CEFIMAX

Bacteria possess a cell wall comprising a glycopeptide polymer commonly known as peptidoglycan, which is synthesized and remodelled through the action of a family of enzymes known as "penicillin-binding proteins" (PBPs). 8 β-lactam antibiotics, including cephalosporins, are PBP inhibitors that, through inhibition of essential PBPs, result in impaired cell wall homeostasis, loss of cell integrity, and ultimately bacterial cell death. 8, 9, 10 Cefixime is a broad-spectrum antibiotic and an Oral-active third-generation semisynthetic cephalosporin. 3, 15, 21 Cephalosporins are beta-lactam antibiotics and can be used to treat gram-positive and gram-negative bacterial infections which include conditions such as skin infections, resistant bacteria, and meningitis.

Examples of third-generation cephalosporins are ceftriaxone, cefotaxime, and ceftazidime.

Third-generation cephalosporins are often a first-line therapy against certain bacterial infections.

However, cefixime is not recommended as a first-line of treatment for uncomplicated urogenital, anorectal, or pharyngeal gonorrhea because cefixime does not provide the same bactericidal effect as ceftriaxone. 24, 16 Generally, cefixime is used to treat uurinary tract infections, middle ear infections, pharyngitis, tonsillitis, exacerbations of chronic bronchitis, and uncomplicated gonorrhea.

The beta-lactam ring of cefixime inhibits bacterial cell wall synthesis by binding to the penicillin-binding proteins which will then result in lysis. 12, 7, 6 Specifically, cephalosporins inhibit penicillin-sensitive enzymes responsible for the final 3D structure of the bacterial cell wall which in turn inhibit bacterial cell wall peptidoglycan synthesis. 19, 20 Additionally, third-generation cephalosporins have been shown to have more stability in the presence of beta-lactamases compared to first.

• and second-generation cephalosporins.

Cefixime was first approved in the United States in 1986.

Cefixime is indicated for the treatment of uncomplicated urinary tract infections caused by Escherichia coli and Proteus mirabilis, otitis media caused by Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pyogenes, pharyngitis and tonsillitis caused by Streptococcus pyogenes, acute exacerbations of chronic bronchitis caused by Streptococcus pneumoniae and Haemophilus influenzae, and uncomplicated gonorrhea (cervical/urethral) caused by Neisseria gonorrhoeae (penicillinase-and non-penicillinase-producing isolates).

Cefixime, a broad-spectrum antibiotic, is an Oral-active third-generation semisynthetic cephalosporin. 3, 21 Like other cephalosporins, the antibacterial action of cefixime results from inhibition of cell wall synthesis.

Also like other cephalosporins, cefixime is stable when in the presence of certain beta-lactamase enzymes, which means certain organisms resistant to penicillins and some cephalosporins due to the presence of beta-lactamases could be susceptible to cefixime.

Use of cefixime can result in hypersensitivity reactions including anaphylactic/anaphylactoid reactions and Clostridium difficile -associated diarrhea (CDAD); it may also be associated with a fall in prothrombin activity.

Cefixime doses should be adjusted for patients that have renal impairment and patients undergoing continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD), while patients on dialysis should be monitored while taking cefixime.

Penicillin-binding protein (Gram positive and gram negative bacteria) Inhibitor.

With oral administration of cefixime, about 40%-50% is absorbed whether administered with or without food.

However, time to maximal absorption is increased approximately 0.8 hours when administered with food.

Cefixime administered as an single oral 200 mg tablet in healthy male volunteers had a corresponding C max of 3.25 mg/L and a corresponding T max of 4 hours.

Administration of cefixime as a 200 mg oral solution in healthy volunteers results in a C max of 3.22 micrograms/mL, while administration of 200 mg and 400 mg cefixime capsules results in a C max of 2.92 micrograms/mL and 4.84 micrograms/mL, respectively.

Administration of cefixime as a 200 mg intravenous solution, a 200 mg oral solution, a 200 mg capsule, and 400 mg capsule results in mean areas under the curve (AUC) of 47.0 μg.h/mL, 26.0 μg.h/mL, 23.6 μg.h/mL, and 39.4 μg.h/mL, respectively.

Cefixime has a volume of distribution averaging 0.1 L/kg of body weight when administered Oral.

There is no evidence of metabolism of cefixime in vivo.

Approximately 50% of absorbed cefixime is excreted unchanged in the urine in 24 hours.

Cefixime has a serum half-life averaging 3-4 hours in healthy subjects and is independent of dosage form. 4, 21 It has ranged up to 9 hours in some normal volunteers.

In individuals with severe renal impairment (5-20 mL/min creatinine clearance), the half-life of cefixime increased to an average of 11.5 hours.

Cefixime administered as an oral suspension with a dose of 8 mg/kg in children with urinary tract infections aged from 6-13 years resulted in a mean apparent total clearance rate of 4.74 ml/min/kg.

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information specific to cefixime is not conclusive.

Symptoms of overdose can include severe vomiting and seizures.

As cefixime is a cephalosporin, it may trigger seizures, particularly in patients with renal impairment when the dosage was not reduced.

Additionally, patients experiencing an overdose are at an increased risk of severe adverse effects such as diarrhea, nausea, loose stools, abdominal pain, dyspepsia, and vomiting.

In case of overdose, no specific antidote exists and this drug is not removed in significant quantities from the circulation by hemodialysis or peritoneal dialysis; however, gastric lavage may be indicated.

Symptomatic and supportive measures are recommended.

Animal studies revealed an oral

LD 50 greater than 10 g/kg in rats.

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.