Cefaclor: Package Insert and Label Information

CEFACLOR- cefaclor suspension
Carlsbad Technology, Inc.

Rx Only

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefaclor for Oral Suspension and other antibacterial drugs, Cefaclor for Oral Suspension, USP, should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Cefaclor, USP, is a semisynthetic cephalosporin antibiotic for oral administration. It is chemically designated as 3-chloro-7-D-(2-phenylglycinamido)-3-cephem-4-carboxylic acid monohydrate. The chemical formula for cefaclor is C15 H14 ClN3 O4 S•H2 O and the molecular weight is 385.82.

Chemical Formula

After mixing, each 5 mL of Cefaclor for Oral Suspension will contain cefaclor monohydrate equivalent to 125 mg (0.34 mmol), 187 mg (0.51 mmol), 250 mg (0.68 mmol), or 375 mg (1.0 mmol) anhydrous cefaclor. The suspensions also contain methylcellulose, sodium lauryl sulfate, sucrose, and xanthan gum, FD&C Red No. 40, strawberry flavor.

The color of drug powder in the dry powder state is white to off-white. After reconstitution, it turns to a red suspension.

CLINICAL PHARMACOLOGY

Cefaclor is well absorbed after oral administration to fasting subjects. Total absorption is the same whether the drug is given with or without food; however, when it is taken with food, the peak concentration achieved is 50% to 75% of that observed when the drug is administered to fasting subjects and generally appears from three fourths to 1 hour later. Following administration of 250 mg, 500 mg, and 1 g doses to fasting subjects, average peak serum levels of approximately 7, 13, and 23 mcg/mL, respectively, were obtained within 30 to 60 minutes. Approximately 60% to 85% of the drug is excreted unchanged in the urine within 8 hours, the greater portion being excreted within the first 2 hours. During this 8-hour period, peak urine concentrations following the 250 mg, 500 mg and 1 g doses were approximately 600, 900 and 1,900 mcg/mL, respectively. The serum half-life in normal subjects is 0.6 to 0.9 hour. In patients with reduced renal function, the serum half-life of cefaclor is slightly prolonged. In those with complete absence of renal function, the plasma half-life of the intact molecule is 2.3 to 2.8 hours. Excretion pathways in patients with markedly impaired renal function have not been determined. Hemodialysis shortens the half-life by 25% to 30%.

Microbiology

Mechanism of Action

As with other cephalosporins, the bactericidal action of cefaclor results from inhibition of cell-wall synthesis.

Mechanism of Resistance

Resistance to cefaclor is primarily through hydrolysis of beta-lactamases, alteration of penicillin-binding proteins (PBPs) and decreased permeability. Pseudomonas spp., Acinetobacter calcoaceticus and most strains of Enterococci (Enterococcus faecalis , group D streptococci), Enterobacter spp., indole-positive Proteus , Morganella morganii (formerly Proteus morganii), Providencia rettgeri (formerly Proteus rettgeri), and Serratia spp. are resistant to cefaclor. Cefaclor is inactive against methicillin-resistant staphylococci. β-lactamase-negative, ampicillin-resistant strains of H. influenzae should be considered resistant to cefaclor despite apparent in vitro susceptibility to this agent.

Antibacterial Activity

Cefaclor 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.

Gram-positive Bacteria

Staphylococcus aureus (methicillin susceptible only)

Coagulase negative staphylococci (methicillin susceptible only)

Streptococcus pneumoniae

Streptococcus pyogenes (group A β-hemolytic streptococci)

Gram-negative Bacteria

Escherichia coli

Haemophilus influenzae (excluding β-lactamase-negative, ampicillin-resistant strains)

Klebsiella spp.

Proteus mirabilis

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoint of cefaclor. However, the safety and effectiveness of cefaclor in treating clinical infections due to these bacteria has not been established in adequate and well-controlled trials.

Gram-negative Bacteria

Citrobacter diversus

Moraxella catarrhalis

Neisseria gonorrhoeae

Anaerobic Bacteria

Bacteroides spp.

Peptococcus spp.

Peptostreptococcus spp.

Propionibacterium acnes

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the result of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized method (broth, agar, or microdilution)1,3. The MIC values should be interpreted according to criteria provided in Table 1.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method2,3. This procedure uses paper disks impregnated with 30 mcg cefaclor to test the susceptibility of microorganisms to cefaclor. The disc diffusion interpretive criteria are provided in Table 1.

