CEFTIBUTEN
DESCRIPTION:
PROCADAX (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-thiazoly)-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.
PROCADAX 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.
PROCADAX Oral Suspension after reconstitution contains ceftibuten dihydrate
equivalent to either 90 mg of ceftibuten per 5 mL or 180 mg of ceftibuten per 5
mL. PROCADAX Oral Suspension is cherry flavored and contains the inactive
ingredients: cherry flavoring, polysorbate 80, silcon dioxide, simethicone,
sodium benzoate, sucrose (approximately 1 g/5 mL), titanium dioxide, and xanthan
gum.
ACTIONS/CLINICAL PHARMACOLOGY:
PHARMACOKINETICS
ABSORPTION:
PROCADAX CAPSULES
Ceftibuten is rapidly absorbed after oral administration of PROCADAX Capsules. The
plasma concentrations and pharmacokinetic parameters of ceftibuten after a
single 400-mg dose of PROCADAX Capsules to 12 healthy adult male volunteers (20 to
39 years of age) are displayed in the table below. When PROCADAX Capsules were
administered once daily for 7 days, the average Cmax was 17.9 mu- g/mL on day 7.
Therefore, ceftibuten accumulation in plasma is about 20% at steady state.
PROCADAX ORAL SUSPENSION
Ceftibuten is rapidly absorbed after oral administration of PROCADAX Oral
Suspension. The plasma concentrations and pharmacokinetic parameters of
ceftibuten after a single 9-mg/kg dose of PROCADAX Oral Suspension to 32 fasting
pediatric patients (6 months to 12 years of age) are displayed in the following
table:
Average Plasma Concentration Average Plasma Concentration
Parameter (in mu-g/mL of ceftibuten (in mu-g/mL of ceftibuten
after a single 400-mg dose) after a single 9-mg/kg dose)
and Derived Pharmacokinetic and Derived Pharmacokinetic
Parameters (+/- 1 SD) Parameters (+/- 1 SD)
(n = 12 healthy adult males) (n = 32 pediatric patients)
1.0 h 6.1 (5.1) 9.3 (6.3)
1.5 h 9.9 (5.9) 8.6 (4.4)
2.0 h 11.3 (5.2) 11.2 (4.6)
3.0 h 13.3 (3.0) 9.0 (3.4)
4.0 h 11.2 (2.9) 6.6 (3.1)
6.0 h 5.8 (1.6) 3.8 (2.5)
8.0 h 3.2 (1.0) 1.6 (1.3)
12.0 h 1.1 (0.4) 0.5 (0.4)
Cmax, mu-g/mL 15.0 (3.3) 13.4 (4.9)
Tmax, h 2.6 (0.9) 2.0 (1.0)
AUC, mu-g--h/mL 73.7 (16.0) 56.0 (16.9)
T 1/2 h 2.4 (0.2) 2.0 (0.6)
Total body 1.3 (0.3) 2.9 (0.7)
clearance
(Cl/F)
mL/min/kg
The absolute bioavailability of PROCADAX Oral Suspension has not been determined.
The plasma concentrations of ceftibuten in pediatric patients are dose
proportional following single doses of PROCADAX Capsules of 200 mg and 400 mg and
of PROCADAX Oral Suspension between 4.5 mg/kg and 9 mg/kg.
DISTRIBUTION:
PROCADAX CAPSULES
The average apparent volume of distribution (V/F) of ceftibuten in 6 adult
subjects is 0.21 L/kg (+/- 1 SD = 0.03 L/kg).
PROCADAX ORAL SUSPENSION
The average apparent volume of distribution (V/F) of ceftibuten in 32 fasting
pediatric patients is 0.5 L/kg (+/- 1 SD = 0.2 L/kg).
PROTEIN BINDING:
Ceftibuten is 65% bound to plasma proteins. The protein binding is independent
of plasma ceftibuten concentration.
