Cefaclor

DESCRIPTION

Cefaclor, USP, is a semisynthetic cephalosporinantibioticfor 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 C₁₅H₁₄ClN₃O₄S•H₂O and the molecular weight is 385.82.

After mixing, each 5 mL of Cefaclor for Oral Suspension will contain cefaclor monohydrate equivalent to 125 mg (0.34 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.

INDICATIONS

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

Otitis mediacaused byStreptococcus pneumoniae, Haemophilus influenzae,staphylococci, andStreptococcus pyogenes

Note:β-lactamase-negative, ampicillin-resistant (BLNAR) strains ofHaemophilus influenzaeshould be considered resistant to cefaclor despite apparentin vitrosusceptibility of some BLNAR strains.

Lower respiratory tract infections,includingpneumonia, caused byStreptococcus pneumoniae, Haemophilus influenzae,andStreptococcus pyogenes

Note:β-lactamase-negative, ampicillin-resistant (BLNAR) strains ofHaemophilus influenzaeshould be considered resistant to cefaclor despite apparentin vitrosusceptibility of some BLNAR strains.

Pharyngitis and Tonsillitis,caused byStreptococcus pyogenes

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

Urinary tract infections,includingpyelonephritisandcystitis, caused byEscherichia coli, Proteus mirabilis, Klebsiellaspp., and coagulase-negative staphylococci

Skin and skin structure infectionscaused byStaphylococcus aureus and Streptococcus pyogenes

适当的文化和易感性研究商店uld 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 Capsule and other antibacterial drugs, Cefaclor Capsule 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.

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.

Cefaclor may be administered in the presence of impaired renal function. Under such a condition, the dosage usually is unchanged (seePRECAUTIONS）.

In the treatment of β-hemolyticstreptococcal infections, a therapeutic dosage of cefaclor should be administered for at least 10 days.

HOW SUPPLIED

Cefaclor Capsule USP 250 mg(blue cap and pink body hard gelatin capsule containing white to slightly yellowish powder imprinted with ”KRC” on both capsule cap and capsule body) contains cefaclor USP (monohydrate) equivalent to 250 mg anhydrous cefaclor.

Bottle of 30 -NDC61442-171-30
Bottle of 100 -NDC61442-171-01
Bottle of 500 -NDC61442-171-05

Cefaclor Capsule USP 500 mg(blue cap and orange body hard gelatin capsule containing white to slightly yellowish powder imprinted with “KRC500” on both capsule cap and capsule body) contains cefaclor USP (monohydrate) equivalent to 500 mg anhydrous cefaclor.

Bottle of 30 -NDC61442-172-30
Bottle of 100 -NDC61442-172-01
Bottle of 500 -NDC61442-172-05

Store at 20°C - 25°C (68°C to 77°F) [See USP Controlled Room Temperature].

Manufactured by: Yung Shin Pharmaceutical Ind. Co., Ltd.Tachia, Taichung 43769, TAIWAN. Revised: Sep 2015

SIDE EFFECTS

Adverse effects considered to be related to therapy with cefaclor are listed below:

Hypersensitivityreactions 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 1 in 200 patients.

Cases ofserum-sickness-likereactions have been reported with the use of cefaclor. These are characterized by findings oferythema multiforme, rashes, and other skin manifestations accompanied byarthritis/关节痛, with or without fever, and differ from classic serum sickness in that there is infrequently associatedlymphadenopathyand proteinuria, no circulating immune complexes, and no evidence to date ofsequelaeof the reaction. Occasionally, solitary symptoms may occur, but do not represent aserum-sickness-likereaction. While further investigation is ongoing,serum-sicknesslike似乎是由于过敏和反应more often occur during or following a 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 1 in 200 (0.5%) in one focused trial to 2 in 8,346 (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 requiring hospitalization, the symptoms have ranged from mild to severe at the time of入学with more of the severe reactions occurring in pediatric patients.Antihistaminesand glucocorticoids appear to enhance resolution of the signs and symptoms. No serious sequelae have been reported.

More severe hypersensitivity reactions, includingStevens-Johnson syndrome,toxic epidermal necrolysis, andanaphylaxishave been reported rarely. Anaphylactoid events may be manifested by solitary symptoms, includingangioedema,asthenia, edema (including face and limbs),dyspnea, paresthesias,syncope,hypotension, or vasodilatation. Anaphylaxis may be more common in patients with a history of penicillinallergy.

Rarely, hypersensitivity symptoms may persist for several months.

Gastrointestinalsymptoms occur in about 2.5% of patients and include diarrhea (1 in 70).

Onset ofpseudomembranous colitissymptoms may occur during or after antibiotic treatment. (see警告）.Nausea and vomiting have been reported rarely. As with some penicillins and some other cephalosporins, transienthepatitisand cholestaticjaundicehave been reported rarely.

Othereffects considered related to therapy includedeosinophilia(1 in 50 patients),genitalpruritus, moniliasis orvaginitis(about 1 in 50 patients), and, rarely,thrombocytopeniaor reversibleinterstitialnephritis.

Causal Relationship Uncertain

CNS-Rarely, reversiblehyperactivity, agitation, nervousness, insomnia, confusion,hypertonia, dizziness, hallucinations, andsomnolencehave been reported.

Transitory abnormalities in clinical laboratory test results have been reported. Although they were of uncertainetiology下面列出,他们作为报警有限公司mation for the physician.

Hepatic-Slight elevations of AST, ALT, or alkaline phosphatase values (1 in 40).

