Cefixime 400 Mg Oral Capsule

Note: For patients with otitis media caused by Streptococcus pneumoniae, overall response was approximately 10% lower for cefixime than for the comparator [see Clinical Studies ( 14)] .

In the treatment of infections due to Streptococcus pyogenes, a therapeutic dosage of cefixime should be administered for at least 10 days.

Note: A suggested dose has been determined for each pediatric weight range. Refer to Table 1. Ensure all orders that specify a dose in milliliters include a concentration, because cefixime for oral suspension is available in two different concentrations (100 mg/5 mL and 200 mg/5 mL).

Before therapy with cefixime is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins, or other drugs. If this product is to be given to penicillin-sensitive patients, caution should be exercised because cross hypersensitivity among beta-lactam antibacterial drugs has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to cefixime occurs, discontinue the drug.

C. difficileproduces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C.  difficilecause 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 antibacterial drug 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 antibacterial drug use not directed against C. difficilemay need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile,and surgical evaluation should be instituted as clinically indicated.

The most commonly seen adverse reactions in U.S. trials of the tablet formulation were gastrointestinal events, which were reported in 30% of adult patients on either the twice daily or the once daily regimen. Five percent (5%) of patients in the U.S. clinical trials discontinued therapy because of drug-related adverse reactions. Individual adverse reactions included diarrhea 16%, loose or frequent stools 6%, abdominal pain 3%, nausea 7%, dyspepsia 3%, and flatulence 4%. The incidence of gastrointestinal adverse reactions, including diarrhea and loose stools, in pediatric patients receiving the suspension was comparable to the incidence seen in adult patients receiving tablets.

Gastrointestinal

Several cases of documented pseudomembranous colitis were identified in clinical trials. The onset of pseudomembranous colitis symptoms may occur during or after therapy.

Hypersensitivity Reactions

Anaphylactic/anaphylactoid reactions (including shock and fatalities), skin rashes, urticaria, drug fever, pruritus, angioedema, and facial edema. Erythema multiforme, Stevens-Johnson syndrome, and serum sickness-like reactions have been reported.

Hepatic

Transient elevations in SGPT, SGOT, alkaline phosphatase, hepatitis, jaundice.

Renal

Transient elevations in BUN or creatinine, acute renal failure.

Central Nervous System

Headaches, dizziness, seizures.

Hemic and Lymphatic System

Transient thrombocytopenia, leukopenia, neutropenia, prolongation in prothrombin time, elevated LDH, pancytopenia, agranulocytosis, and eosinophilia.

Abnormal Laboratory Tests

Hyperbilirubinemia.

Other Adverse Reactions

Genital pruritus, vaginitis, candidiasis, toxic epidermal necrolysis.

Adverse Reactions Reported for Cephalosporin-class Drugs

Allergic reactions, superinfection, renal dysfunction, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic anemia, hemorrhage, and colitis.

Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced [ s ee Dosage and Administration ( 2) and Overdosage ( 10)] . If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.

The administration of cefixime may result in a false positive reaction for glucose in the urine when using glucose tests based on the Benedict's solution or Fehling's solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used. A false positive direct Coombs test has been reported during treatment with other cephalosporins; therefore, it should be recognized that a positive Coombs test may be due to the drug.

Available data from published observational studies, case series, and case reports over several decades with cephalosporin use, including cefixime, in pregnant women have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Reproduction studies have been performed in mice and rats at doses equivalent to 40 and 80 times, respectively, the adult human recommended dose and have revealed no evidence of harm to the fetus due to cefixime (see  Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Maternal gonorrhea may be associated with preterm birth, low neonatal birth weight, chorioamnionitis, intrauterine growth restriction, small for gestational age and premature rupture of membranes. Perinatal transmission of gonorrhea to the offspring can result in infant blindness, joint infections, and bloodstream infections.

Data

Human Data

While available studies cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified a consistent association with cephalosporin use, including cefixime, during pregnancy, and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodological limitations, including small sample size, retrospective data collection, and inconsistent comparator groups.

Animal Data

The results of embryo-fetal development studies in mice and rats show that cefixime, at doses up to 3200 mg/kg/day administered during the period of organogenesis did not adversely affect development. In these studies, in mice and rats, cefixime did not affect postnatal development or reproductive capacity of the F ₁generation or fetal development of the F ₂generation. In an embryo-fetal development study in rabbits, cefixime at doses of 3.2, 10 or 32 mg/kg given daily during the period of organogenesis (gestation days 6 through 18) resulted in abortions and/or maternal deaths at doses > 10 mg/kg (typically associated with the administration of antibiotics in this species), but no malformations were reported at lower doses. A pre- and post-natal development study of cefixime at oral doses up to 3200 mg/kg/day in rats demonstrated no effect on the duration of pregnancy, process of parturition, development and viability of offspring, or reproductive capacity of the F ₁generation and development of their fetuses (F ₂).