TISSUE PENETRATION:
Bronchial Secretions: In a study of 15 adults administered a single 400-mg dose
of ceftibuten and scheduled to undergo bronchoscopy, the mean concentrations in
epithelial lining fluid and bronchial mucosa were 15% and 37%, respectively, of
the plasma concentrations.
Sputum: Ceftibuten sputum levels average approximately 7% of the concomitant
plasma ceftibuten level. In a study of 24 adults administered ceftibuten 200 mg
bid or 400 mg qd, the average Cmax in sputum (1.5 mu-g/mL) occurred at 2 hours
postdose and the average Cmax in plasma (17 mu-g/mL) occurred at 2 hours
postdose.
Middle-Ear Fluid (MEF): In a study of 12 pediatric patients administered 9 mg/
kg, ceftibuten MEF area under the curve (AUC) averaged approximately 70% of the
plasma AUC. In the same study, Cmax values were 14.3 +/- 2.7 mu- g/mL in MEF at
4 hours postdose and 14.5 +/- 3.7 mu-g/mL in plasma at 2 hours postdose.
Tonsillar Tissue: Data on ceftibuten penetration into tonsillar tissue are not
available.
Cerebrospinal Fluid: Data on ceftibuten penetration into cerebrospinal fluid are
not available.
METABOLISM AND EXCRETION:
A study with radiolabeled ceftibuten administered to 6 healthy adult male
volunteers demonstrated that Cis-ceftibuten is the predominant component in both
plasma and urine. About 10% of ceftibuten is converted to the Trans-isomer. The
Trans- isomer is approximately 1/8 as antimicrobially potent as the Cis-isomer.
Ceftibuten is excreted in the urine; 95% of the administered radioactivity was
recovered either in urine or feces. In 6 healthy adult male volunteers,
approximately 56% of the administered dose of ceftibuten was recovered from
urine and 39% from the feces within 24 hours. Because renal excretion is a
significant pathway of elimination, patients with renal dysfunction and patients
undergoing hemodialysis require dosage adjustment (see DOSAGE AND
ADMINISTRATION).
FOOD EFFECT ON ABSORPTION:
Food affects the bioavailability of ceftibuten from PROCADAX Capsules and PROCADAX
Oral Suspension.
The effect of food on the bioavailability of PROCADAX Capsules was evaluated in 26
healthy adult male volunteers who ingested 400 mg of PROCADAX Capsules after an
overnight fast or immediately after a standardized breakfast. Results showed
that food delays the time of Cmax by 1.75 hours, decreases the Cmax by 18%, and
decreases the extent of absorption (AUC) by 8%.
The effect of food on the bioavailability of PROCADAX Oral Suspension was evaluated
in 18 healthy adult male volunteers who ingested 400 mg of PROCADAX Oral Suspension
after an overnight fast or immediately after a standardized breakfast. Results
obtained demonstrated a decrease in Cmax of 26% and an AUC of 17% when PROCADAX
Oral Suspension was administered with a high-fat breakfast, and a decrease in
Cmax of 17% and in AUC of 12% when PROCADAX Oral Suspension was administered with a
low-calorie nonfat breakfast (see PRECAUTIONS).
BIOEQUIVALENCE OF DOSAGE FORMULATIONS:
A study in 18 healthy adult male volunteers demonstrated that a 400-mg dose of
PROCADAX Capsules produced equivalent concentrations to a 400-mg dose of PROCADAX Oral
Suspension. Average Cmax values were 15.6 (3.1) mu-g/mL for the capsule and 17.0
(3.2) mu-g/mL for the suspension. Average AUC values were 80.1 (14.4) mu-g--
hr/mL for the capsule and 87.0 (12.2) mu-g--hr/mL for the suspension.
SPECIAL POPULATIONS:
Geriatric Patients: Ceftibuten pharmacokinetics have been investigated in
elderly (65 years of age and older) men (n = 8) and women (n = 4). Each
volunteer received ceftibuten 200-mg capsules twice daily for 3 1/2 days. The
average Cmax was 17.5 (3.7) mu-g/mL after 3 1/2 days of dosing compared to 12.9
(2.1) mu-g/mL after the first dose; ceftibuten accumulation in plasma was 40% at
steady state. Information regarding the renal function of these volunteers was
not available; therefore, the significance of this finding for clinical use of
PROCADAX Capsules in elderly patients is not clear. Ceftibuten dosage adjustment in
elderly patients may be necessary (see DOSAGE AND ADMINISTRATION).