Hematopoietic-As has also been reported with other β-lactam antibiotics, transient lymphocytosis,leukopenia, and, rarely,hemolytic anemia,aplastic anemia,agranulocytosis, and reversibleneutropeniaof possible clinical significance.

There have been rare reports of increasedprothrombin timewith or without clinical bleeding in patients receiving cefaclor and Coumadin^®concomitantly.

Renal-Slight elevations inBUNor serum creatinine (less than 1 in 500) or abnormalurinalysis(less than 1 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, toxicnephropathy,hemorrhage, false positive test for urinary glucose, elevated bilirubin, elevated LDH, andpancytopenia.

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.Anticonvulsanttherapy can be given if clinically indicated (seeDOSAGE AND ADMINISTRATIONandOVERDOSEsections).

DRUG INTERACTIONS

No Information Provided

警告

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 difficileassociated 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 ofC. difficile.

C. difficileproduces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains ofC. difficilecause increased morbidity and mortality, as these infections can berefractorytoantimicrobialtherapy and may requirecolectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Carefulmedical historyis 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 againstC. difficilemay need to be discontinued. Appropriate fluid andelectrolytemanagement, protein supplementation, antibiotic treatment ofC. 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 aprophylactic指示是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 isessential. 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 intransfusioncross-matching procedures when antiglobulin tests are performed on the minor side or in Coombs' testing of newborns whose mothers have received cephalosporin antibiotics beforeparturition.

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 ofgastrointestinaldisease, particularlycolitis.

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 3 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 mother's 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 5 hours, respectively. Trace amounts were detected at 1 hour. The effect on nursing infants is not known. Caution should be exercised when cefaclor is administered to a nursing woman.

儿童使用

Safety and effectiveness of this product for use in infants less than 1 month of age have not been established.

Geriatric Use

Of the 3,703 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 (seeCLINICAL 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 (seeDOSAGE AND ADMINISTRATION）.

OVERDOSE

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, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in thePhysicians' Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drugkineticsin your patient. Unless 5 times the normal dose of cefaclor has been ingested, gastrointestinal decontamination will not be necessary.

Protect the patient's airway and supportventilationandperfusion. Meticulously monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from thegastrointestinal tractmay be decreased by giving activated charcoal, which, in many cases, is more effective thanemesisor lavage; consider charcoal instead of or in addition togastricemptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient's airway when employing gastric emptying or charcoal.

Forceddiuresis,peritoneal dialysis,hemodialysis,或者木炭血液灌流没有蜜蜂n established as beneficial for an overdose of cefaclor.

CONTRAINDICATIONS

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

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.Pseudomonasspp.,Acinetobacter calcoaceticusand most strains ofEnterococi (Enterococcus faecalis,group D streptococci),Enterobacterspp., indole-positiveProteus, Morganella morganii(formerlyProteus morganii), Providencia rettgeri(formerlyProteus rettgeri)andSerratiaspp. are resistant to cefaclor. Cefaclor is inactive against甲氧西林-resistant staphylococci. -lactamasenegative, ampicillin-resistant strains ofH. influenzaeshould be considered resistant to cefaclor despite apparentin vitrosusceptibility to this agent.

Antibacterial Activity

Cefaclor has been shown to be active against most strains of the following microorganisms bothin vitroand in clinical infections as described in the INDICATIONS AND USAGE section.

Gram-positive Bacteria

Staphylococcus aureus(methicillin susceptible only)
Coagulase negativestaphylococci(methicillin susceptible only)
Streptococcus pneumoniae
Streptococcus pyogenes(group A -hemolytic streptococci)

Gram-negative Bacteria

Escherichia coli
Haemophilus influenzae(excluding -lactamase-negative, ampicillin-resistant strains)
Klebsiellaspp.
Proteus mirabilis

The followingin vitrodata are available,but their clinical significance is unknown.At least 90 percent of the following bacteria exhibit anin vitrominimum 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

Bacteroidesspp.
Peptococcusspp.
Peptostreptococcusspp.
Propionibacterium acnes

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the result ofin vitrosusceptibility 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 method^2,3.

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

Microorganisms1,2	Minimal Inhibitory Concentration (微克/毫升)			Zone Diameter (mm)
	S	I	R	S	I	R
Streptococcus pneumoniae	≤1	2	≥4	-	-	-
1Susceptibility of staphylococci to cefaclor may be deduced from testing only penicillin and either cefoxitin or oxacillin 2Susceptibility ofStreptococcus pyogenesto cefaclor may also be deduced from testing penicillin

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. 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 (微克/毫升)	Zone Diameter (mm)
Escherichia coliATCC 25922	1 – 4	23 – 27
Haemophilus influenzaeATCC 49766	1 – 4	25 – 31
Staphylococcus aureusATCC 25923	--	27 - 31
Staphylococcus aureusATCC 29213	1 – 4	--
Streptococcus pneumoniaeATCC 49619	1 – 4	24 – 32

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI).Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition.CLSI document M07-A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

2. Clinical and Laboratory Standards Institute (CLSI).Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition.CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

3. Clinical and Laboratory Standards Institute (CLSI).Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement.CLSI document M100-S25. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

PATIENT INFORMATION

Patients should be counseled that antibacterial drugs including Cefaclor for Oral Suspension should only be used to treat bacterial infections. They do not treat viral infections (e.g., thecommon cold）.当口服头孢克洛悬挂规定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 dose 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 for Oral Suspension or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or withoutstomach crampsand 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.