Action and Clinical Pharmacology:
Cefixime exerts its bactericidal effect by attaching to penicillin-binding proteins and inhibiting peptidoglycan synthesis, thus causing damage to the bacterial cell wall.:
Pharmacokinetics: Following oral dosing, cefixime attains peak serum levels in approximately 4Â hours. The half-life is about 3Â to 4Â hours and is not dose dependent. Cefixime is excreted by renal and biliary mechanisms. About 50% of the absorbed dose is excreted unchanged in the urine within 24Â hours. There is no evidence of metabolism of cefixime in vivo.
Indications And Clinical Uses:
Treatment of the following infections caused by susceptible strains of the designated microorganisms:
Middle Ear: Otitis media caused by S. pneumoniae, H. influenzae (beta-lactamase positive and negative strains), B. catarrhalis (beta-lactamase positive and negative strains) and S. pyogenes.
Paranasal Sinuses: Sinusitis caused by S. pneumoniae, H. influenzae (beta-lactamase positive and negative strains), and B. catarrhalis (beta-lactamase positive and negative strains).
Urinary Tract: Acute uncomplicated cystitis and urethritis caused by E. coli, P. mirabilis, and Klebsiella species.
Upper Respiratory Tract: Pharyngitis and tonsillitis caused by S. pyogenes.
Lower Respiratory Tract: Acute bronchitis caused by S. pneumoniae, B. catarrhalis (beta-lactamase positive and negative strains) and H. influenzae (beta-lactamase positive and negative strains).
Uncomplicated Gonorrhea: Uncomplicated gonorrhea (cervical/urethral and rectal) caused by N. gonorrhoeae, including penicillinase (beta-lactamase-positive) and nonpenicillinase (beta-lactamase-negative) producing strains.
Appropriate cultures should be taken for susceptibility testing before initiating treatment with cefixime. If warranted, therapy may be instituted before susceptibility results are known; however, once these are obtained, therapy may need to be adjusted.
Patients with known allergies to the cephalosporin or penicillin antibiotics.
Manufacturers’ Warnings In Clinical States: In penicillin-sensitive patients, cefixime should be administered cautiously. Patients may be sensitive to penicillins and not to cephalosporins such as cefixime or be sensitive to both. Medical literature indicates that patients sensitive to cephalosporins are very likely to be penicillin sensitive.
Antibiotics, including cefixime, should be administered cautiously to any patient who has demonstrated some form of allergy, particularly to drugs.
Treatment with broad-spectrum antibiotics such as cefixime alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by C. difficile is a primary cause of antibiotic-associated diarrhea. Pseudomembranous colitis is associated with the use of broad-spectrum antibiotics (including macrolides, semisynthetic penicillins, and cephalosporins); therefore, it is important to consider its diagnosis in patients who develop diarrhea in association with the use of antibiotics. Symptoms of pseudomembranous colitis may occur during or after antibiotic treatment. Such colitis may range in severity from mild to life-threatening.
Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, management should include sigmoidoscopy, appropriate bacteriologic studies, fluids, electrolytes, and protein supplementation. If the colitis does not improve after the drug has been discontinued, or if the symptoms are severe, oral vancomycin should be considered for antibiotic-associated pseudomembranous colitis produced by C. difficile. Other causes of colitis should be excluded.
General: If an allergic reaction to cefixime occurs, the drug should be discontinued, and, if necessary, the patient should be treated with appropriate agents, e.g., pressor amines, antihistamines, or corticosteroids. The possibility of the emergence of resistant organisms which might result in overgrowth should be kept in mind, particularly during prolonged treatment. In such use, careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.
Broad-spectrum antibiotics such as cefixime should be prescribed with caution in individuals with a history of gastrointestinal disease.
Once daily dosing only must be used for urinary tract infections, since twice daily dosing was shown to be not as effective in clinical studies.
Do not use cefixime to treat S. aureus as this strain of staphylococci is resistant to cefixime.
Renal Impairment: Cefixime may be administered in the presence of impaired renal function, but dose modification is recommended for patients with moderate or severe renal impairment (i.e., creatinine clearance of <40 mL/min) (see Dosage).
Bioavailability Differences Between Tablet and Suspension: The area under the time versus concentration curve is greater by approximately 26.4% and the C max is greater by approximately 20.7% with the oral suspension when compared to the tablet after doses of 400 mg. This increased absorption should be taken into consideration if the oral suspension is to be substituted for the tablet. Because of the lack of bioequivalence, tablets should not be substituted for oral suspension particularly in the treatment of otitis media where clinical trial experience with the suspension only is available (see Dosage).
Drug/Laboratory 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 beta-lactams may result in a false-positive reaction for glucose in the 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 Testape) be used. A false-positive direct Coombs test has been reported during treatment with cephalosporin antibiotics; therefore, it should be recognized that a positive Coombs test may be due to the drug.
Pregnancy: The safety of cefixime in the treatment of infection in pregnant women has not been established.
Reproduction studies have been performed in mice and rats at doses up to 400 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to cefixime. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the likely benefits of using cefixime outweighs the potential risk to the fetus and/or the mother.
Labor and Delivery: Cefixime has not been studied for use during labor and delivery.
Lactation: It is not known whether cefixime is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when cefixime is administered to a nursing woman.
Children: Safety and effectiveness of cefixime in children less than 6 months old have not been established.