Patients With Renal Insufficiency: Ceftibuten pharmacokinetics have been
investigated in adult patients with renal dysfunction. The ceftibuten plasma
half-life increased and apparent total clearance (Cl/F) decreased
proportionately with increasing degree of renal dysfunction. In 6 patients with
moderate renal dysfunction (creatinine clearance 30 to 49 mL/min), the plasma
half-life of ceftibuten increased to 7.1 hours and Cl/F decreased to 30 mL/min.
In 6 patients with severe renal dysfunction (creatinine clearance 5 to 29 mL/
min), the half- life increased to 13.4 hours and Cl/F decreased to 16 mL/min. In
6 functionally anephric patients (creatinine clearance <5 mL/min), the half-life
increased to 22.3 hours and Cl/F decreased to 11 mL/min (a 7- to 8-fold change
compared to healthy volunteers). Hemodialysis removed 65% of the drug from the
blood in 2 to 4 hours. These changes serve as the basis for dosage adjustment
recommendations in adult patients with mild to severe renal dysfunction (see
DOSAGE AND ADMINISTRATION).
MICROBIOLOGY:
Ceftibuten exerts its bactericidal action by binding to essential target
proteins of the bacterial cell wall. This binding leads to inhibition of cell-
wall synthesis.
Ceftibuten is stable in the presence of most plasmid-mediated beta-lactamases,
but it is not stable in the presence of chromosomally-mediated cephalosporinases
produced in organisms such as Bacteroides, Citrobacter, Enterobacter,
Morganella, and Serratia. Like other beta-lactam agents, ceftibuten should not
be used against strains resistant to beta-lactams due to general mechanisms such
as permeability or penicillin- binding protein changes like penicillin-
resistant, S. Pneumoniae.
Ceftibuten 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 AEROBES:
Streptococcus Pneumoniae (penicillin-susceptible strains only)
Streptococcus Pyogenes
GRAM-NEGATIVE AEROBES:
Haemophilus Influenzae (including (beta)-lactamase-producing strains)
Moraxella Catarrhalis (including (beta)-lactamase-producing strains)
There are no known organisms which are potential pathogens in the indications
approved for ceftibuten for which ceftibuten exhibits In Vitro activity but for
which the safety and efficacy of ceftibuten in treating clinical infections due
to these organisms, have not been established in adequate and well-controlled
trials.
NOTE: Ceftibuten is INACTIVE In Vitro against Acinetobacter, Bordetella,
Campylobacter, Enterobacter, Enterococcus, Flavobacterium, Hafnia, Listeria,
Pseudomonas, Staphylococcus, and Streptococcus (except Pneumoniae and Pyogenes)
species. In addition, it shows little In Vitro activity against most anaerobes,
including most species of Bacteroides.
SUSCEPTIBILITY TESTING:
Dilution Techniques: Quantitative methods are used to determine antimicrobial
minimal inhibitory concentrations (MICs). These MICs provide estimates of the
susceptibility of bacteria to antimicrobial compounds. The MICs should be
determined using a standardized procedure. Standardized procedures are based on
a dilution method (broth, agar, or microdilution) or equivalent with
standardized inoculum concentrations and standardized concentrations of
ceftibuten powder. The MIC values should be interpreted according to the
following criteria when testing Haemophilus species using Haemophilus Test Media
(HTM):
MIC (MU-G/ML) INTERPRETATION
=2 (S) Susceptible
The current absence of resistant strains precludes defining any categories other
than "Susceptible". Strains yielding results suggestive of a "Nonsusceptible"
category should be submitted to a reference laboratory for further testing.
A report of "Susceptible" implies that an infection due to the strain may be
appropriately treated with the dosage of antimicrobial agent recommended for
that type of infection and infecting species, unless otherwise contraindicated.
Ceftibuten is indicated for penicillin- susceptible only strains of
Streptococcus Pneumoniae. A pneumococcal isolate that is susceptible to
penicillin (MIC =0.06 mu-g/mL) can be considered susceptible to ceftibuten for
approved indications. Testing of ceftibuten against penicillin-intermediate or
penicillin- resistant isolates is not recommended. Reliable interpretive
criteria for ceftibuten are not currently available. Physicians should be
informed that clinical response rates with ceftibuten may be lower in strains
that are not penicillin-susceptible.
Standardized susceptibility test procedures require the use of laboratory
control microorganisms to control the technical aspect of laboratory procedures.
Standard ceftibuten powder should provide the following MIC values:
ORGANISM MIC RANGE (MU-G/ML)
Haemophilus Influenzae
ATCC 49247 0.25-1.0
Diffusion Techniques: Quantitative methods that require measurement of zone
diameters also provide estimates of the susceptibility of bacteria to
antimicrobial compounds. One such standardized procedure requires the use of
standardized inoculum concentrations. This procedure uses paper disks
impregnated with 30 mu-g of ceftibuten to test the susceptibility of
microorganisms to ceftibuten.
Reports from the laboratory providing results of the standard single-disk
susceptibility test with a 30-mu-g ceftibuten disk should be interpreted
according to the following criteria when testing Haemophilus species using
Haemophilus Test Media (HTM):
ZONE DIAMETER (MM) INTERPRETATION
(>/=)28 (S) Susceptible
The current absence of resistant strains precludes defining any categories other
than "Susceptible". Strains yielding results suggestive of a "Nonsusceptible"
category should be submitted to a reference laboratory for further testing.
Interpretation should be as stated above for results using dilution techniques.
Ceftibuten is indicated for penicillin- susceptible only strains of
Streptococcus Pneumoniae. Pneumococcal isolates with oxacillin zone sizes of
(>/=)20 mm are susceptible to penicillin and can be considered susceptible for
approved indications. Reliable disk diffusion tests for ceftibuten do not yet
exist.
As with standardized dilution techniques, diffusion methods require the use of
laboratory control microorganisms that are used to control the technical aspects
of the laboratory procedures. For the diffusion technique, the 30-mu-g
ceftibuten disk should provide the following zone diameters in these laboratory
test quality control strains:
ORGANISM ZONE DIAMETER (MM)
Haemophilus Influenzae
ATCC 49247 29-35
Cephalosporin-class disks should not be used to test for susceptibility to
ceftibuten.
INDICATIONS AND USAGE:
PROCADAX (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 listed below (see DOSAGE AND
ADMINISTRATION and CLINICAL STUDIES section).
ACUTE BACTERIAL EXACERBATIONS OF CHRONIC BRONCHITIS due to Haemophilus
Influenzae (including (beta)-lactamase-producing strains), Moraxella Catarrhalis
(including (beta)-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 (beta)-
lactamase-producing strains), Moraxella Catarrhalis (including (beta)-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 PROCADAX product for the
prophylaxis of subsequent rheumatic fever are not available.
CONTRAINDICATIONS:
PROCADAX (ceftibuten) is contraindicated in patients with known allergy to the
cephalosporin group of antibiotics.
WARNINGS:
BEFORE THERAPY WITH THE PROCADAX 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 PROCADAX 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
PRECAUTIONS:
GENERAL:
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 (see DOSAGE 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.
INFORMATION TO PATIENTS:
Patients should be informed that:
--If the patient is diabetic, he/she should be informed that PROCADAX Oral
Suspension contains 1 gram sucrose per teaspoon of suspension.
--PROCADAX Oral Suspension should be taken at least 2 hours before a meal or at
least 1 hour after a meal (see ACTIONS/CLINICAL PHARMACOLOGY, FOOD EFFECT ON
ABSORPTION).
