Cefzil (Cefprozil)

CEFZIL™

Bristol-Myers Squibb

Cefprozil

Antibiotic

Action And Clinical Pharmacology: 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: Cefprozil is well absorbed following oral administration in both fasting and nonfasting 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. Urinary recovery accounts for 60% of the administered dose.

During the first 4-hour period after drug administration, the average urine concentrations following the 250 mg, 500 mg, and 1 g doses were approximately 170g/mL, 450 g/mL and 600 µg/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 to 20 g/mL. 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.

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).

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 to 60% higher than that of healthy young adults and the average AUC in females was approximately 15 to 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.

Children: Comparable pharmacokinetic parameters of cefprozil are observed between pediatric patients (6 months to 12 years) and adults following oral administration. The maximum plasma concentrations are achieved at 1 to 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 1 000 mg doses, respectively.

Indications And Clinical Uses: For the treatment of the following infections caused by susceptible strains of the designated microorganisms: Upper Respiratory Tract: Pharyngitis/tonsillitis caused by group A b-hemolytic (GABHS) S. pyogenes. 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 caused by S. pneumoniae, H. influenzae. M. (Branhamella) catarrhalis.

Acute sinusitis caused by S. pneumoniae, H. influenzae, (beta-lactamase positive and negative strains), and M. (Branhamella) catarrhalis.

Skin and Skin Structure: Uncomplicated skin and skin-structure infections caused by S. aureus (including penicillinase-producing strains) and S. pyogenes.

Urinary Tract: Uncomplicated urinary tract infections (including acute cystitis) caused by E. coli, K. pneumoniae, P. mirabilis. Cultures and susceptibility studies should be performed when appropriate.

Contra-Indications: In patients with known allergy to the cephalosporin class of antibiotics or to any component of the cefprozil preparations.

Manufacturers’ Warnings In Clinical States: 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 cefzil occurs, discontinue the drug. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures, including oxygen, i.v. fluids, i.v. 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 C. 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).

Precautions: 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), 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 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.

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.

Pregnancy: Reproduction studies have been performed in mice, rats, and rabbits at doses 14, 7 and 0.7 times the maximum human daily dose (1 000 mg) based upon mg/m 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.

Lactation: Less than 1% 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.

Children: 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: 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 events (of probable or unknown relationship to study drug) observed in 4 227 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.

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:

Hepatobiliary: elevations of AST, ALT, alkaline phosphatase, and bilirubin.

Hematopoietic: transiently decreased leukocyte count and eosinophilia.

Renal: slight elevations in BUN and serum creatinine.

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.

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’ 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 Overdose). If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: 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 5 000 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.

Dosage And Administration: 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 q12h. Skin and skin structure: 250 mg q12h or 500 mg q24h. Uncomplicated urinary tract: 500 mg q24h.

Children (2 to 12 years): skin and skin structure: 20 mg/kg q24h.

Acute Sinusitis: 7.5 mg/kg q12h or 15 mg/kg q12h.

The maximum pediatric daily dose should not exceed the maximum daily dose recommended for adults (e.g., 1 g/day).

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 S. 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.

For ease in preparation, the water can be added in 2 portions. Shake well after each addition and prior to use.

Storage of Reconstituted Suspension: The constituted cefprozil oral suspension must be stored in the refrigerator (2 to 8°C) for up to 14 days. Keep container tightly closed. Discard unused portion after 14 days.

Availability And Storage: Powder for Oral Suspension: 125 mg/5 mL: Each 5 mL of constituted, bubble-gum flavored solution contains: anhydrous cefprozil 125 mg. Nonmedicinal ingredients: aspartame, citric acid, colloidal silicone dioxide, FD&C red No. 3, flavors (natural and artificial), glycine, microcrystalline cellulose, polysorbate 80, simethicone, sodium benzoate, sodium carboxymethylcellulose, sodium chloride and sucrose. Energy 6.2 kJ (1.5 kcal)/mL. Bottles of 75 and 100 mL.

250 mg/5 mL: Each 5 mL of constituted, bubble-gum flavored solution contains: anhydrous cefprozil 250 mg. Nonmedicinal ingredients: aspartame, citric acid, colloidal silicone dioxide, FD&C red No. 3, flavors (natural and artificial), glycine, microcrystalline cellulose, polysorbate 80, simethicone, sodium benzoate, sodium carboxymethylcellulose, sodium chloride and sucrose. Energy 5.5 kJ (1.3 kcal)/mL. Bottles of 75 and 100 mL.

Tablets: 250 mg: Each light orange, caplet-shaped, film-coated tablet engraved with 7720 on one side and with 250 on the other side,contains: anhydrous cefprozil 250 mg. Nonmedicinal ingredients: FD&C yellow No. 6, hydroxypropylmethylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, simethicone, sodium starch glycolate and titanium dioxide. Bottles of 100.

500 mg: Each white, caplet-shaped, film-coated tablet, engraved with 7721 on one side and with 500 on the other side, contains: anhydrous cefprozil 500 mg. Nonmedicinal ingredients: hydroxypropylmethylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, simethicone, sodium starch glycolate and titanium dioxide. Bottles of 100.

Store the tablets and powder for oral suspension at room temperature (15 to 30°C) and protect from light and excessive humidity.

CEFZIL™ Bristol-Myers Squibb Cefprozil Antibiotic

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