CEFACLOR EXTENDED-RELEASE TABLETS USP, 375 mg and 500 mg
1215
1087

Cefaclor, USP, the active ingredient in Cefaclor Extended-Release Tablets USP, 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 cefaclor extended-release tablets formulation of cefaclor differs pharmacokinetically from the immediate-release formulation of cefaclor.

C₁₅H₁₄ClN₃O₄S•H₂O MW 385.82

Each cefaclor extended-release 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: FD&C blue #2 - indigo carmine lake, hypromellose, magnesium stearate, mannitol, polyethylene glycol, povidone and titanium dioxide.

The cefaclor extended-release tablet formulation of cefaclor is pharmacokinetically different from the cefaclor immediate-release capsule formulation of cefaclor. (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 extended-release tablet formulation and the suspension formulation. Until further data are available, the pharmacokinetic equivalence of the extended-release tablet and the suspension formulations should NOT be assumed.

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 ß-lactamases; consequently, some ß-lactamase-producing organisms may be susceptible to cefaclor.

Cefaclor extended-release tablets have 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 aerobes:

Staphylococcus aureus

Streptococcus pneumoniae

Streptococcus pyogenes

NOTE: Cefaclor is inactive against methicillin-resistant staphylococci.

Gram-negative aerobes:

Haemophilus influenzae (non-ß-lactamase-producing strains only)

Moraxella catarrhalis (including ß-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 cefaclor extended-release tablets in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.

Gram-positive aerobes:

Staphylococcus epidermidis

Gram-negative aerobes:

Haemophilus parainfluenzae

Klebsiella pneumoniae

Anaerobic bacteria:

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.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefaclor Extended-Release Tablets USP and other antibacterial drugs, Cefaclor Extended-Release Tablets USP 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.

The safety and effectiveness of cefaclor extended-release tablets 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, cefaclor extended-release tablets are 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-ß-lactamase-producing strains only), Moraxella catarrhalis (including ß-lactamase-producing strains) or Streptococcus pneumoniae.

NOTE: In view of the insufficient numbers of isolates of ß-lactamase-producing strains of Haemophilus influenzae that were obtained from clinical trials with cefaclor extended-release tablets 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 cefaclor extended-release tablets for bronchitis known, suspected, or considered potentially to be caused by ß-lactamase-producing H. influenzae.

Secondary bacterial infections of acute bronchitis due to Haemophilus influenzae (non-ß-lactamase-producing strains only), Moraxella catarrhalis (including ß-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. Cefaclor extended-release tablets are generally effective in the eradication of S. pyogenes from the oropharynx; however, data establishing the efficacy of cefaclor extended-release tablets 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 cefaclor extended-release tablets for patients with uncomplicated skin and skin structure infections, it was not possible to adequately evaluate the effectiveness of cefaclor extended-release tablets for skin infections known, suspected, or considered potentially to be caused by S. pyogenes.

Cefaclor extended-release tablets are contraindicated in patients with known hypersensitivity to cefaclor and other cephalosporins.

BEFORE THERAPY WITH CEFACLOR EXTENDED-RELEASE TABLETS 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 CEFACLOR EXTENDED-RELEASE TABLETS OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, INTRAVENOUSFLUIDS, 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.

Prescribing Cefaclor Extended-Release Tablets USP in the absence of a 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.

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.

Patients should be counseled that antibacterial drugs including Cefaclor Extended-Release Tablets USP should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefaclor Extended-Release Tablets USP are 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 Cefaclor Extended-Release Tablets USP or other antibacterial drugs in the future.

Administration of cefaclor extended-release tablets 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's and Fehling's solutions and also with Clinitest^®tablets.

Studies in animals have not been performed to evaluate the carcinogenic or mutagenic potential for cefaclor. Reproduction studies have revealed no evidence of impaired fertility.

Cefaclor extended-release tablets have not been studied for use during labor and delivery. Treatment should be given only if clearly needed.

No studies in lactating women have been performed with cefaclor extended-release tablets. Small amounts of cefaclor (≤ 0.21 µg/mL) have been detected in human milk following administration of single 500-mg doses of cefaclor extended-release tablets. The effect on nursing infants is not known. Caution should be exercised when cefaclor extended-release tablets are administered to a nursing woman.

Safety and effectiveness of cefaclor extended-release tablets in pediatric patients less than 16 years of age have not been established.

Healthy geriatric volunteers (> 65 years old) who received a single 750-mg dose of cefaclor extended-release tablets 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.

There were 3272 patients treated with multiple doses of cefaclor extended-release tablets 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 cefaclor extended-release tablets. 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 cefaclor extended-release tablets 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 investigators during the trials (see Tables 2 and 3).

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 (uled 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 cefaclor extended-release tablets 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.

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 cefaclor extended-release tablets is enhanced when it is administered with food. (See CLINICAL PHARMACOLOGY.) Therefore, cefaclor extended-release tablets 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 INDICATIONS AND USAGE for information about patients for whom cefaclor extended-release tablets are indicated.

NOTE: 500 mg BID of cefaclor extended-release tablets is clinically equivalent to 250 mg TID of cefaclor immediate-release as a capsule in those indications uled in the INDICATIONS AND USAGE section of this label. 500 mg BID of cefaclor extended-release tablets is NOT equivalent to 500 mg TID of other cefaclor formulations.

Elderly patients with normal renal function do not require dosage adjustments.

Cefaclor Extended-Release Tablets USP, 375 mg (based on the anhydrous), are available as film-coated, oval shaped, unscored, dark blue tablets, debossed with “93” on one side and “1215” on the other side. They are available in bottles of 100.

Cefaclor Extended-Release Tablets USP, 500 mg (based on the anhydrous), are available as film-coated, oval shaped, unscored, dark blue tablets, debossed with “93” on one side and “1087” on the other side. They are available in bottles of 100.

Store at controlled room temperature, between 20° and 25°C (68° and 77°F) (see USP).

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

In adequate and well-controlled clinical trials of cefaclor extended-release tablets 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 ß-lactamase-producing H. influenzae. Four patients do not provide adequate data upon which to judge clinical efficacy of cefaclor extended-release tablets against ß-lactamase-producing H. influenzae.

Cefaclor extended-release tablets (375 mg Q12H) (n=115) were compared to cefaclor immediate-release capsules (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:

• overall clinical cure rates were 72% (83 of 115 patients) and 75% (80 of 106 patients), respectively, for cefaclor extended-release tablets and cefaclor immediate-release capsules [95% CI around the 3% difference = -16% to +9%],
• overall bacteriologic eradication rates against Staphylococcus aureus were comparable (see Table 4).

• 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
• 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

Manufactured By:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. G 6/2003