Cefaclor

INDICATIONS AND USAGE 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 (excluding ß-lactamase-negative, ampicillin-resistant isolates), Moraxella catarrhalis, or Streptococcus pneumoniae . NOTE: In view of the insufficient numbers of isolates of ß-lactamase-producing isolates of Haemophilus influenzae that were obtained from clinical trials with cefaclor extended-release tablets for patients with acute bacterial exacerbations of chronic 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 . 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 only). 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 .

DOSAGE AND ADMINISTRATION Cefaclor is administered orally. Adults -- The usual adult dosage is 250 mg every 8 hours. For more severe infections (such as pneumonia) or those caused by less susceptible organisms, doses may be doubled. Pediatric Patients -- The usual recommended daily dosage for pediatric patients is 20 mg/kg/day in divided doses every 8 hours. In more serious infections, otitis media, and infections caused by less susceptible organisms, 40 mg/kg/day are recommended, with a maximum dosage of 1 g/day. Table 1: Cefaclor for Oral Suspension, USP 20 mg/kg/day Weight 125 mg/5 mL 250 mg/5 mL 9 kg 1/2 tsp t.i.d. 18 kg 1 tsp t.i.d. 1/2 tsp t.i.d. 40 mg/kg/day 9 kg 1 tsp t.i.d. 1/2 tsp t.i.d. 18 kg 1 tsp t.i.d. B.I.D. Treatment Option —For the treatment of otitis media and pharyngitis, the total daily dosage may be divided and administered every 12 hours. Table 2: Cefaclor for Oral Suspension, USP 20 mg/kg/day (Pharyngitis) Weight 375 mg/5 mL 18 kg 1/2 tsp b.i.d. 40 mg/kg/day (Otitis Media) 9 kg 1/2 tsp b.i.d. 18 kg 1 tsp b.i.d. Cefaclor may be administered in the presence of impaired renal function. Under such a condition, the dosage usually is unchanged (see PRECAUTIONS ). In the treatment of β-hemolytic streptococcal infections, a therapeutic dosage of cefaclor should be administered for at least 10 days. Directions for Mixing: Add appropriate water volume as indicated in the following table in two portions to dry mixture in the bottle. Shake well after each addition. Each 5 mL (approximately one teaspoonful) will then contain Cefaclor, USP, monohydrate equivalent to 250 mg anhydrous cefaclor, respectively, as shown in the following table. Oversize bottle provides extra space for shaking. Table 3: Cefaclor For Oral Suspension, USP Strength Package Size (when mixed) Water Volume to Add Anhydrous Cefaclor/5 mL (approx. one teaspoonful) 250 mg/5 Ml 150 mL 106 mL 250 mg

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 HYPER-SENSITIVITY 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.

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

Drug Interactions Antacids The extent of absorption of cefaclor extended-release tablets 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 cefaclor extended-release tablets. 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.

ADVERSE REACTIONS Clinical Trials 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 4 and 5 ). Table 4: ADVERSE CLINICAL EVENTS - CEFACLOR EXTENDED-RELEASE TABLETS MULTIPLE DOSE DOSING REGIMENS CLINICAL TRIALS - NORTH AMERICA (n = 1400) Incidence Equal to or Greater Than 1% Event Incidence Headache 4.9% Rhinitis 3.9% Diarrhea 3.8% Nausea 3.4% Vaginitis n = 934 for these events (subset of female participants). 2.4% Vaginal Moniliasis 2.2% Abdominal Pain 1.6% Cough Increased 1.5% Pharyngitis 1.4% Pruritus 1.4% Back Pain 1.0% 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 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. Table 5: ADVERSE CLINICAL LABORATORY EVENTS CEFACLOR EXTENDED-RELEASE TABLETS MULTIPLE DOSE DOSING REGIMENS CLINICAL TRIALS – NORTH AMERICA Event Incidence Incidence Less Than 1%, but Greater Than 0.1% Albumin decreased 0.3% Alkaline phosphatase increased 0.3% ALT/SGPT increased 0.3% Bilirubin total increased 0.3% Blood urea nitrogen (BUN) increased 0.2% Calcium decreased 0.7% Creatine phosphokinase increased 0.7% Creatinine increased 0.5% Eosinophils increased 0.3% Erythrocyte count decreased 0.3% GGT increased 0.2% Hemoglobin decreased 0.2% Lymphocytes decreased 0.3% Mean Cell Volume (MCV) increased 0.7% Neutrophils segmented decreased 0.3% Phosphorous increased 0.7% Platelet count decreased 0.3% Potassium increased 0.4% Sodium decreased 0.3% Sodium increased 0.4% In Postmarketing Experience In addition to the events reported during clinical trials with cefaclor extended-release tablets, 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), paresthesias, 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 WARNINGS .) 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.

