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Cefaclor, USP, the active ingredient in Ceclor® CD (cefaclor extended release tablets), is a semisynthetic cephalosporin antibiotic for oral administration. Cefaclor, USP, is chemically designated as 3-chloro-7-D-(2-phenylglycinamido)-3-cephem-4-carboxylic acid monohydrate. The Ceclor CD formulation of cefaclor differs pharmacokinetically from the Ceclor® formulation of cefaclor. ( See .) Cefaclor monohydrate has a molecular formula of C 15 H 14 ClN 3 O 4 S ·H 2 O and a molecular weight of 385.82.
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Each Ceclor CD tablet contains cefaclor monohydrate equivalent to 375 mg (1.02 mmol) or 500 mg (1.36 mmol) anhydrous cefaclor. In addition, each extended release tablet contains the following inactive ingredients: celluloses; FD&C Blue No. 2; magnesium stearate; mannitol; methacrylic acid copolymer type C; propylene glycol; stearic acid; titanium dioxide; polyethylene glycol; talc; and edible black ink.
: The Ceclor CD formulation of cefaclor is pharmacokinetically different from the Ceclor® Pulvules® formulation. ( See Table 1.) No direct comparisons with the suspension formulation of cefaclor have been conducted; therefore, there are no data with which to compare the pharmacokinetic properties of the CD formulation and the suspension formulation. Until further data are available, the pharmacokinetic equivalence of the CD and the suspension formulations should NOT be assumed.
Absorption and Metabolism : The extent of absorption (AUC) and the maximum plasma concentration (C max ) of cefaclor from Ceclor CD are greater when the extended release tablet is taken with food.
[NOTE: The extent of absorption (AUC) of cefaclor from Ceclor Pulvules is unaffected by food intake; however, when Ceclor Pulvules are taken with food, the C max is decreased.]
There is no evidence of metabolism of cefaclor in humans.
Comparative Serum --Serum pharmacokinetic parameters for Ceclor CD and Ceclor Pulvules are shown in the following table.
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No drug accumulation was noted when Ceclor CD was given twice daily.
The plasma half-life in healthy subjects is independent of dosage form and averages approximately 1 hour.
Food Effect on : When Ceclor CD is taken with food, the AUC is 10% lower while the C max is 12% lower and occurs 1 hour later compared to Ceclor Pulvules. In contrast, when Ceclor CD is taken without food, the AUC is 23% lower while the C max is 67% lower and occurs 0.6 hours later, using an equivalent milligram dose of Ceclor Pulvules as a reference. Therefore, Ceclor CD should be taken with food.
Renal Insufficiency --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%.
Geriatric Patients --In elderly subjects (over age 65) with normal serum creatinine values, higher peak plasma concentrations and AUCs have been observed. This is considered to be primarily a result of an age-related decrement in renal function, and has no apparent clinical significance. Therefore, dosage adjustment is not necessary in elderly subjects with normal serum creatinine values.
Cefaclor has in vitro activity against a broad range of gram-positive and gram-negative bacteria. The bactericidal action of cefaclor results from inhibition of cell-wall synthesis. Cefaclor is stable in the presence of some bacterial (beta)-lactamases; consequently, some (beta)-lactamase-producing organisms may be susceptible to cefaclor.
Ceclor CD has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the section
Staphylococcus aureus
Streptococcus pneumoniae
Streptococcus pyogenes
NOTE: Cefaclor is inactive against methicillin-resistant staphylococci.
Haemophilus influenzae (non-(beta)-lactamase-producing strains only)
Moraxella catarrhalis (including (beta)-lactamase-producing strains)
The following in vitro data are available, but their clinical significance is unknown . Cefaclor exhibits in vitro minimum inhibitory concentrations (MICs) of 8 µg/mL or less (systemic susceptibility breakpoint) against most (>/=90%) strains of the following microorganisms; however, the safety and effectiveness of Ceclor CD in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.
Staphylococcus epidermidis
Haemophilus parainfluenzae
Klebsiella pneumoniae
Peptococcus niger
Peptostreptococci
Propionibacterium acnes
NOTE: Acinetobacter calcoaceticus, Enterobacter spp., Entercoccus spp., Morganella morganii, Proteus vulgaris, Providencia spp., Pseudomonas spp., and Serratia spp. are resistant to cefaclor.