DRUG INTERACTIONS:
Theophylline: Twelve healthy male volunteers were administered one 200-mg
ceftibuten capsule twice daily for 6 days. With the morning dose of ceftibuten
on day 6, each volunteer received a single intravenous infusion of theophylline
(4 mg/kg). The pharmacokinetics of theophylline were not altered. The effect of
ceftibuten on the pharmacokinetics of theophylline administered orally has not
been investigated.
Antacids Or H2-Receptor Antagonists: The effect of increased gastric pH on the
bioavailability of ceftibuten was evaluated in 18 healthy adult volunteers. Each
volunteer was administered one 400-mg ceftibuten capsule. A single dose of
liquid antacid did not affect the Cmax or AUC of ceftibuten; however, 150 mg of
ranitidine q12h for 3 days increased the ceftibuten Cmax by 23% and ceftibuten
AUC by 16%. The clinical relevance of these increases is not known.
DRUG/LABORATORY TEST INTERACTIONS:
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 mu-g/mL.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY:
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/m(squared)/day).
PREGNANCY TERATOGENIC EFFECTS: PREGNANCY CATEGORY B:
Ceftibuten was not teratogenic in the pregnant rat at oral doses up to 400 mg/
kg/day (approximately 8.6 times the human dose based on mg/m(squared)/day).
Ceftibuten was not teratogenic in the pregnant rabbit at oral doses up to 40 mg
/kg/day (approximately 1.5 times the human dose based on mg/m(squared)/day) and
has revealed no evidence of harm to the fetus. There are no adequate and well-
controlled studies in pregnant women. Because animal reproduction studies are
not always predictive of human response, this drug should be used during
pregnancy only if clearly needed.
LABOR AND DELIVERY:
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.
NURSING MOTHERS:
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.
PEDIATRIC USE:
The safety and efficacy of ceftibuten in infants less than 6 months of age has
not been established.
GERIATRIC PATIENTS:
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.
DRUG INTERACTIONS:
Theophylline: Twelve healthy male volunteers were administered one 200-mg
ceftibuten capsule twice daily for 6 days. With the morning dose of ceftibuten
on day 6, each volunteer received a single intravenous infusion of theophylline
(4 mg/kg). The pharmacokinetics of theophylline were not altered. The effect of
ceftibuten on the pharmacokinetics of theophylline administered orally has not
been investigated.
Antacids Or H2-Receptor Antagonists: The effect of increased gastric pH on the
bioavailability of ceftibuten was evaluated in 18 healthy adult volunteers. Each
volunteer was administered one 400-mg ceftibuten capsule. A single dose of
liquid antacid did not affect the Cmax or AUC of ceftibuten; however, 150 mg of
ranitidine q12h for 3 days increased the ceftibuten Cmax by 23% and ceftibuten
AUC by 16%. The clinical relevance of these increases is not known.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
ADVERSE EVENTS
CLINICAL TRIALS:
PROCADAX CAPSULES (adult patients)
In clinical trials, 1728 adult patients (1092 US and 636 international) were
treated with the recommended dose of ceftibuten capsules (400 mg per day). There
were no deaths or permanent disabilities thought due to drug toxicity in any of
the patients in these studies. Thirty-six of 1728 (2%) patients discontinued
medication due to adverse events thought by the investigators to be possibly,
probably, or almost certainly related to drug toxicity. The discontinuations
were primarily for gastrointestinal disturbances, usually diarrhea, vomiting, or
nausea. Six of 1728 (0.3%) patients were discontinued due to rash or pruritus
thought related to ceftibuten administration.
In the US trials, the following adverse events were thought by the investigators
to be possibly, probably, or almost certainly related to ceftibuten capsules in
multiple-dose clinical trials (n = 1092 ceftibuten-treated patients).
