Cefprozil powder, for suspension

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CEFPROZIL FOR ORAL SUSPENSION USP

125 mg/5 mL and 250 mg/5 mL

Rx only

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 bacteria.

Description

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Cefprozil is a semi-synthetic broad-spectrum cephalosporin antibiotic.

Cefprozil is a cis and trans isomeric mixture (90% cis). The chemical name for the monohydrate is (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 monohydrate, and the structural formula is:

cefprozilfos-1

Cefprozil is a white to yellowish powder with a molecular formula for the monohydrate of C 18H 19N 3O 5S.H 2O and a molecular weight of 407.45.

Cefprozil for oral suspension is intended for oral administration.

Cefprozil for oral suspension contains cefprozil equivalent to 125 mg or 250 mg of anhydrous cefprozil per 5 mL constituted suspension. In addition, the oral suspension contains the following inactive ingredients: aspartame, bubble gum flavor, anhydrous citric acid, colloidal silicon dioxide, FD&C Red No. 40 Aluminum Lake, glycine, microcrystalline cellulose and sodium carboxymethylcellulose, sodium benzoate, sodium chloride and sucrose.

Clinical pharmacology

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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)
MeanPlasmaCefprozil
Concentrations(mcg/mL)
Peakappx.
8hourUrinaryExcretion(%)

1.5h
4h
8h

250mg
6.1
1.7
0.2
60%
500mg
10.5
3.2
0.4
62%
1000mg
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 (65years 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 1to 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)PlasmaCefprozil
Concentrations(mcg/mL)

an=11 bn=5 cn=9 dn=11

Population
Dose
1h
2h
4h
6h
T (h)
children
(n=18)
7.5mg/kg
4.70
(1.57)
3.99
(1.24)
0.91
(0.30)
0.23 a
(0.13)
0.94
(0.32)
adults
(n=12)
250mg
4.82
(2.13)
4.92
(1.13)
1.70 b
(0.53)
0.53
(0.17)
1.28
(0.34)
children
(n=19)
15mg/kg
10.86
(2.55)
8.47
(2.03)
2.75
(1.07)
0.61 c
(0.27)
1.24
(0.43)
adults
(n=12)
500mg
8.39
(1.95)
9.42
(0.98)
3.18 d
(0.76)
1.00 d
(0.24)
1.29
(0.14)
children
(n=10)
30mg/kg
16.69
(4.26)
17.61
(6.39)
8.66
(2.70)
--
2.06
(0.21)
adults
(n=12)
1000mg
11.99
(4.67)
16.95
(4.07)
8.36
(4.13)
2.79
(1.77)
1.27
(0.12)

Indications and usage

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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:

Contraindications

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Cefprozil is contraindicated in patients with known allergy to the cephalosporin class of antibiotics.

Warnings

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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 -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 difficileassociated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefprozil, 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. difficileproduces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficilecause 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. difficilemay 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.

Precautions

General:

Prescribing cefprozil for oral suspension in the absence of proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria.

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 these patients because high and/or prolonged plasma antibiotic concentrations can occur in such individuals from usual doses. 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.

Cefprozil should be prescribed with caution in individuals with a history of gastrointestinal disease particularly colitis.

Positive direct Coombs tests have been reported during treatment with cephalosporin antibiotics.

Information for patients:

Phenylketonurics: Cefprozil for oral suspension contains phenylalanine 28 mg per 5 mL (1 teaspoonful) constituted suspension for both the 125 mg/5 mL and 250 mg/5 mL dosage forms.

Patients should be counseled that antibacterial drugs including cefprozil for oral suspension should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefprozil for oral suspension is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cefprozil for oral suspension or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

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.

Drug/laboratory test interactions:

Cephalosporin antibiotics may produce a false positive reaction for glucose in the urine with copper reduction tests (Benedicts or Fehlings solution or with Clinitest ®tablets), but not with enzyme-based tests for glycosuria (e.g., Clinistix ®). 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.

