SUPRAX (cefixime 200 mg) Dailymed

Spl Product Data Elements Section

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Suprax (cefixime) chewable tablets and other antibacterial drugs, Suprax (cefixime) chewable tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Description

Suprax (cefixime) chewable tablet is a semisynthetic, cephalosporin antibiotic for oral administration. Chemically, it is (6R,7R)-7-[2-(2-Amino-4-thia-zolyl)glyoxylamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2-carboxylic acid, 7²-(Z)-[O-(carboxymethyl) oxime] trihydrate.

Molecular weight = 507.50 as the trihydrate. Chemical Formula is C₁₆H₁₅N₅O₇S₂.3H₂O

The structural formula for cefixime is:
Each chewable tablet contains either 100 mg or 150 mg or 200 mg of cefixime as the trihydrate. In addition the tablet contains the following inactive ingredients: aspartame, colloidal silicon dioxide, crospovidone, low substituted hydroxypropyl cellulose, magnesium stearate, mannitol, fantasy flavour permaseal, tutti frutti flavour and F D & C Red # 40 Aluminium Lake.

Clinical Pharmacology

Suprax (cefixime) chewable tablets are bioequivalent to oral suspension.

Suprax (cefixime) tablets, given orally, is about 40%-50% absorbed whether administered with or without food; however, time to maximal absorption is increased approximately 0.8 hours when administered with food. Suprax (cefixime) chewable tablets or oral suspension produces average peak concentrations approximately 25%-50% higher than the cefixime immediate-release tablets, when tested in normal adult volunteers. Two hundred and 400 mg doses of Suprax (cefixime) chewable tablets or oral suspension produce average peak concentrations of 3 mcg/mL (range 1 to 4.5 mcg/mL) and 4.6 mcg/mL (range 1.9 to 7.7 mcg/mL), respectively, when tested in normal adult volunteers. The area under the time versus concentration curve is greater by approximately 10%-25% with the Suprax (cefixime) chewable tablets or oral suspension than with the cefixime immediate-release tablets after doses of 100 to 400 mg, when tested in normal adult volunteers. This increased absorption should be taken into consideration if the Suprax (cefixime) chewable tablet or oral suspension is to be substituted for cefixime immediate-release tablet. Because of the lack of bioequivalence, cefixime immediate-release tablets should not be substituted for cefixime chewable tablets or oral suspension in the treatment of otitis media. (See   DOSAGE AND ADMINISTRATION ). Cross-over studies of cefixime immediate-release tablets versus chewable tablets or suspension have not been performed in children.

Peak serum concentrations occur between 2 and 6 hours following oral administration of    400 mg of Suprax (cefixime) chewable tablets or cefixime suspension.

Peak serum concentrations occur between 2 and 5 hours following a single administration of 200 mg of chewable tablets or suspension.

TABLE

Serum Levels of Cefixime after Administration of Immediate-Release Tablets (mcg/mL)
DOSE	1h	2h	4h	6h	8h	12h	24h
100 mg	0.3	0.8	1	0.7	0.4	0.2	0.02
200 mg	0.7	1.4	2	1.5	1	0.4	0.03
400 mg	1.2	2.5	3.5	2.7	1.7	0.6	0.04
Serum Levels of Cefixime after Administration of Chewable Tablets or Oral Suspension (mcg/mL)
DOSE	1h	2h	4h	6h	8h	12h	24h
100 mg	0.7	1.1	1.3	0.9	0.6	0.2	0.02
200 mg	1.2	2.1	2.8	2	1.3	0.5	0.07
400 mg	1.8	3.3	4.4	3.3	2.2	0.8	0.07

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. 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 immediate release tablets or suspension, there was little accumulation of drug in serum or urine after dosing for 14 days. The serum half-life of cefixime in healthy subjects is independent of dosage form and averages 3-4 hours but may range up to 9 hours in some normal volunteers. Average AUCs at steady state in elderly patients are approximately 40% higher than average AUCs in other healthy adults.

In subjects with moderate impairment of renal function (20 to 40 mL/min creatinine clearance), the average serum half-life of cefixime is prolonged to 6.4 hours. In severe renal impairment (5 to 20 mL/min creatinine clearance), the half-life increased to an average of 11.5 hours. The drug is not cleared significantly from the blood by hemodialysis or peritoneal dialysis. However, a study indicated that with doses of 400 mg, patients undergoing hemodialysis have similar blood profiles as subjects with creatinine clearances of 21-60 mL/min. There is no evidence of metabolism of cefixime in vivo.

