MEGACEF

Cefixime is a semisynthetic, cephalosporin antibacterial for oral administration.

Chemically, it is ( 6R,7R )-7-[2-(2-Amino-4-thiazolyl)glyoxylamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo [4.2.0] oct-2-­ene-2-carboxylic acid, 7 2 -( Z )-[ O -(carboxy methyl) oxime] trihydrate.

Molecular weight = 507.50 as the trihydrate.

Chemical Formula is

C 16 H 15 N 5 O 7 S 2.3H 2 O. The structural formula for cefixime is: Inactive ingredients contained in cefixime powder for oral suspension USP are: colloidal silicon dioxide, strawberry guarana flavor, sucrose, and xanthan gum.

• bronchial and pulmonary infections,.

• acute medium otitis, particularly recurrent,.

• acute pyelonephritis in relay of parenteral antibiotic therapy of at least 4 days,.

• low urinary infections in children over 3 years of age and outside of severe infectious states.

The occurrence of any adverse event or the occurrence of any adverse event is likely to be a serious disease.

Cefixime is a semisynthetic cephalosporin antibacterial drug. 12.3 Pharmacokinetics Cefixime chewable tablets are bioequivalent to oral suspension.

Cefixime tablets and suspension, given orally, are about 40% to 50% absorbed whether administered with or without food; however, time to maximal absorption is increased approximately 0.8 hours when administered with food.

A single 200 mg tablet of cefixime produces an average peak serum concentration of approximately 2 mcg/mL (range to 4 mcg/mL); a single 400 mg tablet produces an average peak concentration of approximately 3.7 mcg/mL (range 1.3 to 7.7 mcg/mL).

The oral suspension produces average peak concentrations approximately 25% to 50% higher than the tablets, when tested in normal adult volunteers.

Two hundred and 400 mg doses of oral suspension produce average peak concentrations of 3 mcg/mL (range 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 (AUC) is greater by approximately 10% to 25% with the oral suspension than with the tablet after doses of to 400 mg, when tested in normal adult volunteers.

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 in the treatment of otitis media.

Cross-over studies of tablet versus suspension have not been performed in children.

The 400 mg capsule is bioequivalent to the 400 mg 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 and 6 hours following oral administration of a single 200 mg tablet, a single 400 mg tablet or 400 mg of cefixime suspension.

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

Peak serum concentrations occur between and 8 hours following oral administration of a single 400 mg capsule.

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 tablet or 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.

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 to 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.

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: Difference between age groups was significant. (p<0.05) Pharmacokinetic Parameters (mean ± SD) for Cefixime in Both Young & Elderly Subjects Pharmacokinetic parameter Young Elderly C max (mg/L) 4.74 ± 1.43 5.68 ± 1.83 T max (h) 3.9 ± 0.3 4.3 ± 0.6 AUC (mg.h/L) 34.9 ± 12.2 49.5 ± 19.1 T ½ (h) 3.5 ± 0.6 4.2 ± 0.4 C ave (mg/L)* 1.42 ± 0.5 1.99 ± 0.75 However, these increases were not clinically significant.

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 to 60 mL/min. 12.4 Microbiology Mechanism of Action 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 influenzae and Neisseria gonorrhoeae is most often associated with alterations in penicillin-binding proteins (PBPs).

Cefixime may have limited activity against

Enterobacteriaceae producing extended spectrum beta-lactamases (ESBLs).

Pseudomonas species, Enterococcus species, strains of Group D streptococci, Listeria monocytogenes, most strains of staphylococci (including methicillin-resistant strains), most strains of Enterobacter species, most strains of Bacteroides fragilis, and most strains of Clostridium species are resistant to cefixime.

Cefixime has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections.

Gram-positive Bacteria Streptococcus pneumoniae Streptococcus pyogenes

Gram-negative Bacteria Escherichia coli Haemophilus influenzae Moraxella catarrhalis Neisseria gonorrhoeae Proteus mirabilis The following in vitro data are available, but their clinical significance is unknown.

