tissue ranged from 37-47 or 46-82% of concurrent plasma concentrations, respectively.

Information on distribution of cefprozil into CSF is not available.

Cefprozil is distributed into milk in low concentrations following oral administration (i.e., in concentrations less than 0.3% of the dose). In a study in women who received a single 1-g dose of oral cefprozil, concentrations of the drug in breast milk over the next 24 hours ranged from 0.25-3.36 mcg/mL.

Cefprozil is 35-45% bound to plasma proteins; binding is independent of drug concentration over the range of 2-20 mcg/mL.

Elimination

In adults with normal renal function, the plasma half-life of cefprozil averages 1-1.4 hours and renal clearance of the drug averages 1.78-2.53 mL/minute per kg. The plasma half-life of the drug in pediatric patients 6 months to 12 years of age averages 0.94-2.1 hours.

Cefprozil is eliminated principally in urine by glomerular filtration and tubular secretion. Approximately 54-70% of a single oral dose of the drug is eliminated unchanged in urine within 24 hours. In adults with normal renal function who receive a single 250-mg, 500-mg, or 1-g oral dose of cefprozil, concentrations of the drug in urine over the first 4 hours following the dose average 700, 1000, and 2900 mcg/mL, respectively. Renal clearance of the drug following a single 1-g dose of cefprozil reportedly is 40% lower in healthy adults 65 years of age and older than in healthy adults 20-40 years of age.

The plasma half-life of cefprozil is prolonged in patients with renal impairment and, depending on the degree of impairment, may average 5.2-5.9 hours. In a study in patients with hepatic impairment who received a single 1-g oral dose of cefprozil, the plasma half-life of the drug averaged 2.2 hours.

Cefprozil is removed by hemodialysis.