ADVERSE REACTIONS
CEFTIBUTEN CAPSULES
US CLINICAL TRIALS IN ADULT PATIENTS
(n = 1092)
----------------------------------------------------------------------------------------------------------------------
Incidence equal to or Nausea 4%
greater than 1% Headache 3%
Diarrhea 3%
Dyspepsia 2%
Dizziness 1%
Abdominal pain 1%
Vomiting 1%
----------------------------------------------------------------------------------------------------------------------
Incidence less than 1% but Anorexia, Constipation, Dry
greater than 0.1% mouth, Dyspnea, Dysuria,
Eructation, Fatigue, Flatulence,
Loose stools, Moniliasis,
Nasal congestion, Paresthesia,
Pruritus, Rash, Somnolence,
Taste perversion, Urticaria,
Vaginitis
---------------------------------------------------------------------------------------------------------------------
LABORATORY VALUE CHANGES*
CEFTIBUTEN CAPSULES
US CLINICAL TRIALS IN ADULT PATIENTS
--------------------------------------------------------------------------------------------------------------------
Incidence equal to or up BUN 4%
greater than 1% up Eosinophils 3%
down Hemoglobin 2%
up ALT (SGPT) 1%
up Bilirubin 1%
----------------------------------------------------------------------------------------------------------------------
Incidence less than 1% but up Alk phosphatase
greater than 0.1% up Creatinine
up Platelets
down Platelets
down Leukocytes
up AST (SGOT)
* Changes in laboratory values with possible clinical significance regardless
of whether or not the investigator thought that the change was due to drug
toxicity.
PROCADAX ORAL SUSPENSION (pediatric patients)
In clinical trials, 1152 pediatric patients (772 US and 380 international), 97%
of whom were younger than 12 years of age, were treated with the recommended
dose of ceftibuten (9 mg/kg once daily up to a maximum dose of 400 mg per day)
for 10 days. There were no deaths, life-threatening adverse events, or permanent
disabilities in any of the patients in these studies. Eight of 1152 (<1%)
patients discontinued medication due to adverse events thought by the
investigators to be possibly, probably, or almost certainly related to drug
toxicity. The discontinuations were primarily (7 out of 8) for gastrointestinal
disturbances, usually diarrhea or vomiting. One patient was discontinued due to
a cutaneous rash thought possibly related to ceftibuten administration.
In the US trials, the following adverse events were thought by the investigators
to be possibly, probably, or almost certainly related to ceftibuten oral
suspension in multiple-dose clinical trials (n = 772 ceftibuten-treated
patients).
ADVERSE REACTIONS
CEFTIBUTEN ORAL SUSPENSION
US CLINICAL TRIALS IN PEDIATRIC PATIENTS
(n = 772)
--------------------------------------------------------------------------------------------------------------------------------
Incidence Diarrhea* 4%
equal to or Vomiting 2%
greater than 1% Abdominal pain 2%
Loose stools 2%
--------------------------------------------------------------------------------------------------------------------------------
Incidence Agitation, Anorexia,
less than 1% but Dehydration, Diaper dermatitis,
greater than 0.1% Dizziness, Dyspepsia,
Fever, Headache, Hematuria,
Hyperkinesia, Insomnia,
Irritability, Nausea, Pruritus,
Rash, Rigors, Urticaria
-------------------------------------------------------------------------------------------------------------------------------
*NOTE: The incidence of diarrhea in pediatric patients =2 years old was 8%
(23/301) compared with 2% (9/471) in pediatric patients >2 years old.
LABORATORY VALUE CHANGES*
CEFTIBUTEN ORAL SUSPENSION
US CLINICAL TRIALS IN PEDIATRIC PATIENTS
---------------------------------------------------------------------------------------------------------------------------------
Incidence equal to or up Eosinophils 3%
greater than 1% up BUN 2%
down Hemoglobin 1%
up Platelets 1%
---------------------------------------------------------------------------------------------------------------------------
Incidence less than 1% but up ALT (SGPT)
greater than 0.1% up AST (SGOT)
up Alk phosphatase
up Bilirubin
up Creatinine
-----------------------------------------------------------------------------
* Changes in laboratory values with possible clinical significance regardless
of whether or not the investigator thought that the change was due to drug
toxicity.