Adequate data on CSF levels of cefixime are not available.

Microbiology

As with other cephalosporins, bactericidal action of cefixime results from inhibition of cell-wall synthesis. Cefixime is highly stable in the presence of beta-lactamase enzymes. As a result, many organisms resistant to penicillins and some cephalosporins due to the presence of beta-lactamases, may be susceptible to cefixime. Cefixime has been shown to be active against most strains of the following organisms both in vitro and in clinical infections (see INDICATIONS AND USAGE ):

Gram-positive Organisms.

Streptococcus pneumoniae,

Streptococcus pyogenes.

Gram-negative Organisms.

Haemophilus influenzae

(beta-lactamase positive and negative strains),

Moraxella (Branhamella) catarrhalis

(most of which are beta-lactamase positive),

Escherichia coli,

Proteus mirabilis,

Neisseria gonorrhoeae

(including penicillinase- and non-penicillinase-producing strains).

Cefixime has been shown to be active in vitro against most strains of the following organisms; however, clinical efficacy has not been established.

Gram-positive Organisms.

Streptococcus agalactiae.

Gram-negative Organisms.

Haemophilus parainfluenzae

(beta-lactamase positive and negative strains),

Proteus vulgaris,

Klebsiella pneumoniae,

Klebsiella oxytoca,

Pasteurella multocida,

Providencia species,

Salmonella species,

Shigella species,

Citrobacter amalonaticus,

Citrobacter diversus,

Serratia marcescens.

Note: Pseudomonas species, strains of group D streptococci (including enterococci), Listeria monocytogenes, most strains of staphylococci (including methicillin-resistant strains) and most strains of Enterobacter are resistant to cefixime. In addition, most strains of Bacteroides fragilis and Clostridia are resistant to cefixime.

Susceptibility Testing

Susceptibility Tests:

Diffusion Techniques

Quantitative methods that require measurement of zone diameters give an estimate of antibiotic susceptibility. One such procedure^1-3 has been recommended for use with disks to test susceptibility to cefixime. Interpretation involves correlation of the diameters obtained in the disk test with minimum inhibitory concentration (MIC) for cefixime.

Reports from the laboratory giving results of the standard single-disk susceptibility test with a 5-mcg cefixime disk should be interpreted according to the following criteria:

Recommended Susceptibility Ranges: Agar Disk Diffusion
Organisms	Resistant	Moderately Susceptible	Susceptible
Neisseria gonorrhoeaea	--	--	≥31 mm
All other organisms	≤15 mm	16 - 18 mm	≥ 19 mm
 a Using GC Agar Base with a defined 1% supplement without cysteine.

A report of "Susceptible" indicates that the pathogen is likely to be inhibited by generally achievable blood levels. A report of "Moderately Susceptible" indicates that inhibitory concentrations of the antibiotic may well be achieved if high dosage is used or if the infection is confined to tissues and fluids (e.g. urine) in which high antibiotic levels are attained. A report of "Resistant" indicates that achievable concentrations of the antibiotic are unlikely to be inhibitory and other therapy should be selected.

Standardized procedures require the use of laboratory control organisms. The 5-mcg disk should give the following zone diameter:

Header$Organism	Zone  diameter  ( mm )
E .  coli ATCC 25922	23-27
N .  gonorrhoeae ATCC 49226Using GC Agar Base with a defined 1% supplement without cysteine. Â	37-45

The class disk for cephalosporin susceptibility testing (the cephalothin disk) is not appropriate because of spectrum differences with cefixime. The 5-mcg cefixime disk should be used for all in vitro testing of isolates.

Dilution Techniques

Broth or agar dilution methods can be used to determine the minimum inhibitory concentration (MIC) value for susceptibility of bacterial isolates to cefixime. The recommended susceptibility breakpoints are as follows:

MIC Interpretive Standards (mcg/mL)
Organisms	Resistant	Moderately Susceptible	Susceptible
Neisseria gonorrhoeaea	--	--	     ≤ 0.25Â
All other organisms	≥ 4	2Â	≤ 1Â

As with standard diffusion methods, dilution procedures require the use of laboratory control organisms. Standard cefixime powder should give the following MIC ranges in daily testing of quality control organisms:

Organism	MIC  range  ( mcg / mL )
aUsing GC Agar Base with a defined 1% supplement without cysteine.
E .  coli ATCC 25922      Â	0.25-1
S .  aureus ATCC 29213    Â	8-32
N .  gonorrhoeae ATCC 49226a Â	0.008-0.03