:Five percent of patients in the clinical trials discontinued therapy because of drug-related adverse reactions. Thirty-six percent of the pediatric patient population experienced at least one adverse reaction (mild 25%, moderate 9%, severe 2%). Forty-seven percent of the adult patients experienced at least one adverse reaction (mild 24%, moderate 19%, severe 4%). The most commonly seen adverse reactions in the clinical trials of the tablet formulation were gastrointestinal events, which were reported in 37% of all adult patients treated (mild 21%, moderate 13%, severe 3%). The predominant adverse events seen in adults in clinical trials with cefixime were diarrhea 15%, (mild 7.2%, moderate 6.2%, severe 1.5%), headache 11%, stool changes 12%, nausea 9%, abdominal pain 5%, and dyspepsia 3%. The rates of the most prevalent adverse reactions were similar in the once a day and twice a day dosing regimens with the exception of headache which appears slightly more frequently in adults dosed once a day (12.9%) versus twice a day (8%). Other than for generally mild rashes or emesis which were each observed in 5% of children treated, the incidence of adverse reactions in pediatric patients receiving the suspension was generally comparable to the incidence seen in adult patients receiving tablets. These symptoms usually responded to symptomatic therapy or ceased when cefixime was discontinued.
Several patients developed severe diarrhea and/or documented pseudomembranous colitis, and a few required hospitalization.
The following adverse reactions have been reported following the use of cefixime. Incidence rates were less than 1 in 50 (less than 2%), except as otherwise noted.
CNS: headaches (11%) and dizziness (3%).
Gastrointestinal: diarrhea (15%), stool changes (12%), nausea (9%), abdominal pain (5%), dyspepsia (3%), flatulence (3%) and vomiting (2%). Pseudomembranous colitis has been reported rarely.
Hepatic: transient elevations of AST, ALT and alkaline phosphatase.
Renal: transient elevations in BUN or creatinine.
Hemic and Lymphatic: transient thrombocytopenia, leukopenia, and eosinophilia. Prolongation in prothrombin time was seen rarely.
Hypersensitivity: skin rashes, urticaria, drug fever and pruritus.
Other: genital pruritus, vaginitis and candidiasis.
When cefixime was used as single 400 mg dose therapy in clinical trials in the treatment of uncomplicated gonorrhea, adverse reactions which were considered to be related to cefixime therapy, were reported for 5.9% (21/358) of patients. Clinically mild gastrointestinal side effects occurred in 3.7% of all patients, moderate events occurred in 0.9% of all patients and no adverse reactions were reported as severe. Individual event rates included diarrhea 1% and loose or frequent stools 1%. Incidence rates for all other adverse reactions reported for adults in these trials were less than 1%.
In addition to the adverse reactions listed above which have been observed in patients treated with cefixime, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics. Allergic reactions were reported including anaphylaxis, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, superinfection, renal dysfunction, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic anemia, and hemorrhage. Abnormal laboratory tests were reported including positive Coombs test, elevated bilirubin, elevated LDH, pancytopenia, neutropenia and agranulocytosis.
Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced (see Dosage and Overdose). If seizures associated with cefixime occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.
Symptoms And Treatment Of Overdose:
OverdoseGastric lavage may be indicated; otherwise, no specific antidote exists. Cefixime is not removed in significant quantities from the circulation by hemodialysis or peritoneal dialysis.
Dosage And Administration:
Adults: The recommended dose is 400 mg once daily. When necessary, a dose of 200 mg given twice daily may be considered except for urinary tract infections where once daily dosing must be used. For treatment of uncomplicated gonococcal infections, a single oral dose of 400 mg is recommended.
Children: The recommended dose is 8 mg/kg/day once daily. When necessary, a dose of 4 mg/kg given twice daily may be considered except for urinary tract infections where once daily dosing must be used.
Children weighing more than 50 kg or older than 12 years should be treated with the recommended adult dose. Safety and effectiveness in infants aged less than 6 months have not been established.
Otitis media should be treated with the suspension. Clinical studies of otitis media were conducted with the suspension only and the suspension results in higher peak blood levels than the tablet when administered at the same dose. Therefore, the tablet should not be substituted for the suspension in the treatment of otitis media (see Precautions).
Duration of Therapy: Duration of dosage in clinical trials was 10 to 14 days. The duration of treatment should be guided by the patient’s clinical and bacteriological response.
In the treatment of infections due to S. pyogenes, a therapeutic dose of cefixime should be administered for at least 10 days.
Renal Impairment: Cefixime may be administered in the presence of impaired renal function. Normal dose and schedule may be employed in patients with creatinine clearances of 40 mL/min or greater. Patients whose clearance is between 20 and 40 mL/min should be given 75% of the standard daily dosage. Patients whose creatinine clearance is less than 20 mL/min should be given 50% of the standard daily dosage. Experience in children with renal impairment is very limited.
Dosage And Administration:
Powder for Oral Suspension: Each 5 mL of reconstituted suspension contains: cefixime 100 mg. Nonmedicinal ingredients: artificial strawberry flavor, sodium benzoate, sucrose and xanthan gum. Gluten- and lactose-free. Bottles of 50, 75 and 100 mL.
Tablets: Each rectangular, white, film-coated tablet, with rounded corners and beveled edges and a divided break line on each side, contains: cefixime 400 mg. Nonmedicinal ingredients: dibasic calcium phosphate, hydroxypropyl methylcellulose 2910, light mineral oil, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium lauryl sulfate and titanium dioxide. Gluten- and lactose-free. Bottles of 50.
Store at controlled room temperature 15 to 30°C.
SUPRAX® Rhône-Poulenc Rorer Cefixime Antibiotic