Table 1: Susceptibility Test Interpretive Criteria for Cefaclor
1 Susceptibility of staphylococci to cefaclor may be deduced from testing only penicillin and either cefoxitin or oxacillin2 Susceptibility of Streptococcus pyogenes to cefaclor may also be deduced from testing penicillin
Microorganisms1,2 Minimal Inhibitory Concentration (mcg/mL) Zone Diameter (mm)
S I R S I R
Streptococcus pneumoniae ≤1 2 ≥4

A report of Susceptible indicates that antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the site of infection necessary to inhibit growth of the pathogen. 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 a high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1,2,3 Standard cefaclor powder should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 30 mcg disk the criteria in Table 2 should be achieved.

Table 2: Acceptable Quality Control Ranges for Cefaclor
QC Strain Minimal Inhibitory Concentration (mcg/mL) Zone Diameter (mm)
Escherichia coli ATCC 25922 1 — 4 23 — 27
Haemophilus influenzae ATCC 49766 1 — 4 25 — 31
Staphylococcus aureus ATCC 25923 27 — 31
Staphylococcus aureus ATCC 29213 1 — 4
Streptococcus pneumoniae ATCC 49619 1 — 4 24 — 32

INDICATIONS AND USAGE

Cefaclor is indicated in the treatment of the following infections when caused by susceptible strains of the designated microorganisms:

Otitis media caused by Streptococcus pneumoniae , Haemophilus influenzae , staphylococci, and Streptococcus pyogenes

Note: β-lactamase-negative, ampicillin-resistant (BLNAR) strains of Haemophilus influenzae should be considered resistant to cefaclor despite apparent in vitro susceptibility of some BLNAR strains.

Lower respiratory tract infections, including pneumonia, caused by Streptococcus pneumoniae , Haemophilus influenzae , and Streptococcus pyogenes

Note: β-lactamase-negative, ampicillin-resistant (BLNAR) strains of Haemophilus influenzae should be considered resistant to cefaclor despite apparent in vitro susceptibility of some BLNAR strains.

Pharyngitis and Tonsillitis, caused by Streptococcus pyogenes

Note: Penicillin is the usual drug of choice in the treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Cefaclor is generally effective in the eradication of streptococci from the nasopharynx; however, substantial data establishing the efficacy of cefaclor in the subsequent prevention of rheumatic fever are not available at present.

Urinary tract infections, including pyelonephritis and cystitis, caused by Escherichia coli , Proteus mirabilis , Klebsiella spp., and coagulase-negative staphylococci

Skin and skin structure infections caused by Staphylococcus aureus and Streptococcus pyogenes

Appropriate culture and susceptibility studies should be performed to determine susceptibility of the causative organism to cefaclor.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefaclor for Oral Suspension and other antibacterial drugs, Cefaclor 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.

CONTRAINDICATIONS

Cefaclor is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.

WARNINGS

BEFORE THERAPY WITH CEFACLOR IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFACLOR, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-HYPERSENSITIVITY 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 CEFACLOR 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.

Antibiotics, including cefaclor, should be administered cautiously to any patient who has demonstrated some form of allergy, particularly to drugs.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Cefaclor for Oral Suspension, USP, 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.

PRECAUTIONS

General

Prescribing cefaclor in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increase the risk of the development of drug-resistant bacteria.

Prolonged use of cefaclor 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 the cephalosporin antibiotics. It should be recognized that a positive Coombs’ test may be due to the drug, e.g., in hematologic studies or in transfusion cross-matching procedures when antiglobulin tests are performed on the minor side or in Coombs’ testing of newborns whose mothers have received cephalosporin antibiotics before parturition.

Cefaclor should be administered with caution in the presence of markedly impaired renal function. Since the half-life of cefaclor in anuria is 2.3 to 2.8 hours, dosage adjustments for patients with moderate or severe renal impairment are usually not required. Clinical experience with cefaclor under such conditions is limited; therefore, careful clinical observation and laboratory studies should be made.

As with other β-lactam antibiotics, the renal excretion of cefaclor is inhibited by probenecid.

Antibiotics, including cephalosporins, should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

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