CEDAX^®
(ceftibuten capsules) and (ceftibuten for oral suspension)

CEDAX (ceftibuten capsules) and (ceftibuten for oral suspension) contain the active ingredient ceftibuten as ceftibuten dihydrate. Ceftibuten dihydrate is a semisynthetic cephalosporin antibiotic for oral administration. Chemically, it is (+)-(6R,7R)-7-[(Z)-2-(2-Amino-4-thiazolyl)-4-carboxycrotonamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, dihydrate. Its molecular formula is C₁₅H₁₄N₄O₆S₂•2H₂O. Its molecular weight is 446.43 as the dihydrate.

Ceftibuten dihydrate has the following structural formula:

CEDAX Capsules contain ceftibuten dihydrate equivalent to 400 mg of ceftibuten. Inactive ingredients contained in the capsule formulation include: magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The capsule shell and/or band contains gelatin, sodium lauryl sulfate, titanium dioxide, and polysorbate 80. The capsule shell may also contain benzyl alcohol, sodium propionate, edetate calcium disodium, butylparaben, propylparaben, and methylparaben.

CEDAX Oral Suspension after reconstitution contains ceftibuten dihydrate equivalent to 90 mg of ceftibuten per 5 mL. CEDAX Oral Suspension is cherry flavored and contains the inactive ingredients: cherry flavoring, polysorbate 80, silicon dioxide, simethicone, sodium benzoate, sucrose (approximately 1 g/5 mL), titanium dioxide, and xanthan gum.

CEDAX (ceftibuten) is indicated for the treatment of individuals with mild-to-moderate infections caused by susceptible strains of the designated microorganisms in the specific conditions uled below (seeDOSAGE AND ADMINISTRATION and CLINICAL STUDIES section).

Acute Bacterial Exacerbations of Chronic Bronchitis due to Haemophilus influenzae (including β-lactamase-producing strains), Moraxella catarrhalis (including β-lactamase-producing strains), or Streptococcus pneumoniae (penicillin-susceptible strains only).

NOTE: In acute bacterial exacerbations of chronic bronchitis clinical trials where Moraxella catarrhalis was isolated from infected sputum at baseline, ceftibuten clinical efficacy was 22% less than control.

Acute Bacterial Otitis Media due to Haemophilus influenzae (including β-lactamase-producing strains), Moraxella catarrhalis (including β-lactamase-producing strains), or Streptococcus pyogenes.

NOTE: Although ceftibuten used empirically was equivalent to comparators in the treatment of clinically and/or microbiologically documented acute otitis media, the efficacy against Streptococcus pneumoniae was 23% less than control. Therefore, ceftibuten should be given empirically only when adequate antimicrobial coverage against Streptococcus pneumoniae has been previously administered.

Pharyngitis and Tonsillitis due to Streptococcus pyogenes.

NOTE: Only penicillin by the intramuscular route of administration has been shown to be effective in the prophylaxis of rheumatic fever. Ceftibuten is generally effective in the eradication of Streptococcus pyogenes from the oropharynx; however, data establishing the efficacy of the CEDAX product for the prophylaxis of subsequent rheumatic fever are not available.

CEDAX (ceftibuten) is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.

BEFORE THERAPY WITH THE CEDAX PRODUCT IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFTIBUTEN, OTHER 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 ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO THE CEDAX PRODUCT OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, INTRAVENOUS FLUIDS, INTRAVENOUS ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ceftibuten, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of "antibiotic-associated colitis".

After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile.

As with other broad-spectrum antibiotics, prolonged treatment may result in the possible emergence and overgrowth of resistant organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

The dose of ceftibuten may require adjustment in patients with varying degrees of renal insufficiency, particularly in patients with creatinine clearance less than 50 mL/min or undergoing hemodialysis (seeDOSAGE AND ADMINISTRATION). Ceftibuten is readily dialyzable. Dialysis patients should be monitored carefully, and administration of ceftibuten should occur immediately following dialysis.

Ceftibuten should be prescribed with caution to individuals with a history of gastrointestinal disease, particularly colitis.

Patients should be informed that:

• If the patient is diabetic, he/she should be informed that CEDAX Oral Suspension contains 1 gram sucrose per teaspoon of suspension.
• CEDAX Oral Suspension should be taken at least 2 hours before a meal or at least 1 hour after a meal (see CLINICAL PHARMACOLOGY, Food Effect on Absorption).

There have been no chemical or laboratory test interactions with ceftibuten noted to date. False-positive direct Coombs' tests have been reported during treatment with other cephalosporins. Therefore, it should be recognized that a positive Coombs' test could be due to the drug. The results of assays using red cells from healthy subjects to determine whether ceftibuten would cause direct Coombs' reactions in vitro showed no positive reaction at ceftibuten concentrations as high as 40 µg/mL.