Carcinogenesis and mutagenesis and impairment of fertility

Long term in vivostudies have not been performed to evaluate the carcinogenic potential of cefprozil.

Cefprozil was not found to be mutagenic in either the Ames Salmonellaor E. coliWP2 urvA reversion assays or the Chinese hamster ovary cell HGPRT forward gene mutation assay and it did not induce chromosomal abnormalities in Chinese hamster ovary cells or unscheduled DNA synthesis in rat hepatocytes in vitro. Chromosomal aberrations were not observed in bone marrow cells from rats dosed orally with over 30 times the highest recommended human dose based upon mg/m 2.

Impairment of fertility was not observed in male or female rats given oral doses of cefprozil up to 18.5 times the highest recommended human dose based upon mg/m 2.

Labor and delivery

Cefprozil has not been studied for use during labor and delivery. Treatment should only be given if clearly needed.

Nursing mothers

Small amounts of cefprozil (<0.3% of dose) have been detected in human milk following administration of a single 1 gram dose to lactating women. The average levels over 24 hours ranged from 0.25 to 3.3 mcg/mL. Caution should be exercised when Cefprozil for oral suspension is administered to a nursing woman, since the effect of cefprozil on nursing infants is unknown.

Pediatric use

(See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION.)

The safety and effectiveness of cefprozil in the treatment of otitis media have been established in the age groups 6 months to 12 years. Use of cefprozil for the treatment of otitis media is supported by evidence from adequate and well-controlled studies of cefprozil in pediatric patients. (See CLINICAL STUDIES.)

The safety and effectiveness of cefprozil in the treatment of pharyngitis/tonsillitis or uncomplicated skin and skin-structure infections have been established in the age groups 2 to 12 years. Use of cefprozil for the treatment of these infections is supported by evidence from adequate and well-controlled studies of cefprozil in pediatric patients.

The safety and effectiveness of cefprozil in the treatment of acute sinusitis have been established in the age groups 6 months to 12 years. Use of cefprozil in these age groups is supported by evidence from adequate and well-controlled studies of cefprozil in adults.

Safety and effectiveness in pediatric patients below the age of 6 months have not been established for the treatment of otitis media or acute sinusitis, or below the age of 2 years for the treatment of pharyngitis/tonsillitis or uncomplicated skin and skin-structure infections. However, accumulation of other cephalosporin antibiotics in newborn infants (resulting from prolonged drug half-life in this age group) has been reported.

Geriatric use

Of the more than 4500 adults treated with cefprozil in clinical studies, 14% were 65 years and older, while 5% were 75 years and older. When geriatric patients received the usual recommended adult doses, their clinical efficacy and safety were comparable to clinical efficacy and safety in nongeriatric adult patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals to the effects of cefprozil cannot be excluded (see CLINICAL PHARMACOLOGY).

Cefprozil is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function. See DOSAGE AND ADMINISTRATION for dosing recommendations for patients with impaired renal function.

Adverse reactions

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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:

Overdosage

Single 5000 mg/kg oral doses of cefprozil caused no mortality or signs of toxicity in adult, weanling, or neonatal rats, or adult mice. A single oral dose of 3000 mg/kg caused diarrhea and loss of appetite in cynomolgus monkeys, but no mortality.

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 for oral suspension is administered orally.

Population/Infection
Dosage(mg)
Duration(days)

aIn the treatment of infections due to Streptococcus pyogenes, cefprozil for oral suspension should be administered for at least 10 days.

bNot to exceed recommended adult doses.

