SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 6 DRUG INTERACTIONS 7 DOSAGE AND ADMINISTRATION 7 OVERDOSAGE 8 ACTION AND CLINICAL PHARMACOLOGY. 8 STORAGE AND STABILITY 10 DOSAGE FORMS, COMPOSITION AND PACKAGING 10
PHARMACEUTICAL INFORMATION 11 CLINICAL TRIALS 12 MICROBIOLOGY 12 TOXICOLOGY 17 REFERENCES 23
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APO-CEFPROZIL
Cefprozil Tablets (cefprozil as cefprozil monohydrate)
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | Tablets 250 mg, 500 mg | None For a complete listing see Dosage Forms, Composition and Packaging section. |
APO-CEFPROZIL (cefprozil) is indicated for the 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 Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis.
(including acute cystitis) caused by
Cultures and susceptibility studies should be performed when appropriate.
APO-CEFPROZIL (cefprozil) is contraindicated in patients with known allergy to the cephalosporin class of antibiotics or to any component of the cefprozil preparations.
Before therapy with APO-CEFPROZIL (cefprozil) is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to APO- 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 APO-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.
General
Prolonged use of APO-CEFPROZIL may result in the overgrowth of nonsusceptible 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.
Gastrointestinal
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).
Renal
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 APO-CEFRPOZIL (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 APO-CEFPROZIL, should be given with caution to patients receiving concurrent treatment with potent diuretics since these agents are suspected of adversely affecting renal function.
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.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse drug 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 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.
Most Common Clinical Trial Adverse Drug Reactions (> 1%)
| Body System | Adverse Events considered likely to be Drug-Related (n = 4227) | |
| Event | Percentage of Patients with ADR | |
| Gastrointestinal System | Diarrhea Nausea Vomiting | 2.7 2.3 1.4 |
| Skin/Hypersensitivity | Rash | 1.2 |
Less Common Clinical Trial Adverse Drug Reactions (<1%)
Hepatobiliary:
As with some penicillins and some other cephalosporin antibiotics, cholestatic jaundice has been reported rarely.
Hypersensitivity:
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.
Gastrointestinal:
Abdominal pain (0.9%)
CNS:
Confusion, dizziness, drowsiness, headache, hyperactivity, insomnia and nervousness. Causal relationship is uncertain and all were reversible.
Other:
Genital pruritus (0.8%) and vaginitis (0.7%).
Abnormal Hematologic and Clinical Chemistry Findings
Laboratory abnormalities
Transitory abnormalities in clinical laboratory test results of uncertain etiology have been reported during clinical trials as follows:
Hepatobiliary:
Elevations of AST, ALT, alkaline phosphatase, and bilirubin.
Hematopoietic:
Transiently decreased leukocyte count and eosinophilia.
Renal:
Slight elevations in BUN and serum creatinine.
Post Market Adverse Drug Reactions
Adverse reactions reported from post-marketing experience and which were not seen in the clinical trials include serum sickness, pseudomembraneous colitis, Stevens-Johnson syndrome and exfoliative dermatitis. The association between these events and cefprozil administration is unknown. 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-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 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.
APO-CEFPROZIL (cefprozil) is administered orally (with or without food), in the treatment of infections due to susceptible bacteria in the following doses:
Upper respiratory tract (Pharyngitis / Tonsillitis) 500 mg q24h Acute sinusitis 250 mg or 500 mg q12h Skin & skin structure 250 mg ql2h or 500 mg q24h Uncomplicated urinary tract 500 mg q24h
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 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.
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.
Mechanism of Action
Cefprozil is a semi synthetic 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
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 co-administered with antacid. Average plasma concentrations after administration of cefprozil to fasting subjects are shown in the following table. Urinary recovery accounts for 60% of the administered dose.
| Dosage | Mean Plasma Cefprozil * Concentration (ug/mL) | 8-hour Urinary Excretion | ||
| Peak ~ 1.5 hr | 4 hr | 8 hr | ||
| 250 mg | 6.2 | 1.7 | 0.2 | 60% |
| 500 mg | 10.5 | 3.2 | 0.4 | 62% |
| 1 g | 18.3 | 8.4 | 1.0 | 54% |
Data represent mean values from 12 healthy, young male volunteers. 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 ug/mL, 450 ug/mL and 600 ug/mL, respectively. The average plasma half-life in normal subjects is 1.3 hours. Plasma protein binding is approximately 36% and is independent of concentration in the range of 2 ug/mL to 20 ug/mL. There is no evidence of accumulation of cefbrozil 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
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 WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINSTRATION).
Hepatic Insufficiency
In patients with impaired hepatic function, no differences in pharmacokinetic parameters were observed, when compared to normal control subjects.
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.
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.
Store at room temperature (15degC - 30degC).
In addition to the active ingredient, cefprozil, each tablet also contains the non-medicinal ingredients methylcellulose, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide and sunset yellow aluminum lake (250 mg). APO-CEFPROZIL 250 mg Tablets: Each light orange, capsule shaped, film-coated tablet, engraved "APO" on one side and "CPZ 250" on the reverse side contains 250 mg of cefprozil. Available in bottles of 100 tablets. APO-CEFPROZIL 500 mg Tablets: Each white, capsule shaped, film-coated tablet, engraved "APO" on one side and "CPZ 500" on the reverse side contains 500 mg of cefprozil. Available in bottles of 100 tablets.