CLINICAL PHARMACOLOGY Pharmacokinetics 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. Absorption and Metabolism The extent of absorption (AUC) and the maximum plasma concentration (C max ) of cefaclor from cefaclor extended-release tablets are greater when the extended-release tablet is taken with food. [ NOTE: The extent of absorption (AUC) of cefaclor from cefaclor immediate-release capsules is unaffected by food intake; however, when cefaclor immediate-release capsules are taken with food, the C max is decreased.] There is no evidence of metabolism of cefaclor in humans. Comparative Serum Pharmacokinetics Serum pharmacokinetic parameters for cefaclor extended-release tablets and cefaclor immediate-release capsules are shown in the table below. Table 1: COMPARATIVE PHARMACOKINETICS OF CEFACLOR IMMEDIATE-RELEASE CAPSULES VS. CEFACLOR EXTENDED-RELEASE TABLETS IN FASTING AND FED STATES Parameter Cefaclor Extended-Release Tablets Cefaclor Extended-Release Tablets Cefaclor Immediate-Release Capsules 375 mg 500 mg 2 x 250 mg fed fast fed fast fed fast n = 10 n = 16 n = 16 n = 15 n = 16 C max 3.7 (1.1) NA 8.2 (4.2) 5.4 (1.6) 9.3 (2.7) 16.8 (4.7) T max 2.7 (1.0) NA 2.5 (0.8) 1.5 (0.7) 1.5 (0.6) 0.9 (0.4) AUC 9.9 (2.2) NA 18.1 (4.2) 14.8 (4.0) 20.5 (2.8) 19.2 (5.0) (± 1 standard deviation) NA = data not available No drug accumulation was noted when cefaclor extended-release tablets were given twice daily. The plasma half-life in healthy subjects is independent of dosage form and averages approximately 1 hour. Food Effect on Pharmacokinetics When cefaclor extended-release tablets are taken with food, the AUC is 10% lower while the C max is 12% lower and occurs 1 hour later compared to cefaclor immediate-release capsules. In contrast, when cefaclor extended-release tablets are 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 cefaclor immediate-release capsules as a reference. Therefore, cefaclor extended-release tablets should be taken with food. Special Populations 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 Healthy geriatric volunteers (≥ 65 years old) who received a single 750 mg dose of cefaclor extended­release 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 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. 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 ß-lactamases alteration of penicillin-binding proteins (PBPs) and decreased permeability. Pseudomonas spp., Acinetobacter calcoaceticus and most isolates 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, ß-lactamase-negative, ampicillin-resistant isolates of H. influenzae should be considered resistant to cefaclor despite apparent in vitro susceptibility to this agent. List of Microorganisms Cefaclor has been shown to be active against most isolates 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) Streptococcus pneumoniae Streptococcus pyogenes Gram-negative Bacteria Haemophilus influenzae (excluding β-lactamase-negative, ampicillin-resistant isolates) Moraxella catarrhalis The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoint for cefaclor against isolates of similar genus or organism group. However, the efficacy of cefaclor in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled trials. Gram-positive Bacteria Staphylococcus epidermidis (methicillin susceptible only) Gram-negative Bacteria Haemophilus parainfluenzae Klebsiella pneumoniae Anaerobic Bacteria Peptococcus niger Peptostreptococci Propionibacterium acnes Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC .