DESCRIPTION SECTION.

DESCRIPTION. Cefaclor Capsules, USP are semisynthetic cephalosporin antibiotic for oral administration. It is chemically designated as 3-chloro-7-D-(2-phenylglycinamido)-3-cephem-4-carboxylic acid monohydrate. The molecular formula for cefaclor is C15H14ClN3O4SoH2O and the molecular weight is 385.82. Each capsule contains cefaclor monohydrate equivalent to 250 mg (0.68 mmol) or 500 mg (1.36 mmol) anhydrous cefaclor. The capsules also contain black iron oxide, croscarmellose sodium, FD C Red No.3, FD C Blue No.2, gelatin, magnesium stearate, corn starch, and titanium dioxide.The color of the capsule powder is white to off white. Cefaclor Capsules, USP are semisynthetic cephalosporin antibiotic for oral administration. It is chemically designated as 3-chloro-7-D-(2-phenylglycinamido)-3-cephem-4-carboxylic acid monohydrate. The molecular formula for cefaclor is C15H14ClN3O4SoH2O and the molecular weight is 385.82.Each capsule contains cefaclor monohydrate equivalent to 250 mg (0.68 mmol) or 500 mg (1.36 mmol) anhydrous cefaclor. The capsules also contain black iron oxide, croscarmellose sodium, FD C Red No.3, FD C Blue No.2, gelatin, magnesium stearate, corn starch, and titanium dioxide.The color of the capsule powder is white to off white. Chemical Structure.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Adverse effects considered to be related to therapy with cefaclor are listed below: Hypersensitivity reactions have been reported in about 1.5% of patients and include morbilliform eruptions (1 in 100). Pruritus, urticaria, and positive Coombs tests each occur in less than in 200 patients. Cases of serum-sickness-like reactions have been reported with the use of cefaclor. These are characterized by findings of erythema multiforme, rashes, 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. Occasionally, solitary symptoms may occur, but do not represent serum-sickness-like reaction. While further investigation is ongoing, serum-sickness-like reactions appear to be due to hypersensitivity and more often occur during or following second (or subsequent) course of therapy with cefaclor. Such reactions have been reported more frequently in pediatric patients than in adults with an overall occurrence ranging from in 200 (0.5%) in one focused trial to in 8,346 (0.024%) in overall clinical trials (with an incidence in pediatric patients in clinical trials of 0.055%) to in 38,000 (0.003%) in spontaneous event reports. Signs and symptoms usually occur few days after initiation of therapy and subside within few days after cessation of therapy; occasionally these reactions have resulted in hospitalization, usually of short duration (median hospitalization 2 to days, based on postmarketing surveillance studies). In those 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. Antihistamines and glucocorticoids appear to enhance resolution of the signs and symptoms. No serious sequelae have been reported. More 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, asthenia, edema (including face and limbs), dyspnea, paresthesias, syncope, hypotension, or vasodilatation. Anaphylaxis may be more common in patients with history of penicillin allergy. Rarely, hypersensitivity symptoms may persist for several months. Gastrointestinal symptoms occur in about 2.5% of patients and include diarrhea (1 in 70). Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment (See WARNING). Nausea and vomiting have been reported rarely. As with some penicillins and some other cephalosporins, transient hepatitis and cholestatic jaundice have been reported rarely. Other effects considered related to therapy included eosinophilia(1 in 50 patients), genital pruritus, moniliasis or vaginitis(about in 50 patients), and, rarely, thrombocytopenia or reversible interstitial nephritis. Causal Relationship UncertainCNS-Rarely, reversible hyperactivity, agitation, nervousness, insomnia, confusion, hypertonia, dizziness, hallucinations, and somnolence have been reported. Transitory abnormalities in clinical laboratory test results have been reported. Although they were of uncertain etiology, they are listed below to serve as alerting information for the physician. Hepatic-Slight elevations of AST, ALT, or alkaline phosphatase values (1 in 40). Hematopoietic-As has also been reported with other -lactam antibiotics, transient lymphocytosis, leukopenia, and, rarely, hemolytic anemia, aplastic anemia, agranulocytosis, and reversible neutropenia of possible clinical significance. There have been rare reports of increased prothrombin time with or without clinical bleeding in patients receiving cefaclor and warfarin concomitantly. Renal-Slight elevations in BUN or serum creatinine (less than in 500) or abnormal urinalysis (less than in 200). Cephalosporin-class Adverse Reactions. In addition to the adverse reactions listed above that have been observed in patients treated with cefaclor, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics: fever, abdominal pain, superinfection, renal dysfunction, toxic nephropathy, hemorrhage, false positive test for urinary glucose, elevated bilirubin, elevated LDH, and pancytopenia. Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated (See DOSAGE AND ADMINISTRATION and OVERDOSAGEsections). To report SUSPECTED ADVERSE REACTIONS, Contact Hikma Pharmaceuticals USA Inc. at 1-877-233-2001 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CLINICAL PHARMACOLOGY SECTION.

