Label: CEFDINIR capsule

Pharmacokinetics and Drug Metabolism

Microbiology

Mechanism of Action

As with other cephalosporins, bactericidal activity of cefdinir results from inhibition of cell wall synthesis. Cefdinir is stable in the presence of some, but not all, β-lactamase enzymes. As a result, many organisms resistant to penicillins and some cephalosporins are susceptible to cefdinir.

Mechanism of Resistance

Resistance to cefdinir is primarily through hydrolysis by some β-lactamases, alteration of penicillin-binding proteins (PBPs) and decreased permeability. Cefdinir is inactive against most strains of Enterobacterspp., Pseudomonasspp., Enterococcusspp., penicillin-resistant streptococci, and methicillin-resistant staphylococci. β-lactamase negative, ampicillin-resistant (BLNAR) H. influenzaestrains are typically non-susceptible to cefdinir.

Antimicrobial Activity

Cefdinir has been shown to be active against most strains of the following microorganisms, both in vitroand in clinical infections as described in INDICATIONS AND USAGE.

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.

Adults and Adolescents

Community-Acquired Pneumoniacaused by Haemophilus influenzae(including β-lactamase producing strains), Haemophilus parainfluenzae(including β-lactamase producing strains), Streptococcus pneumoniae(penicillin-susceptible strains only), and Moraxella catarrhalis(including β-lactamase producing strains) (see CLINICAL STUDIES).

Acute Exacerbations of Chronic Bronchitiscaused by Haemophilus influenzae(including β-lactamase producing strains), Haemophilus parainfluenzae(including β-lactamase producing strains), Streptococcus pneumoniae(penicillin-susceptible strains only), and Moraxella catarrhalis(including β-lactamase producing strains).

Acute Maxillary Sinusitiscaused by Haemophilus influenzae(including β-lactamase producing strains), Streptococcus pneumoniae(penicillin-susceptible strains only), and Moraxella catarrhalis(including β-lactamase producing strains).

NOTE:For information on use in pediatric patients, see Pediatric Use  and DOSAGE AND ADMINISTRATION.

Pharyngitis/Tonsillitis caused by Streptococcus pyogenes(see CLINICAL STUDIES).

NOTE:Cefdinir is effective in the eradication of S. pyogenesfrom the oropharynx. Cefdinir has not, however, been studied for the prevention of rheumatic fever following S. pyogenespharyngitis/tonsillitis. Only intramuscular penicillin has been demonstrated to be effective for the prevention of rheumatic fever.

Uncomplicated Skin and Skin Structure Infections caused by Staphylococcus aureus(including β-lactamase producing strains) and Streptococcus pyogenes.

Pediatric Patients

Acute Bacterial Otitis Mediacaused by Haemophilus influenzae(including β-lactamase producing strains), Streptococcus pneumoniae(penicillin-susceptible strains only), and Moraxella catarrhalis(including β-lactamase producing strains).

Pharyngitis/Tonsillitis caused by Streptococcus pyogenes(see CLINICAL STUDIES).

NOTE: Cefdinir is effective in the eradication of S. pyogenesfrom the oropharynx. Cefdinir has not, however, been studied for the prevention of rheumatic fever following S. pyogenespharyngitis/tonsillitis. Only intramuscular penicillin has been demonstrated to be effective for the prevention of rheumatic fever.

Uncomplicated Skin and Skin Structure Infections caused by Staphylococcus aureus(including β-lactamase producing strains) and Streptococcus pyogenes.

General

Prescribing cefdinir 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.

As with other broad-spectrum antibiotics, prolonged treatment may result in the possible emergence and overgrowth of resistant organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate alternative therapy should be administered.

Cefdinir, as with other broad-spectrum antimicrobials (antibiotics), should be prescribed with caution in individuals with a history of colitis.

In patients with transient or persistent renal insufficiency (creatinine clearance <30 mL/min), the total daily dose of cefdinir should be reduced because high and prolonged plasma concentrations of cefdinir can result following recommended doses (see DOSAGE AND ADMINISTRATION).

Information for Patients

Patients should be counseled that antibacterial drugs including cefdinir should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefdinir is 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 cefdinir or other antibacterial drugs in the future.

Antacids containing magnesium or aluminum interfere with the absorption of cefdinir. If this type of antacid is required during cefdinir therapy, cefdinir should be taken at least 2 hours before or after the antacid.

Iron supplements, including multivitamins that contain iron, interfere with the absorption of cefdinir. If iron supplements are required during cefdinir therapy, cefdinir should be taken at least 2 hours before or after the supplement.

Iron-fortified infant formula does not significantly interfere with the absorption of cefdinir.