ADULTS(13yearsandolder)


UPPERRESPIRATORYTRACT


Pharyngitis/Tonsillitis
500q24h
10 a
AcuteSinusitis
250q12hor
10
(Formoderatetosevereinfections,thehigherdoseshouldbeused)
500q12h

LOWERRESPIRATORYTRACT


SecondaryBacterialInfectionofAcuteBronchitisandAcuteBacterial
ExacerbationofChronicBronchitis
500q12h
10
SKINANDSKINSTRUCTURE


UncomplicatedSkinandSkinStructureInfections
250q12hor
10

500q24hor


500q12h

CHILDREN(2years-12years)


UPPERRESPIRATORYTRACT b


Pharyngitis/Tonsillitis
7.5mg/kgq12h
10 a
SKINANDSKINSTRUCTURE b


UncomplicatedSkinandSkinStructureInfections
20mg/kgq24h
10
INFANTS&CHILDREN(6months-12years)


UPPERRESPIRATORYTRACT b


OtitisMedia
15mg/kgq12h
10
(See INDICATIONS AND USAGEand CLINICAL STUDIES)

AcuteSinusitis
7.5mg/kgq12hor
10
(Formoderatetosevereinfections,thehigherdoseshouldbeused)
15mg/kgq12h

How supplied

Cefprozil for oral suspension, USP is a pink coloured powder, forming pink coloured suspension with characteristic odour on constitution.

Cefprozil For Oral Suspension, USP 125 mg/5 mL is available as follows:

50 mL Bottle NDC 68180-401-01

75 mL Bottle NDC 68180-401-02

100 mL Bottle NDC 68180-401-03

Cefprozil For Oral Suspension, USP 250 mg/5 mL is available as follows:

50 mL Bottle NDC 68180-402-01

75 mL Bottle NDC 68180-402-02

100 mL Bottle NDC 68180-402-03

All powder formulations for oral suspension contain cefprozil in a bubble-gum flavored mixture.

Clinical studies

References

  1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically-Third Edition. Approved Standard NCCLS Document M7-A3, Vol.13, No. 25, NCCLS, Villanova, PA, December 1993.
  2. National Committee for Clinical Laboratory Standards. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria-Third Edition. Approved Standard NCCLS Document M11-A3, Vol. 13, No. 26, NCCLS, Villanova, PA, December 1993.
  3. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests-Fifth Edition. Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, December 1993.
  4. Clintest ®and Clinistix ®are registered trademarks of Bayer HealthCare LLC.

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Manufactured for: Manufactured by

Lupin Pharmaceuticals, Inc.Lupin Limited

Baltimore, Maryland 21202Mumbai 400 098

United StatesINDIA

Revised December 2007ID#: 213042

Ingredients and appearance - Product information

Cefprozil powder, for suspension- Cefprozil

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 57297-401
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Cefprozil ( UNII: 4W0459ZA4V)( Cefprozil anhydrous - UNII: 1M698F4H4E ) 125 mgin 5 mL

Inactive Ingredients

Ingredient Name Code
Anhydrous citric acid ( UNII: XF417D3PSL)
Aspartame ( UNII: Z0H242BBR1)
Fd&c red no. 40 ( UNII: WZB9127XOA)
Glycine ( UNII: TE7660XO1C)
Silicon dioxide ( UNII: ETJ7Z6XBU4)
Sodium benzoate ( UNII: OJ245FE5EU)
Sucrose ( UNII: C151H8M554)
Carboxymethylcellulose sodium ( UNII: K679OBS311)
Cellulose, microcrystalline ( UNII: OP1R32D61U)
Sodium chloride ( UNII: 451W47IQ8X)

Product Characteristics

Flavor BUBBLE GUM

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA065261 USA

Labeler - LUPIN LIMITED( 675923163)

Establishment

Name ID/FEI Business Operations
LUPIN LIMITED 675923163 manufacture( 57297-401, 57297-402), pack( 57297-401, 57297-402)

Package label.principal display panel

NDC 68180-401-01

Cefprozil for Oral Suspension USP

125 mg/5 mL

Rx only

50 mL (when mixed)

NDC 68180-402-01

Cefprozil for Oral Suspension USP

250 mg/5 mL

Rx only

50 mL (when mixed)

Data represent mean values of 12 healthy volunteers.