Long-term animal studies have not been performed to evaluate the carcinogenic potential of ceftibuten. No mutagenic effects were seen in the following studies: in vitro chromosome assay in human lymphocytes, in vivo chromosome assay in mouse bone marrow cells, Chinese Hamster Ovary (CHO) cell point mutation assay at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus, and in a bacterial reversion point mutation test (Ames). No impairment of fertility occurred when rats were administered ceftibuten orally up to 2000 mg/kg/day (approximately 43 times the human dose based on mg/m²/day).

Ceftibuten has not been studied for use during labor and delivery. Its use during such clinical situations should be weighed in terms of potential risk and benefit to both mother and fetus.

It is not known whether ceftibuten (at recommended dosages) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ceftibuten is administered to a nursing woman.

The safety and efficacy of ceftibuten in infants less than 6 months of age has not been established.

The usual adult dosage recommendation may be followed for patients in this age group. However, these patients should be monitored closely, particularly their renal function, as dosage adjustment may be required.

The following adverse experiences have been reported during worldwide post-marketing surveillance: aphasia, jaundice, melena, psychosis, serum sickness-like reactions, stridor, and toxic epidermal necrolysis.

In addition to the adverse reactions uled above that have been observed in patients treated with ceftibuten capsules, the following adverse events and altered laboratory tests have been reported for cephalosporin-class antibiotics:

•  allergic reactions, anaphylaxis, drug fever, Stevens-Johnson syndrome, renal dysfunction, toxic nephropathy, hepatic cholestasis, aplastic anemia, hemolytic anemia, hemorrhage, false-positive test for urinary glucose, neutropenia, pancytopenia, and agranulocytosis. Pseudomembranous colitis; onset of symptoms may occur during or after antibiotic treatment (seeWARNINGS).

Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced (seeDOSAGE AND ADMINISTRATION and OVERDOSAGE). If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.

Overdosage of cephalosporins can cause cerebral irritation leading to convulsions. Ceftibuten is readily dialyzable and significant quantities (65% of plasma concentrations) can be removed from the circulation by a single hemodialysis session. Information does not exist with regard to removal of ceftibuten by peritoneal dialysis.

The recommended doses of CEDAX Oral Suspension are presented in the table below. CEDAX Oral Suspension must be administered at least 2 hours before or 1 hour after a meal.

Pediatric patients weighing more than 45 kg should receive the maximum daily dose of 400 mg.

CEDAX Capsules and CEDAX Oral Suspension may be administered at normal doses in the presence of impaired renal function with creatinine clearance of 50 mL/min or greater. The recommendations for dosing in patients with varying degrees of renal insufficiency are presented in the following table.

In patients undergoing hemodialysis two or three times weekly, a single 400-mg dose of ceftibuten capsules or a single dose of 9 mg/kg (maximum of 400 mg of ceftibuten) oral suspension may be administered at the end of each hemodialysis session.

After mixing, the suspension may be kept for 14 days and must be stored in the refrigerator. Keep tightly closed. Shake well before each use. Discard any unused portion after 14 days.

CEDAX Capsules, containing 400 mg of ceftibuten (as ceftibuten dihydrate) are white, opaque capsules imprinted with the product name and strength, are available as follows:

20 Capsules/Bottle (NDC 45809-401-20)

Store the capsules between 2° and 25°C (36° and 77°F). Replace cap securely after each opening.

CEDAX Oral Suspension is an off-white to cream-colored powder that, when reconstituted as directed, contains ceftibuten equivalent to 90 mg/5 mL, supplied as follows:

90 mg/5 mL
  18 mg/mL 30-mL Bottle (NDC 45809-801-30)
  18 mg/mL 60-mL Bottle (NDC 45809-801-60)
  18 mg/mL 90-mL Bottle (NDC 45809-801-90)
  18 mg/mL 120-mL Bottle (NDC 45809-801-12)

Prior to reconstitution, the powder must be stored between 2° and 25°C (36° and 77°F). Once it is reconstituted, the oral suspension is stable for 14 days when stored in the refrigerator between 2° and 8°C (36° and 46°F).

Three clinical trials (two domestic, the third abroad) have been conducted testing ceftibuten in the treatment of acute exacerbations of chronic bronchitis (AECB). Overall, the clinical outcome among patients who had signs and symptoms of AECB, who had a gram stain showing a predominance of PMNs and few epithelial cells, and who were evaluated at approximately 1 to 2 weeks after completing therapy were equivalent to comparators. The bacterial eradication rates of specific pathogens are presented below.

Four clinical trials (three domestic, the fourth abroad) have been conducted testing ceftibuten in the treatment of acute bacterial otitis media. Overall, the clinical outcome among patients who had signs and symptoms of acute bacterial otitis media and who were evaluated at approximately 1 to 2 weeks after completing therapy were equivalent to comparators. Tympanocentesis was performed on patients in three of the above-mentioned studies; the bacterial eradication rates of specific pathogens are presented below.

• National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically – Third Edition. Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25, NCCLS, Villanova, PA. December, 1993.
• National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests – Fifth Edition. Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA. December, 1993.

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Shionogi USA, Inc., Florham Park, NJ 07932
Manufactured by Schering Corporation CED01PIB02
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Rev. 12/04