At least 90 percent of the following bacteria exhibit an in vitro minimum 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.

antibiotic of the beta-lactamin family, of the 3rd generation cephalosporins group, ATC code: J01DD08 Like other cephalosporins, the mechanism of action of cefixime is based on inhibition of bacterial wall synthesis.

Cefixime presents bactericidal activity in vitro vis-à-vis many gram-positive or Gram-negative germs.

D'ACTIVITE ANTIBACTERIENNE Critical concentrations separate sensitive strains from strains of intermediate sensitivity and these strains, from resistance: S £ 1 mg/L and R > 2 mg/L The prevalence of acquired resistance may vary with geography and time for certain species.

Therefore, it is useful to have information on the prevalence of local resistance, especially for the treatment of severe infections.

These data can only provide an orientation on the likelihood of susceptibility of a bacterial strain to this antibiotic.

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Gastric lavage may be indicated; otherwise, no specific antidote exists.

Cefixime is not removed in significant quantities from the circulation by hemodialysis or peritoneal dialysis.

Adverse reactions in small numbers of healthy adult volunteers receiving single doses up to 2 g of cefixime did not differ from the profile seen in patients treated at the recommended doses.

Cefixime for oral suspension is contraindicated in patients with known allergy to cefixime or other cephalosporins.

Contraindicated in patients with known allergy to cefixime or other cephalosporins.

400 mg daily Pediatric patients (6 months and older): 8 mg/kg/day 2.1 Adults The recommended dose of cefixime is 400 mg daily.

This may be given as a 400 mg tablet or capsule daily or the 400 mg tablet may be split and given as one half tablet every 12 hours.

For the treatment of uncomplicated cervical/urethral gonococcal infections, a single oral dose of 400 mg is recommended.

The capsule and tablet may be administered without regard to food.

In the treatment of infections due to Streptococcus pyogenes, a therapeutic dosage of cefixime should be administered for at least 10 days. 2.2 Pediatric Patients (6 months or older) The recommended dose is 8 mg/kg/day of the suspension.

This may be administered as a single daily dose or may be given in two divided doses, as 4 mg/kg every 12 hours.

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 three different concentrations (100 mg/5 mL, 200 mg/5 mL, and 500 mg/5 mL).

Suggested doses for pediatric patients * The preferred concentrations of oral suspension to use are 100 mg/5 mL or 200 mg/5 mL for pediatric patients in these weight ranges.

Doses are suggested for each weight range and rounded for ease of administration Cefixime for oral suspension Cefixime chewable tablet 100 mg/5 mL 200 mg/5 mL 500 mg/5 mL Patient Weight (kg) Dose/Day (mg) Dose/Day (mL) Dose/Day (mL) Dose/Day (mL) Dose to 7.5* 50 2.5 -

• 7.6 to 10* 80 4 2 -

• 10.1 to 12.5 100 5 2.5 1 1 tablet of 100 mg 12.6 to 20.5 150 7.5 4 1.5 1 tablet of 150 mg 20.6 to 28 200 10 5 2 1 tablet of 200 mg 28.1 to 33 250 12.5 6 2.5 1 tablet of 100 mg and 1 tablet of 150 mg 33.1 to 40 300 15 7.5 3 2 tablets of 150 mg 40.1 to 45 350 17.5 9 3.5 1 tablet of 150 mg and 1 tablet of 200 mg 45.1 or greater 400 20 10 4 2 tablets of 200 mg Children weighing more than 45 kg or older than 12 years should be treated with the recommended adult dose.

Cefixime chewable tablets must be chewed or crushed before swallowing.

Otitis media should be treated with the chewable tablets or suspension.

Clinical trials of otitis media were conducted with the chewable tablets or suspension, and the chewable tablets or suspension results in higher peak blood levels than the tablet when administered at the same dose.