Susceptibility Testing: 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 procedure. Standardized procedures are based on a dilution method 1 (broth, agar, or microdilution) or equivalent with standardized inoculum concentrations and standardized amounts of cefaclor powder. The MIC values should be interpreted according to the following criteria:
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A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in blood reaches the concentrations usually achievable. 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 high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard cefaclor powder should provide the following MIC values:
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Diffusion Techniques : Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure 2 requires the use of standarized inoculum concentrations. This procedure uses paper disks impregnated with 30-µg cefaclor to test the susceptibility of microorganisms to cefaclor.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-µg cefaclor disk should be interpreted according to the following criteria:
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When testing * H. Influenzae, the following interpretive criteria should be used:
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*Disk susceptibility tests performed using Haemophilus Test Medium (HTM) 2
Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for cefaclor.
As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30-µg cefaclor disk should provide the following zone diameters in these laboratory test quality control strains:
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The safety and effectiveness of Ceclor CD in treating some of the indications and pathogens for which other formulations of cefaclor are approved have NOT been established. When administered at the recommended dosages and durations of therapy, Ceclor CD is indicated for the treatment of patients with the following mild to moderate infections when caused by susceptible strains of the designated organisms. ( See DOSAGE AND ADMINISTRATION and CLINICAL STUDIES sections.)
Acute bacterial exacerbations of chronic bronchitis due to Haemophilus influenzae (non-(beta)-lactamase-producing strains only), Moraxella catarrhalis (including (beta)-lactamase-producing strains) or Streptococcus pneumoniae.
NOTE: In view of the insufficient numbers of isolates of (beta)-lactamase-producing strains of Haemophilus influenzae that were obtained from clinical trials with Ceclor CD for patients with acute bacterial exacerbations of chronic bronchitis or secondary bacterial infections of acute bronchitis, it was not possible to adequately evaluate the effectiveness of Ceclor CD for bronchitis known, suspected, or considered potentially to be caused by (beta)-lactamase-producing H. influenzae.
Secondary bacterial infections of acute bronchitis due to Haemophilus influenzae (non-(beta)-lactamase-producing strains only), Moraxella catarrhalis (including (beta)-lactamase-producing strains), or Streptococcus pneumoniae. (See above NOTE .)
Pharyngitis and tonsillitis due to Streptococcus pyogenes.
NOTE: Only penicillin by the intramuscular route of administration has been shown to be effective in the prophylaxis of rheumatic fever. Ceclor CD is generally effective in the eradication of S. pyogenes from the oropharynx; however, data establishing the efficacy of Ceclor CD for the prophylaxis of subsequent rheumatic fever are not available.
Uncomplicated skin and skin and structure infections due to Staphylococcus aureus (methicillin-susceptible).
NOTE: In view of the insufficient numbers of isolates of Streptococcus pyogenes that were obtained from clinical trials with Ceclor CD for patients with uncomplicated skin and skin structure infections, it was not possible to adequately evaluate the effectiveness of Ceclor CD for skin infections known, suspected, or considered potentially to be caused by S. pyogenes.
Ceclor CD is contraindicated in patients with known hypersensitivity to cefaclor and other cephalosporins.
BEFORE THERAPY WITH CECLOR CD 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-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 CECLOR CD 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.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including cefaclor, and may range 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.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth by clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of "antibiotic-associated colitis."
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against Clostridium difficile.
General: Superinfection (overgrowth by non-susceptible organisms) should always be considered a possibility in a patient being treated with a broad-spectrum antimicrobial. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.
Antacids --The extent of absorption of Ceclor CD is diminished if magnesium or aluminum hydroxide-containing antacids are taken within 1 hour of administration; H 2 blockers do not alter either the rate or the extent of absorption of Ceclor CD.
Probenecid --The renal excretion of cefaclor is inhibited by probenecid.
Warfarin --There have been rare reports of increased prothrombin time with or without clinical bleeding in patients receiving cefaclor and warfarin concomitantly. No specific studies have been performed to rule in or rule out this potential drug/drug interaction.
Laboratory Test Interactions: Administration of Ceclor CD may result in a false-positive reaction for glucose in the urine. This phenomenon has been seen in patients taking cephalosporin antibiotics when the test is performed using Benedict' and Fehling' solutions and also with Clinitest®tablets.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies in animals have not been performed to evaluate the carinogenic or mutagenic potential for cefaclor. Reproduction studies have revealed no evidence of impaired fertility.