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 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.

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Drug Interactions

Drug/Laboratory Test Interactions

A false-positive reaction for ketones in the urine may occur with tests using nitroprusside, but not with those using nitroferricyanide. The administration of cefdinir may result in a false-positive reaction for glucose in urine using Clinitest ®, Benedict’s solution, or Fehling’s solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix ®or Tes-Tape ®) be used. Cephalosporins are known to occasionally induce a positive direct Coombs’ test.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of cefdinir has not been evaluated. No mutagenic effects were seen in the bacterial reverse mutation assay (Ames) or point mutation assay at the hypoxanthine-guanine phosphoribosyltransferase locus (HGPRT) in V79 Chinese hamster lung cells. No clastogenic effects were observed in vitroin the structural chromosome aberration assay in V79 Chinese hamster lung cells or in vivoin the micronucleus assay in mouse bone marrow. In rats, fertility and reproductive performance were not affected by cefdinir at oral doses up to 1000 mg/kg/day (70 times the human dose based on mg/kg/day, 11 times based on mg/m 2/day).

Pregnancy

Labor and Delivery

Cefdinir has not been studied for use during labor and delivery.

Nursing Mothers

Following administration of single 600 mg doses, cefdinir was not detected in human breast milk.

Pediatric Use

Safety and efficacy in neonates and infants less than 6 months of age have not been established. Use of cefdinir for the treatment of acute maxillary sinusitis in pediatric patients (age 6 months through 12 years) is supported by evidence from adequate and well-controlled studies in adults and adolescents, the similar pathophysiology of acute sinusitis in adult and pediatric patients, and comparative pharmacokinetic data in the pediatric population.

Geriatric Use

Efficacy is comparable in geriatric patients and younger adults. While cefdinir has been well-tolerated in all age groups, in clinical trials geriatric patients experienced a lower rate of adverse events, including diarrhea, than younger adults. Dose adjustment in elderly patients is not necessary unless renal function is markedly compromised (see DOSAGE AND ADMINISTRATION).

Clinical Trials - Cefdinir Capsules (Adult and Adolescent Patients)

In clinical trials, 5093 adult and adolescent patients (3841 U.S. and 1252 non-U.S.) were treated with the recommended dose of cefdinir capsules (600 mg/day). Most adverse events were mild and self-limiting. No deaths or permanent disabilities were attributed to cefdinir. One hundred forty-seven of 5093 (3%) patients discontinued medication due to adverse events thought by the investigators to be possibly, probably, or definitely associated with cefdinir therapy. The discontinuations were primarily for gastrointestinal disturbances, usually diarrhea or nausea. Nineteen of 5093 (0.4%) patients were discontinued due to rash thought related to cefdinir administration.

In the U.S., the following adverse events were thought by investigators to be possibly, probably, or definitely related to cefdinir capsules in multiple-dose clinical trials (N = 3841 cefdinir-treated patients):

The following laboratory value changes of possible clinical significance, irrespective of relationship to therapy with cefdinir, were seen during clinical trials conducted in the U.S.:

Clinical Trials - Cefdinir for Oral Suspension (Pediatric Patients)

In clinical trials, 2289 pediatric patients (1783 U.S. and 506 non-U.S.) were treated with the recommended dose of cefdinir suspension (14 mg/kg/day). Most adverse events were mild and self-limiting. No deaths or permanent disabilities were attributed to cefdinir. Forty of 2289 (2%) patients discontinued medication due to adverse events considered by the investigators to be possibly, probably, or definitely associated with cefdinir therapy. Discontinuations were primarily for gastrointestinal disturbances, usually diarrhea. Five of 2289 (0.2%) patients were discontinued due to rash thought related to cefdinir administration.

In the U.S., the following adverse events were thought by investigators to be possibly, probably, or definitely related to cefdinir suspension in multiple-dose clinical trials (N = 1783 cefdinir-treated patients):

NOTE: In both cefdinir- and control-treated patients, rates of diarrhea and rash were higher in the youngest pediatric patients. The incidence of diarrhea in cefdinir-treated patients ≤2 years of age was 17% (95/557) compared with 4% (51/1226) in those >2 years old. The incidence of rash (primarily diaper rash in the younger patients) was 8% (43/557) in patients ≤2 years of age compared with 1% (8/1226) in those >2 years old.