Therefore, the tablet or capsule should not be substituted for the chewable tablets or suspension in the treatment of otitis media.

In the treatment of infections due to Streptococcus pyogenes, a therapeutic dosage of cefixime should be administered for at least 10 days. 2.3 Renal Impairment Cefixime for oral suspension may be administered in the presence of impaired renal function.

Normal dose and schedule may be employed in patients with creatinine clearances of 60 mL/min or greater.

Table for dose adjustments for adults with renal impairment.

Neither hemodialysis nor peritoneal dialysis removes significant amounts of drug from the body.

Table 2.

Impairment The preferred concentrations of oral suspension to use are 200 mg/5 mL or 500 mg/5 mL for patients with this renal dysfunction Renal Dysfunction Cefixime for oral suspension Tablet Chewable Tablet Creatinine Clearance (mL/min) 100 mg/5 mL 200 mg/5 mL 500 mg/5 mL 400 mg 200 mg Dose/Day (mL) Dose/Day (mL) Dose/Day (mL) Dose/Day Dose/Day 60 or greater Normal dose Normal dose Normal dose Normal dose Normal dose to 59 OR renal hemodialysis* 13 6.5 2.6 Not Appropriate Not Appropriate 20 or less OR continuous peritoneal dialysis 8.6 4.4 1.8 0.5 tablet 1 tablet 2.4 Reconstitution Directions for Oral Suspension Strength Bottle Size Reconstitution Directions 100 mg/5 mL 100 mL To reconstitute, suspend with 70 mL water.

Tap the bottle several times to loosen powder contents prior to reconstitution.

Add approximately half the total amount of water for reconstitution and shake well.

Add the remainder of water and shake well. 200 mg/5 mL 75 mL To reconstitute, suspend with 52.5 mL water.

Add the remainder of water and shake well. 100 mg/5 mL and 200 mg/5 mL 50 mL To reconstitute, suspend with 35 mL water.

Add the remainder of water and shake well.

After reconstitution, the suspension may be kept for 14 days either at room temperature, or under refrigeration, without significant loss of potency.

Keep tightly closed.

Shake well before using.

Discard unused portion after 14 days.

Cefixime for oral suspension

USP 100 mg/5 mL is off-white to pale yellow colored powder.

• Each 5 mL of reconstituted off-white to pale yellow, strawberry flavored suspension contains cefixime trihydrate equivalent to 100 mg cefixime. 50 mL Bottles NDC 65862-751-50 100 mL Bottles NDC 65862-751-01 Cefixime for oral suspension USP 200 mg/5 mL is off-white to pale yellow colored powder.

• Each 5 mL of reconstituted off-white to pale yellow, strawberry flavored suspension contains cefixime trihydrate equivalent to 200 mg cefixime. 50 mL Bottles NDC 65862-752-50 75 mL Bottles NDC 65862-752-75 Storage Prior to Reconstitution: Store drug powder at 20° to 25°C (68° to 77°F) .

Store at room temperature or under refrigeration.

Shake well before using.

Discard unused portion after 14 days.

Keep tightly closed.

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.

Reproduction studies have been performed in mice and rats at doses equivalent to and 80 times, respectively, the adult human recommended dose and have revealed no evidence of harm to the fetus due to cefixime.

The estimated 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 to 4% and to 20%, respectively.

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.

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 1 generation or fetal development of the F 2 generation.

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 1 generation and development of their fetuses (F 2 ).

Safety and effectiveness of cefixime in pediatric patients younger than 6 months of age have not been established.

The incidence of gastrointestinal adverse reactions, including diarrhea and loose stools, in the pediatric patients receiving the suspension, was comparable to the incidence seen in adult patients receiving tablets.

Clinical studies did not include sufficient numbers of subjects aged and older to determine whether they respond differently than younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

A pharmacokinetic study in the elderly detected differences in pharmacokinetic parameters.

These differences were small and do not indicate a need for dosage adjustment of the drug in the elderly.