IN POST-MARKETING EXPERIENCE:
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.
CEPHALOSPORIN-CLASS ADVERSE REACTIONS:
In addition to the adverse reactions listed 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 (see WARNINGS).
Several cephalosporins have been implicated in triggering seizures, particularly
in patients with renal impairment when the dosage was not reduced (see DOSAGE
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:
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.
DOSAGE AND ADMINISTRATION:
The recommended doses of PROCADAX Oral Suspension are presented in the table below.
PROCADAX ORAL SUSPENSION MUST BE ADMINISTERED AT LEAST 2 HOURS BEFORE OR 1 HOUR
AFTER A MEAL.
Type of infection (as qualified in Daily
the INDICATIONS AND USAGE Maximum Dose and
section of this labeling) Dose Frequency Duration
-----------------------------------------------------------------------------------------------------------------------------------------------
ADULTS (12 YEARS OF AGE AND OLDER): 400 mg 400 mg QD 10 days
Acute Bacterial Exacerbations of
Chronic Bronchitis due to H.
Influenzae (including (beta)-lactamase-
producing strains), M. Catarrhalis
(including
(beta)-lactamase-producing strains), or
Streptococcus Pneumoniae(penicillin-
susceptible strains only).
(See INDICATIONS AND USAGE--NOTE.)
Pharyngitis and tonsillitis due to
S. Pyogenes.
Acute Bacterial Otitis Media due to
H. Influenzae (including
(beta)-lactamase-producing strains),
M. Catarrhalis (including
(beta)-lactamase-producing strains),
or S. Pyogenes.
(See INDICATIONS AND USAGE--NOTE.)
-----------------------------------------------------------------------------------------------------------------------------------
PEDIATRIC PATIENTS: 400 mg 9 mg/kg QD 10 days
Pharyngitis and tonsillitis due to S.
Pyogenes.
Acute Bacterial Otitis Media due to
H. Influenzae (including (beta)-
lactamase-producing strains), and
M. Catarrhalis (including
(beta)-lactamase-producing
strains), or S. Pyogenes.
(See INDICATIONS AND USAGE--NOTE.)
------------------------------------------------------------------------------------------------------------------------------------------
CEFTIBUTEN ORAL SUSPENSION
PEDIATRIC DOSAGE CHART
CHILD'S WEIGHT 90 mg/5 mL 180 mg/5 mL
10 kg 22 lbs 1 tsp QD 1/2 tsp QD
20 kg 44 lbs 2 tsp QD 1 tsp QD
40 kg 88 lbs 4 tsp QD 2 tsp QD
PEDIATRIC PATIENTS WEIGHING MORE THAN 45 KG SHOULD RECEIVE THE MAXIMUM DAILY
DOSE OF 400 MG.
RENAL IMPAIRMENT:
PROCADAX Capsules and PROCADAX 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.
Creatinine Clearance Recommended Dosing
(mL/min) Schedules
>50 9 mg/kg or 400 mg Q24h
(normal dosing schedule)
30-49 4.5 mg/kg or 200 mg Q24h
5-29 2.25 mg/kg or 100 mg Q24h
HEMODIALYSIS PATIENTS:
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.
DIRECTIONS FOR MIXING PROCADAX ORAL SUSPENSION:
DIRECTIONS FOR MIXING PROCADAX ORAL SUSPENSION
---------------------------------------------------------------------------------------------------------------------------------------------
Final
Concentration Bottle Size Amount of Water Directions
30 mL Suspend in 28 mL First tap the bottle to
of water loosen powder. Then
add water in two portions,
shaking well after each
aliquot.
60 mL Suspend in 53 mL
90 mg per 5 mL of water
90 mL Suspend in 78 mL
of water
120 mL Suspend in 103 mL
of water
30 mL Suspend in 28 mL
180 mg per 5 mL of water
60 mL Suspend in 53 mL
of water
120 mL Suspend in 103 mL
of water
-----------------------------------------------------------------------------------------------------------------------------------------------------------------
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.
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