Usage in Pregnancy--Teratogenic Effect: Pregnancy Category B: Reproduction studies using cefaclor have been performed in mice, rats, and ferrets at doses up to 3-5 times the maximum human dose (1500 mg/day) based on mg/m 2 . These studies have revealed no harm to the fetus due to cefaclor. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response. Ceclor CD should be used during pregnancy only if clearly needed.
Labor and Delivery: Ceclor CD has not been studied for use during labor and delivery. Treatment should be given only if clearly needed.
Nursing Mothers: No studies in lactating women have been performed with Ceclor CD. Small amounts of cefaclor (</=0.21 µg/mL) have been detected in human milk following administration of single 500-mg doses of Ceclor. The effect on nursing infants is not known. Caution should be exercised when Ceclor CD is administered to a nursing woman.
Pediatric Use: Safety and effectiveness of Ceclor CD in pediatric patients less than 16 years of age have not been established.
Geriatric Use: Healthy geriatric volunteers (>/=65 years old) who received a single 750-mg dose of Ceclor CD had 40%-50% higher AUC and 20% lower renal clearance values when compared to healthy adult volunteers less than 45 years of age. These differences are considered to be primarily a result of age-related decreases in renal function. In clinical studies when geriatric patients received the usual recommended adult doses, clinical efficacy and safety were comparable to results in non-geriatric adult patients. No dosage changes are recommended for healthy geriatric patients.
Clinical Trials: There were 3272 patients treated with multiple doses of Ceclor CD in controlled clinical trials and an additional 211 subjects in pharmacology studies. There were no deaths in these trials thought to be related to toxicity from Ceclor CD. Treatment was discontinued in 1.7% of patients due to adverse events thought to be possibly or probably drug-related.
The following adverse clinical and laboratory events were reported during the Ceclor CD clinical trials conducted in North America at doses of 375 mg or 500 mg BID; however, relatedness of the adverse events to the drug was not assigned by clinical investigations during the trials (See Tables 2 and 3).
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Adverse reactions occurring during the clinical trials with cefaclor extended release tablets with an incidence of less than 1% but greater than 0.1% included the following (listed alphabetically):
Accidental injury, anorexia, anxiety, arthralgia, asthma, bronchitis, chest pain, chills, congestive heart failure, conjunctivitis, constipation, dizziness, dysmenorrhea, dyspepsia, dysuria, ear pain, edema, fever, flatulence, flu syndrome, gastritis, infection, insomnia, leukorrhea, lung disorder, maculopapular rash, malaise, menstrual disorder, myalgia, nausea and vomiting, neck pain, nervousness, nocturia, otitis media, pain, palpitation, peripheral edema, rash, respiratory disorder, sinusitis, somnolence, surgical procedure, sweating, tremor, urticaria, vomiting.
NOTE: One case of serum-sickness-like reaction was reported among the 3272 adult patients treated with Ceclor CD during the controlled clinical trials. These reactions have also been reported with the use of cefaclor in other oral formulations and are seen more frequently in pediatric patients than in adults. These reactions are characterized by findings of erythema multiforme, rash, and other skin manifestations accompanied by arthritis/arthralgia, with or without fever, and differ from classic serum sickness in that there is infrequently associated lymphadenopathy and proteinuria, no circulating immune complexes and no evidence to date of sequelae of the reaction. While further investigation is ongoing, serum-sickness-like reactions appear to be due to hypersensitivity and more often occur during or following a second (or subsequent) course of therapy with cefaclor. Such reactions have been reported with overall occurrence ranging from 1 in 200 (0.5%) in one focused trial; to 2 in 8346 (0.024%) in overall clinical trials (with an incidence in pediatric patients in clinical trials of 0.055%); to 1 in 38,000 (0.003%) in spontaneous event reports. Signs and symptoms usually occur a few days after initiation of therapy and subside within a few days after cessation of therapy. Occasionally these reactions have resulted in hospitalization, usually of short duration (median hospitalization = 2 to 3 days, based on postmarketing surveillance studies). In those patients requiring hospitalization, the symptoms have ranged from mild to severe at the time of admission with more of the severe reactions occurring in pediatric patients.