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 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 hours, the greater portion being excreted within the first 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 ActionAs 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 Enterococi (Enterococcus faecalis, group 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, lactamase-negative, ampicillin-resistant strains of H. influenzae should be considered resistant to cefaclor despite apparent in vitro susceptibility to this agent.Antibacterial ActivityCefaclor 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 BacteriaStaphylococcus aureus (methicillin-susceptible only)Coagulase negative staphylococci (methicillin-susceptible only)Streptococcus pneumoniaeStreptococcus pyogenes (group -hemolytic streptococci)Gram-negative BacteriaEscherichia coliHaemophilus influenzae (excluding -lactamase-negative, ampicillin-resistant strains)Klebsiella spp.Proteus mirabilisThe 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 BacteriaCitrobacter diversusMoraxella catarrhalisNeisseria gonorrhoeaeAnaerobic BacteriaBacteroides spp.Peptococcus spp.Peptostreptococcus spp.Propionibacterium acnes. Susceptibility Test 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.

INDICATIONS & USAGE SECTION.

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 Lower respiratory tract infections, including pneumonia caused by Streptococcus pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes 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 staphylococciSkin 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 and other antibacterial drugs, Cefaclor 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.

INFORMATION FOR PATIENTS SECTION.

Information for Patients. Patients should be counseled that antibacterial drugs including cefaclor should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefaclor is prescribed to treat 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 or other antibacterial drugs in the future.Diarrhea is common problem caused by antibiotecs 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.

OVERDOSAGE SECTION.

OVERDOSAGE. Signs and Symptoms-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. If other symptoms are present, it is probable that they are secondary to an underlying disease state, an allergic reaction, or the effects of other intoxication. Treatment-To obtain up-to-date information about the treatment of overdose, good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. Unless times the normal dose of cefaclor has been ingested, gastrointestinal decontamination will not be necessary. Protect the patients airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patients vital signs, blood gases, serum electrolytes, etc. 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. Safeguard the patients airway when employing gastric emptying or charcoal. Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of cefaclor.

PRECAUTIONS SECTION.

PRECAUTIONS. General. Prescribing cefaclor in the absence of proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases 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 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 -lactam antibiotics, the renal excretion of cefaclor is inhibited by probenecid.Antibiotics, including cephalosporins, should be prescribed with caution in individuals with history of gastrointestinal disease, particularly colitis.. Information for Patients. Patients should be counseled that antibacterial drugs including cefaclor should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefaclor is prescribed to treat 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 or other antibacterial drugs in the future.Diarrhea is common problem caused by antibiotecs 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/Laboratory Test Interactions. Patients receiving cefaclor may show false-positive reaction for glucose in the urine with tests that use Benedicts and Fehlings solutions and also with Clinitest(R) tablets. There have been reports of increased anticoagulant effect when cefaclor and oral anticoagulants were administered concomitantly.. Carcinogenesis, Mutagenesis, Impairment of Fertility. Studies have not been performed to determine potential for carcinogenicity, mutagenicity, or impairment of fertility. Pregnancy-Teratogenic Effects-Pregnancy Category B. Reproduction studies have been performed in mice and rats at doses up to 12 times the human dose and in ferrets given times the maximum human dose and 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, this drug should be used during pregnancy only if clearly needed. Labor and Delivery. The effect of cefaclor on labor and delivery is unknown. Nursing Mothers. Small amounts of cefaclor have been detected in mothers milk following administration of single 500 mg doses. Average levels were 0.18, 0.20, 0.21, and 0.16 mcg/mL at 2, 3, 4, and hours respectively. Trace amounts were detected at hour. The effect on nursing infants is not known. Caution should be exercised when cefaclor is administered to nursing woman. Pediatric Use. Safety and effectiveness of this product for use in pediatric patients less than month of age have not been established. Geriatric Use. Of the 3703 patients in clinical studies of cefaclor, 594 (16.0%) were 65 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.This drug is known to be substantially excreted by the kidney (See CLINICAL PHARMACOLOGY), 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).

WARNINGS SECTION.

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 -LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH 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, 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 and 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 difficile, and surgical evaluation should be instituted as clinically indicated.