There are no available data on the presence of cefixime in human milk, the effects on the breast-fed infant, or the effects on milk production. Cefixime is present in animal milk (see Data). When a drug is present in animal milk, it is likely the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for cefixime and any potential adverse effects on the breast-fed infant from cefixime or from the mother's underlying condition.

Data

In a study on disposition of cefixime in pregnant and lactating rats, continuous intra-peritoneal infusion of 2.54 mg/kg/day of ¹⁴C-cefixime from days 10 to 14 postpartum resulted in steady state plasma concentrations of radioactivity in the dams that were 70 times greater than in their nursing pups.

After 102 hours of drug infusion, total radioactivity in the body of the pups, including the stomach and intestinal contents, was 1.5% of the ¹⁴C-cefixime estimated to be in the mother's body at steady state. ¹

The 400 mg cefixime capsule is bioequivalent to the 400 mg cefixime tablet under fasting conditions. However, food reduces the absorption following administration of the capsule by approximately 15% based on AUC and 25% based on C _max.

Peak serum concentrations occur between 2 and 6 hours following oral administration of a single 200 mg tablet, a single 400 mg cefixime tablet or 400 mg of cefixime for oral suspension. Peak serum concentrations occur between 2 and 5 hours following a single administration of 200 mg of cefixime for oral suspension. Peak serum concentrations occur between 3 and 8 hours following oral administration of a single 400 mg cefixime capsule.

Distribution

Serum protein binding is concentration independent with a bound fraction of approximately 65%. In a multiple dose study conducted with a research formulation which is less bioavailable than the cefixime tablet or cefixime for oral suspension, there was little accumulation of drug in serum or urine after dosing for 14 days. Adequate data on CSF levels of cefixime are not available.

Elimination

Metabolism and Excretion

There is no evidence of metabolism of cefixime in vivo.Approximately 50% of the absorbed dose is excreted unchanged in the urine in 24 hours. In animal studies, it was noted that cefixime is also excreted in the bile in excess of 10% of the administered dose. The serum half-life of cefixime in healthy subjects is independent of dosage form and averages 3 to 4 hours but may range up to 9 hours in some normal volunteers.

Specific Populations

Geriatric Patients : Average AUCs at steady state in elderly patients are approximately 40% higher than average AUCs in other healthy adults. Differences in the pharmacokinetic parameters between 12 young and 12 elderly subjects who received 400 mg of cefixime once daily for 5 days are summarized as follows:

As with other cephalosporins, the bactericidal action of cefixime results from inhibition of cell wall synthesis. Cefixime is stable in the presence of certain beta-lactamase enzymes. As a result, certain organisms resistant to penicillins and some cephalosporins due to the presence of beta-lactamases may be susceptible to cefixime.

Resistance

Resistance to cefixime in isolates of Haemophilus influenzaeand Neisseria gonorrhoeaeis most often associated with alterations in penicillin-binding proteins (PBPs). Cefixime may have limited activity against Enterobacteriaceae producing extended spectrum beta-lactamases (ESBLs). Pseudomonasspecies, Enterococcusspecies, strains of Group D streptococci, Listeria monocytogenes,most strains of staphylococci (including methicillin-resistant strains), most strains of Enterobacterspecies, most strains of Bacteroides fragilis,and most strains of Clostridiumspecies are resistant to cefixime.

Antimicrobial Activity

Cefixime has been shown to be active against most isolates of the following microorganisms, both in vitroand in clinical infections [see Indications and Usage ( 1)].

Gram-positive Bacteria

Streptococcus pneumoniae

Streptococcus pyogenes

Gram-negative Bacteria

Escherichia coli

Haemophilus influenzae

Moraxella catarrhalis

Neisseria gonorrhoeae

Proteus mirabilis

The following in vitrodata are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitrominimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefixime against isolates of similar genus or organism group. However, the efficacy of cefixime in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-positive Bacteria

Streptococcus agalactiae

Gram-negative Bacteria

Citrobacter amalonaticus

Citrobacter diversus

Haemophilus parainfluenzae

Klebsiella oxytoca

Klebsiella pneumoniae

Pasteurella multocida

Proteus vulgaris

Providenciaspecies

Salmonellaspecies

Serratia marcescens

Shigellaspecies

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.