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In Postmarketing Experience : In addition to the events reported during clinical trials with Ceclor CD, the following adverse experiences are among those that have been reported during worldwide postmarketing surveillance: allergic reaction, anaphylactoid reaction, angioedema, face edema, hypotension, Stevens-Johnson syndrome, syncope, paresthesia, vasodilatation, and vertigo.
Other Adverse Reactions Associated With Other Formulations of Cefaclor : In addition to the above, the following other adverse reactions and altered laboratory tests have been associated with cefaclor in other oral formulations:
Clinical : Severe hypersensitivity reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and anaphylaxis, have been reported rarely. Anaphylactoid events may be manifested by solitary symptoms, including angioedema, edema (including face and limbs), parasthesias, syncope, or vasodilatation. Anaphylaxis may be more common in patients with a history of penicillin allergy. Rarely, hypersensitivity symptoms may persist for several months.
Symptoms of pseudomembranous colitis may appear either during or after antibiotic treatment. ( See .)
Laboratory : Abnormal urinalysis, eosinophilia, leukopenia, neutropenia, transient elevations in AST, and transient thrombocytopenia have been reported.
Cephalosporin-Class Reactions : In addition to the adverse reactions listed above, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics:
Clinical : Confusion, erythema multiforme, genital pruritus, hepatic dysfunction including cholestasis, hemolytic anemia, reversible hyperactivity, hypertonia, and reversible interstitial nephritis.
Laboratory --Positive direct Coombs' test.
The toxic symptoms following an overdose of cefaclor may include nausea, vomiting, epigastric distress, and diarrhea. The severity of the epigastric distress and the diarrhea are dose-related.
Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage. Consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed.
Although cefaclor is considered dialyzable, neither forced diuresis, peritoneal dialysis, hemodialysis, nor charcoal hemoperfusion have been demonstrated to be beneficial in an overdose of cefaclor.
The absorption of Ceclor CD is enhanced when it is administered with food. ( See .) Therefore, Ceclor CD should be administered with meals (i.e., at least within one hour of eating ). The extended release tablets should not be cut, crushed, or chewed.
See for information about patients for whom Ceclor CD is indicated.
NOTE: 500 mg BID of Ceclor CD is clinically equivalent to 250 mg TID of cefaclor as a pulvule in those indications listed in the section of this label. 500 mg BID of Ceclor CD is NOT equivalent to 500 mg TID of other cefaclor formulations .
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Elderly patients with normal renal function do not require dosage adjustments.
Tablets (extended release):
375 mg, blue (UC 5391)--(60s) NDC 51479-036-60
500 mg, blue (UC 5392)--(60s) NDC 51479-035-60
500 mg, blue (UC5392)--(14s) NDC 51479-035-03
(CDpak™, Tray of 3)
Store at controlled room temperature, 15° to 30°C (59° to 86°F).
ACUTE BACTERIAL EXACERBATIONS OF CHRONIC BRONCHITIS AND SECONDARY BACTERIAL INFECTIONS OF ACUTE BRONCHITIS: In adequate and well-controlled clinical trials of Ceclor CD in the treatment of acute bacterial exacerbations of chronic bronchitis (ABECB) and secondary bacterial infections of acute bronchitis (SBIAB), only 4 evaluable patients with ABECB and no evaluable patients with SBIAB had infections caused by (beta)-lactamase-producing H. influenzae . Four patients do not provide adequate data upon which to judge clinical efficacy of Ceclor CD against (beta)-lactamase-producing H. influenzae .
UNCOMPLICATED SKIN AND SKIN STRUCTURE INFECTIONS: Ceclor CD (375 mg Q12H) (n=115) was compared to Ceclor Pulvules (250 mg TID) (n=106) for the treatment of patients with uncomplicated skin and skin structure infections, including cellulitis, pyoderma, abscess, and impetigo. Patients were treated for 7 to 10 days and were evaluated for clinical resolution and bacterial eradication approximately one week after completing therapy. To be evaluable, all patients had to have a recognized pathogen isolated from the skin infection just prior to the initiation of therapy. The results of this randomized, double-blinded, U.S. trial demonstrated:
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DURA PHARMACEUTICALS
Literature revised September 20, 1999
Manufactured by
Eli Lilly and Company
Indianapolis, IN 46285, USA
Distributed by DURA Pharmaceuticals, Inc.
San Diego, CA 92121
PV 2741 UCP CCD001B99
Copyright © 1997, 1999, Eli Lilly and Company.
All rights reserved.
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