The following laboratory value changes of possible clinical significance, irrespective of relationship to therapy with cefdinir, were seen during clinical trials conducted in the U.S.:

Postmarketing Experience

The following adverse experiences and altered laboratory tests, regardless of their relationship to cefdinir, have been reported during extensive postmarketing experience, beginning with approval in Japan in 1991: shock, anaphylaxis with rare cases of fatality, facial and laryngeal edema, feeling of suffocation, serum sickness-like reactions, conjunctivitis, stomatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, erythema nodosum, acute hepatitis, cholestasis, fulminant hepatitis, hepatic failure, jaundice, increased amylase, acute enterocolitis, bloody diarrhea, hemorrhagic colitis, melena, pseudomembranous colitis, pancytopenia, granulocytopenia, leukopenia, thrombocytopenia, idiopathic thrombocytopenic purpura, hemolytic anemia, acute respiratory failure, asthmatic attack, drug-induced pneumonia, eosinophilic pneumonia, idiopathic interstitial pneumonia, fever, acute renal failure, nephropathy, bleeding tendency, coagulation disorder, disseminated intravascular coagulation, upper GI bleed, peptic ulcer, ileus, loss of consciousness, allergic vasculitis, possible cefdinir-diclofenac interaction, cardiac failure, chest pain, myocardial infarction, hypertension, involuntary movements, and rhabdomyolysis.

Cephalosporin Class Adverse Events

The following adverse events and altered laboratory tests have been reported for cephalosporin-class antibiotics in general:

Allergic reactions, anaphylaxis, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal dysfunction, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic anemia, hemorrhage, false-positive test for urinary glucose, neutropenia, pancytopenia, and agranulocytosis. Pseudomembranous colitis symptoms may begin during or after antibiotic treatment (see WARNINGS).

Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced (see DOSAGE AND ADMINISTRATIONand OVERDOSAGE). If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.

Patients With Renal Insufficiency

For adult patients with creatinine clearance <30 mL/min, the dose of cefdinir should be 300 mg given once daily.

Creatinine clearance is difficult to measure in outpatients. However, the following formula may be used to estimate creatinine clearance (CL cr) in adult patients. For estimates to be valid, serum creatinine levels should reflect steady-state levels of renal function.

Males:              CL cr=       (weight) (140 – age)        
                                       (72) (serum creatinine)

Females:           CL cr= 0.85 x above value

where creatinine clearance is in mL/min, age is in years, weight is in kilograms, and serum creatinine is in mg/dL. 1

The following formula may be used to estimate creatinine clearance in pediatric patients:

CL cr=      K  x   body length or height 
                            serum creatinine

where K=0.55 for pediatric patients older than 1 year 2and 0.45 for infants (up to 1 year) 3.

In the above equation, creatinine clearance is in mL/min/1.73 m 2, body length or height is in centimeters, and serum creatinine is in mg/dL.

For pediatric patients with a creatinine clearance of <30 mL/min/1.73 m 2, the dose of cefdinir should be 7 mg/kg (up to 300 mg) given once daily.

Patients on Hemodialysis

Hemodialysis removes cefdinir from the body. In patients maintained on chronic hemodialysis, the recommended initial dosage regimen is a 300 mg or 7 mg/kg dose every other day. At the conclusion of each hemodialysis session, 300 mg (or 7 mg/kg) should be given. Subsequent doses (300 mg or 7 mg/kg) are then administered every other day.

Community-Acquired Bacterial Pneumonia

In a controlled, double-blind study in adults and adolescents conducted in the U.S., cefdinir BID was compared with cefaclor 500 mg TID. Using strict evaluability and microbiologic/clinical response criteria 6 to 14 days posttherapy, the following clinical cure rates, presumptive microbiologic eradication rates, and statistical outcomes were obtained:

In a second controlled, investigator-blind study in adults and adolescents conducted primarily in Europe, cefdinir BID was compared with amoxicillin/clavulanate 500/125 mg TID. Using strict evaluability and clinical response criteria 6 to 14 days posttherapy, the following clinical cure rates, presumptive microbiologic eradication rates, and statistical outcomes were obtained:

Streptococcal Pharyngitis/Tonsillitis

In four controlled studies conducted in the United States, cefdinir was compared with 10 days of penicillin in adult, adolescent, and pediatric patients. Two studies (one in adults and adolescents, the other in pediatric patients) compared 10 days of cefdinir QD or BID to penicillin 250 mg or 10 mg/kg QID. Using strict evaluability and microbiologic/clinical response criteria 5 to 10 days posttherapy, the following clinical cure rates, microbiologic eradication rates, and statistical outcomes were obtained:

Two studies (one in adults and adolescents, the other in pediatric patients) compared 5 days of cefdinir BID to 10 days of penicillin 250 mg or 10 mg/kg QID. Using strict evaluability and microbiologic/clinical response criteria 4 to 10 days posttherapy, the following clinical cure rates, microbiologic eradication rates, and statistical outcomes were obtained: