CEFPODOXIME PROXETIL
DESCRIPTION:
Cefpodoxime proxetil is an orally administered, extended spectrum, semi-
synthetic antibiotic of the cephalosporin class. The chemical name is (RS)-1-
(isopropoxycarbonyloxy)ethyl (+)-(6R,7R)-7-(2-(2-amino- 4-thiazolyl)-2-[(Z)-
methoxyimino]acetamido)-3-met hoxymethyl-8-oxo-5-thia-1-azabicyclo(4.2.0)oct- 2-
ene-2-carboxylate.
Its empirical formula is C21H27N5O9S2.
The molecular weight of cefpodoxime proxetil is 557,6.
Cefpodoxime proxetil is a prodrug; its active metabolite is cefpodoxime. All
doses of cefpodoxime proxetil in this insert are expressed in terms of the
active cefpodoxime moiety. The drug is supplied both as film-coated tablets and
as flavored granules for oral suspension.
CEPODEM Tablets contain cefpodoxime proxetil equivalent to 100 mg or 200 mg of
cefpodoxime activity and the following inactive ingredients:
carboxymethylcellulose calcium, carnauba wax, FD&C Yellow No. 6,
hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose hydrous, magnesium
stearate, propylene glycol, sodium lauryl sulfate and titanium dioxide. In
addition, the 100 mg film-coated tablets contain D&C Yellow No. 10 and the 200
mg film-coated tablets contain FD&C Red No. 40.
Each 5 mL of CEPODEM for Oral Suspension contains cefpodoxime proxetil equivalent
to 50 mg or 100 mg of cefpodoxime activity after constitution and the following
inactive ingredients: artificial flavorings, butylated hydroxy anisole (BHA),
carboxymethylcellulose sodium, carrageenan, citric acid, colloidal silicon
dioxide, croscarmellose sodium, hydroxypropylcellulose, lactose, lactose
hydrous, maltodextrin, microcrystalline cellulose, natural flavorings, propylene
glycol alginate, sodium citrate hydrous, sodium benzoate, starch, sucrose, and
vegetable oil.
ACTIONS/CLINICAL PHARMACOLOGY:
ABSORPTION AND EXCRETION:
Cefpodoxime proxetil is a prodrug that is absorbed from the gastrointestinal
tract and de- esterified to its active metabolite, cefpodoxime. Following oral
administration of 100 mg of cefpodoxime proxetil to fasting subjects,
approximately 50% of the administered cefpodoxime dose was absorbed
systemically. Over the recommended dosing range (100 to 400 mg), approximately
29 to 33% of the administered cefpodoxime dose was excreted unchanged in the
urine in 12 hours. There is minimal metabolism of cefpodoxime In Vivo.
EFFECTS OF FOOD:
The extent of absorption (mean AUC) and the mean peak plasma concentration
increased when film- coated tablets were administered with food. Following a 200
mg tablet dose taken with food, the AUC was 21 to 33% higher than under fasting
conditions, and the peak plasma concentration averaged 3.1 mcg/mL in fed
subjects versus 2.6 mcg/mL in fasted subjects. Time to peak concentration was
not significantly different between fed and fasted subjects.
When a 200 mg dose of the suspension was taken with food, the extent of
absorption (mean AUC) and mean peak plasma concentration in fed subjects were
not significantly different from fasted subjects, but the rate of absorption was
slower with food (48% increase in Tmax).
PHARMACOKINETICS OF CEFPODOXIME PROXETIL FILM- COATED TABLETS:
Over the recommended dosing range, (100 to 400 mg), the rate and extent of
cefpodoxime absorption exhibited dose-dependency; dose- normalized Cmax and AUC
decreased by up to 32% with increasing dose. Over the recommended dosing range,
the Tmax was approximately 2 to 3 hours and the T1/2 ranged from 2.09 to 2.84
hours. Mean Cmax was 1.4 mcg/mL for the 100 mg dose, 2.3 mcg/mL for the 200 mg
dose, and 3.9 mcg/mL for the 400 mg dose. In patients with normal renal
function, neither accumulation nor significant changes in other pharmacokinetic
parameters were noted following multiple oral doses of up to 400 mg Q 12 hours.
CEFPODOXIME PLASMA LEVELS (mcg/mL) IN FASTED ADULTS AFTER FILM-COATED TABLET
ADMINISTRATION (Single Dose)
DOSE TIME AFTER ORAL INGESTION
------------- ----------------------------------------------------------------------------------------------------------------------------
(cefpodoxime
equivalents) 1HR 2HR 3HR 4HR 6HR 8HR 12HR
100 mg 0.98 1.4 1.3 1.0 0.59 0.29 0.08
200 mg 1.5 2.2 2.2 1.8 1.2 0.62 0.18
400 mg 2.2 3.7 3.8 3.3 2.3 1.3 0.38
PHARMACOKINETICS OF CEFPODOXIME PROXETIL SUSPENSION:
In adult subjects, a 100 mg dose of oral suspension produced an average peak
cefpodoxime concentration of approximately 1.5 mcg/mL (range: 1.1 to 2.1
mcg/mL), which is equivalent to that reported following administration of the
100 mg tablet. Time to peak plasma concentration and area under the plasma
concentration-time curve (AUC) for the oral suspension were also equivalent to
those produced with film-coated tablets in adults following a 100 mg oral dose.
The pharmacokinetics of cefpodoxime were investigated in 29 patients aged 1 to
17 years. Each patient received a single, oral, 5 mg/kg dose of cefpodoxime oral
suspension. Plasma and urine samples were collected for 12 hours after dosing.
The plasma levels reported from this study are as follows:
CEFPODOXIME PLASMA LEVELS (mcg/mL) IN FASTED PATIENTS (1 to 17 YEARS OF AGE)
AFTER SUSPENSION ADMINISTRATION
DOSE TIME AFTER ORAL INGESTION
---------------- -------------------------------------------------------------------------------------------------------------------------
(cefpodoxime
equivalents) 1HR 2HR 3HR 4HR 6HR 8HR 12HR
5 mg/kg(1) 1.4 2.1 2.1 1.7 0.90 0.40 0.090
1. Dose did not exceed 200 mg.
DISTRIBUTION:
Protein binding of cefpodoxime ranges from 22 to 33% in serum and from 21 to 29%
in plasma.
Skin Blister:
Following multiple-dose administration every 12 hours for 5 days of 200 mg or
400 mg cefpodoxime proxetil, the mean maximum cefpodoxime concentration in skin
blister fluid averaged 1.6 and 2.8 mcg/mL, respectively. Skin blister fluid
cefpodoxime levels at 12 hours after dosing averaged 0.2 and 0.4 mcg/mL for the
200 mg and 400 mg multiple-dose regimens, respectively.
Tonsil Tissue:
Following a single, oral 100 mg cefpodoxime proxetil film-coated tablet, the
mean maximum cefpodoxime concentration in tonsil tissue averaged 0.24 mcg/g at 4
hours post-dosing and 0.09 mcg/g at 7 hours post-dosing. Equilibrium was
achieved between plasma and tonsil tissue within 4 hours of dosing. No detection
of cefpodoxime in tonsillar tissue was reported 12 hours after dosing. These
results demonstrated that concentrations of cefpodoxime exceeded the MIC90 of S.
Pyogenes for at least 7 hours after dosing of 100 mg of cefpodoxime proxetil.
Lung Tissue:
Following a single, oral 200 mg cefpodoxime proxetil film-coated tablet, the
mean maximum cefpodoxime concentration in lung tissue averaged 0.63 mcg/g at 3
hours post-dosing, 0.52 mcg/g at 6 hours post-dosing, and 0.19 mcg/g at 12 hours
post-dosing. The results of this study indicated that cefpodoxime penetrated
into lung tissue and produced sustained drug concentrations for at least 12
hours after dosing at levels that exceeded the MIC90 for S. Pneumoniae and H.
Influenzae.
CSF:
Adequate data on CSF levels of cefpodoxime are not available.
EFFECTS OF DECREASED RENAL FUNCTION:
Elimination of cefpodoxime is reduced in patients with moderate to severe renal
impairment (<50 mL/min creatinine clearance). (See PRECAUTIONS and DOSAGE AND
ADMINISTRATION.) In subjects with mild impairment of renal function (50 to 80
mL/min creatinine clearance), the average plasma half-life of cefpodoxime was
3.5 hours. In subjects with moderate (30 to 49 mL/min creatinine clearance) or
severe renal impairment (5 to 29 mL/min creatinine clearance), the half- life
increased to 5.9 and 9.8 hours, respectively. Approximately 23% of the
administered dose was cleared from the body during a standard 3-hour
hemodialysis procedure.
EFFECT OF HEPATIC IMPAIRMENT (CIRRHOSIS):
Absorption was somewhat diminished and elimination unchanged in patients with
cirrhosis. The mean cefpodoxime T1/2 and renal clearance in cirrhotic patients
were similar to those derived in studies of healthy subjects. Ascites did not
appear to affect values in cirrhotic subjects. No dosage adjustment is
recommended in this patient population.
PHARMACOKINETICS IN ELDERLY SUBJECTS:
Elderly subjects do not require dosage adjustments unless they have diminished
renal function. (See PRECAUTIONS.) In healthy geriatric subjects, cefpodoxime
half-life in plasma averaged 4.2 hours (vs 3.3 in younger subjects) and urinary
recovery averaged 21% after a 400 mg dose was administered every 12 hours. Other
pharmacokinetic parameters (Cmax, AUC, and Tmax) were unchanged relative to
those observed in healthy young subjects.
MICROBIOLOGY:
Cefpodoxime is active IN VITRO against a wide range of gram-positive and gram-
negative bacteria. Cefpodoxime 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
cefpodoxime.
The bactericidal activity of cefpodoxime results from its inhibition of cell
wall synthesis. Cefpodoxime is usually active against the following organisms In
Vitro and in clinical infections. (See INDICATIONS AND USAGE.)
Gram-Positive Aerobes:
Staphylococcus Aureus (including penicillinase- producing strains)
NOTE: Cefpodoxime is inactive against methicillin-resistant staphylococci.
Staphylococcus Saprophyticus
Streptococcus Pneumoniae
Streptococcus Pyogenes
Gram-Negative Aerobes:
Escherichia Coli
Haemophilus Influenzae (Including Beta-Lactamase- Producing Strains)
Klebsiella Pneumoniae
Moraxella (Branhamella) Catarrhalis
Neisseria Gonorrhoeae (Including Penicillinase- Producing Strains)
Proteus Mirabilis
The following In Vitro data are available; However, Their Clinical Significance
Is Unknown.
Cefpodoxime exhibits In Vitro minimum inhibitory concentrations of 2.0 mcg/mL or
less against most strains of the following organisms. The safety and
effectiveness of cefpodoxime proxetil in treating infections due to these
organisms have not been established in adequate and well- controlled trials.
Gram-Positive Aerobes:
Streptococcus Agalactiae
Streptococcus SPP. (GROUPS C, F, G)
NOTE: Cefpodoxime is inactive against most strains of Enterococcus.
Gram-Negative Aerobes:
Citrobacter Diversus
Haemophilus Parainfluenzae
Klebsiella Oxytoca
Proteus Vulgaris
Providencia Rettgeri
NOTE: Cefpodoxime is inactive against most strains of Pseudomonas and
Enterobacter.
Anaerobes
Peptostreptococcus Magnus
SUSCEPTIBILITY TESTING
DIFFUSION TECHNIQUES: Quantitative methods that require measurement of zone
diameters give the most precise estimate of the susceptibility of bacteria to
antimicrobial agents. One such standardized procedure1 recommended for use with
the 10 mcg cefpodoxime disk is the National Committee for Clinical Laboratory
Standards (NCCLS) approved procedure.
Interpretation involves correlation of the diameters obtained in the disk test
with the minimum inhibitory concentration (MIC) for cefpodoxime.
Reports from the laboratory giving results of the standardized single disk
susceptibility test using a 10 mcg cefpodoxime disk should be interpreted
according to the following criteria:
ZONE DIAMETER (MM) INTERPRETATION
------------------ ---------------------------------------------------------------------
(>/=)21 (S) Susceptible
18-20 (I) Intermediate
(=)17 (R) Resistant
A report of "Susceptible" indicates that the pathogen is likely to be inhibited
by generally achievable blood levels.
A report of "Intermediate" indicates that the result should be considered
equivocal, and, if the organism is not fully susceptible to alternative,
clinically feasible drugs, the test should be repeated. This category implies
clinical applicability in body sites where the drug is physiologically
concentrated or in situations where high dosage of drug can be used. This
category provides a buffer zone that prevents small uncontrolled technical
factors from causing major discrepancies in interpretation. 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 10
mcg disk should give the following zone diameters:
ORGANISM ZONE DIAMETER (MM)
-------------- ------------------------------------------------------------
Escherichia Coli ATCC 25922 23-28
Staphylococcus Aureus
ATCC 25923 19-25
Cephalosporin "class disks" should not be used to test for susceptibility to
cefpodoxime.
Dilution Technique: Use a standardized dilution method(REF. 2) (broth, agar,
microdilution) or equivalent with cefpodoxime susceptibility powder. The MIC
values should be interpreted according to the following criteria:
MIC (MCG/ML) INTERPRETATION
------------ ------------------------------------------------------
(=)2 (S) Susceptible
4 (I) Intermediate
(>/=)8 (R) Resistant
As with standard diffusion methods, dilution procedures require the use of
laboratory control organisms. Standard cefpodoxime susceptibility powder should
give the following MIC values:
ORGANISM MIC RANGE (MCG/ML)
---------------------------- -----------------------------------------------------------------
Escherichia Coli ATCC 25922 0.25-1
Staphylococcus Aureus
ATCC 29213 1-8
NOTE: Susceptibility testing by dilution methods requires the use of cefpodoxime
susceptibility powder.
Cefpodoxime proxetil granules for oral use should NOT be used for In Vitro
susceptibility tests.
INDICATIONS AND USAGE:
Cefpodoxime proxetil is indicated for the treatment of patients with mild to
moderate infections caused by susceptible strains of the designated
microorganisms in the conditions listed below. Recommended dosages, durations of
therapy, and applicable patient populations vary among these infections. Please
see DOSAGE AND ADMINISTRATION for specific recommendations.
LOWER RESPIRATORY TRACT
Community-acquired pneumonia caused by S. Pneumoniae or H. Influenzae (including
beta- lactamase-producing strains).
Acute Bacterial Exacerbation Of Chronic Bronchitis caused by S. Pneumoniae, H.
Influenzae (non-beta-lactamase-producing strains only), or M. Catarrhalis. Data
are insufficient at this time to establish efficacy in patients with acute
bacterial exacerbations of chronic bronchitis caused by beta-lactamase-producing
strains of H. Influenzae.
SEXUALLY TRANSMITTED DISEASES
ACUTE, UNCOMPLICATED URETHRAL AND CERVICAL GONORRHEA caused by Neisseria
gonorrhoeae (including penicillinase-producing strains)
ACUTE, UNCOMPLICATED ANO-RECTAL INFECTIONS IN WOMEN due to Neisseria Gonorrhoeae
(including penicillinase-producing strains).
NOTE: The efficacy of cefpodoxime in treating male patients with rectal
infections caused by N. Gonorrhoeae has not been established. Data do not
support the use of cefpodoxime proxetil in the treatment of pharyngeal
infections due to N. Gonorrhoeae in men or women.
SKIN AND SKIN STRUCTURES
UNCOMPLICATED SKIN AND SKIN STRUCTURE INFECTIONS caused by Staphylococcus Aureus
(including penicillinase-producing strains) or Streptococcus Pyogenes. Abscesses
should be surgically drained as clinically indicated.
NOTE: In clinical trials, successful treatment of uncomplicated skin and skin
structure infections was dose-related.
The effective therapeutic dose for skin infections was higher than those used in
other recommended indications. (See DOSAGE AND ADMINISTRATION.) UPPER
RESPIRATORY TRACT
ACUTE OTITIS MEDIA caused by Streptococcus Pneumoniae, Haemophilus Influenzae
(including beta-lactamase-producing strains), or Moraxella (Branhamella)
Catarrhalis.
Pharyngitis and/or Tonsillitis caused by Streptococcus Pyogenes
NOTE: Only penicillin by the intramuscular route of administration has been
shown to be effective in the prophylaxis of rheumatic fever. Cefpodoxime
proxetil is generally effective in the eradication of streptococci from the
oropharynx.
However, data establishing the efficacy of cefpodoxime proxetil for the
prophylaxis of subsequent rheumatic fever are not available.
URINARY TRACT
UNCOMPLICATED URINARY TRACT INFECTIONS (CYSTITIS) caused by Escherichia Coli,
Klebsiella Pneumoniae, Proteus Mirabilis, or Staphylococcus Saprophyticus.
NOTE: In considering the use of cefpodoxime proxetil in the treatment of
cystitis, cefpodoxime proxetil's lower bacterial eradication rates should be
weighed against the increased eradication rates and different safety profiles of
some other classes of approved agents. (See CLINICAL STUDIES section.)
Appropriate specimens for bacteriological examination should be obtained in
order to isolate and identify causative organisms and to determine their
susceptibility to cefpodoxime. Therapy may be instituted while awaiting the
results of these studies. Once these results become available, antimicrobial
therapy should be adjusted accordingly.
CONTRAINDICATIONS:
Cefpodoxime proxetil is contraindicated in patients with a known allergy to
cefpodoxime or to the cephalosporin group of antibiotics.
WARNINGS:
BEFORE THERAPY WITH CEFPODOXIME PROXETIL IS INSTITUTED, CAREFUL INQUIRY SHOULD
BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY
REACTIONS TO CEFPODOXIME, OTHER CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF
CEFPODOXIME IS TO BE ADMINISTERED 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 CEFPODOXIME PROXETIL
OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY
REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING
OXYGEN, INTRAVENOUS FLUIDS, INTRAVENOUS ANTIHISTAMINE, AND AIRWAY MANAGEMENT, AS
CLINICALLY INDICATED. PSEUDOMEMBRANOUS COLITIS HAS BEEN REPORTED WITH NEARLY ALL
ANTIBACTERIAL AGENTS, INCLUDING CEFPODOXIME, 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 ANTI
BACTERIAL AGENTS.
EXTREME CAUTION SHOULD BE OBSERVED WHEN USING THIS PRODUCT IN PATIENTS AT
INCREASED RISK FOR ANTIBIOTIC-INDUCED, PSEUDOMEMBRANOUS COLITIS BECAUSE OF
EXPOSURE TO INSTITUTIONAL SETTINGS, SUCH AS NURSING HOMES OR HOSPITALS WITH
ENDEMIC C. DIFFICILE.
Treatment with broad-spectrum antibiotics, including cefpodoxime proxetil,
alters the normal flora of the colon and may permit overgrowth of clostridia.
Studies indicate a toxin produced by Clostridium Difficile is the primary cause
of "antibiotic-associated colitis".
After the diagnosis of pseudomembranous colitis has been established,
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 oral antibacterial drug effective
against C. Difficile.
A concerted effort to monitor for C. Difficile in cefpodoxime treated patients
with diarrhea was undertaken because of an increased incidence of diarrhea
associated with C. Difficile in early trials in normal subjects. C. Difficile
organisms or toxin was reported in 10% of the cefpodoxime- treated adult
patients with diarrhea; however, no specific diagnosis of pseudomembranous
colitis was made in these patients.
In post-marketing experience outside the United States, reports of
pseudomembranous colitis associated with the use of cefpodoxime proxetil have
been received.
PRECAUTIONS:
GENERAL
In patients with transient or persistent reduction in urinary output due to
renal insufficiency, the total daily dose of cefpodoxime proxetil should be
reduced because high and prolonged serum antibiotic concentrations can occur in
such individuals following usual doses. Cefpodoxime, like other cephalosporins,
should be administered with caution to patients receiving concurrent treatment
with potent diuretics. (See DOSAGE AND ADMINISTRATION).
As with other antibiotics, prolonged use of cefpodoxime proxetil may result in
overgrowth of non-susceptible organisms. Repeated evaluation of the patient's
condition is essential. If superinfection occurs during therapy, appropriate
measures should be taken.
DRUG INTERACTIONS
ANTACIDS: Concomitant administration of high doses of antacids (sodium
bicarbonate and aluminum hydroxide) or H2 blockers reduces peak plasma levels by
24% to 42% and the extent of absorption by 27% to 32%, respectively. The rate of
absorption is not altered by these concomitant medications. Oral anti-
cholinergics (e.g., propantheline) delay peak plasma levels (47% increase in
Tmax), but do not affect the extent of absorption (AUC).
PROBENECID: As with other beta-lactam antibiotics, renal excretion of
cefpodoxime was inhibited by probenecid and resulted in an approximately 31%
increase in AUC and 20% increase in peak cefpodoxime plasma levels.
NEPHROTOXIC DRUGS: Although nephrotoxicity has not been noted when cefpodoxime
proxetil was given alone, close monitoring of renal function is advised when
cefpodoxime proxetil is administered concomitantly with compounds of known
nephrotoxic potential.
DRUG/LABORATORY TEST INTERACTIONS
Cephalosporins, including cefpodoxime proxetil, are known to occasionally induce
a positive direct Coombs' test.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Long-term animal carcinogenesis studies of cefpodoxime proxetil have not been
performed. Mutagenesis studies of cefpodoxime, including the Ames test both with
and without metabolic activation, the chromosome aberration test, the
unscheduled DNA synthesis assay, mitotic recombination and gene conversion, the
forward gene mutation assay and the in vivo micronucleus test, were all
negative. No untoward effects on fertility or reproduction were noted when 100
mg/kg/day or less (2 times the human dose based on mg/m(squared)) was
administered orally to rats.
PREGNANCY-TERATOGENIC EFFECTS:
Pregnancy Category B
Cefpodoxime proxetil was neither teratogenic nor embryocidal when administered
to rats during organogenesis at doses up to 100 mg/kg/day (2 times the human
dose based on mg/m(squared)) or to rabbits at doses up to 30 mg/kg/day (1-2
times the human dose based on mg/m(squared)).
There are, however, no adequate and well- controlled studies of cefpodoxime
proxetil use 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:
Cefpodoxime proxetil has not been studied for use during labor and delivery.
Treatment should only be given if clearly needed.
NURSING MOTHERS:
Cefpodoxime is excreted in human milk. In a study of 3 lactating women, levels
of cefpodoxime in human milk were 0%, 2% and 6% of concomitant serum levels at 4
hours following a 200 mg oral dose of cefpodoxime proxetil. At 6 hours post-
dosing, levels were 0%, 9% and 16% of concomitant serum levels. Because of the
potential for serious reactions in nursing infants, a decision should be made
whether to discontinue nursing or to discontinue the drug, taking into account
the importance of the drug to the mother.
PEDIATRIC USE
Safety and efficacy in infants less than 5 months of age have not been
established.
GERIATRIC USE
Of the 3338 patients in multiple-dose clinical studies of cefpodoxime proxetil
film-coated tablets, 521 (16%) were 65 and over, while 214 (6%) were 75 and
over. No overall differences in effectiveness or safety were observed between
the elderly and younger patients. In healthy geriatric subjects with normal
renal function, cefpodoxime half-life in plasma averaged 4.2 hours and urinary
recovery averaged 21% after a 400 mg dose was given every 12 hours for 15 days.
Other pharmacokinetic parameters were unchanged relative to those observed in
healthy younger subjects.
Dose adjustment in elderly patients with normal renal function is not necessary.
DRUG INTERACTIONS:
ANTACIDS: Concomitant administration of high doses of antacids (sodium
bicarbonate and aluminum hydroxide) or H2 blockers reduces peak plasma levels by
24% to 42% and the extent of absorption by 27% to 32%, respectively. The rate of
absorption is not altered by these concomitant medications. Oral anti-
cholinergics (e.g., propantheline) delay peak plasma levels (47% increase in
Tmax), but do not affect the extent of absorption (AUC).
PROBENECID: As with other beta-lactam antibiotics, renal excretion of
cefpodoxime was inhibited by probenecid and resulted in an approximately 31%
increase in AUC and 20% increase in peak cefpodoxime plasma levels.
NEPHROTOXIC DRUGS: Although nephrotoxicity has not been noted when cefpodoxime
proxetil was given alone, close monitoring of renal function is advised when
cefpodoxime proxetil is administered concomitantly with compounds of known
nephrotoxic potential.
(See also PRECAUTIONS)
ADVERSE REACTIONS:
CLINICAL TRIALS:
FILM-COATED TABLETS (MULTIPLE DOSE):
In clinical trials using multiple doses of cefpodoxime proxetil film-coated
tablets, 3338 patients were treated with the recommended dosages of cefpodoxime
(100 to 400 mg Q 12 hours). There were no deaths or permanent disabilities
thought related to drug toxicity. Eighty-one (2.4%) patients discontinued
medication due to adverse events thought possibly- or probably-related to drug
toxicity. Sixty-six (66%) of the 100 patients who discontinued therapy (whether
thought related to drug therapy or not) did so because of gastrointestinal
disturbances, usually diarrhea. The percentage of cefpodoxime proxetil-treated
patients who discontinued study drug because of adverse events was significantly
greater at a dose of 800 mg daily than at a dose of 400 mg daily or at a dose of
200 mg daily. Adverse events thought possibly- or probably-related to
cefpodoxime in multiple dose clinical trials (N=3338 cefpodoxime-treated
patients) were:
INCIDENCE GREATER THAN 1%:
Diarrhea 7.2%
Diarrhea or loose stools were dose related: decreasing from 10.6% of patients
receiving 800 mg per day to 5.9% for those receiving 200 mg per day. Of patients
with diarrhea, 10% had C. DIFFICILE organism or toxin in the stool. (See
WARNINGS.)
Nausea 3.8%
Vaginal Fungal Infections 3.1%
Abdominal Pain 1.6%
Rash 1.4%
Headache 1.1%
Vomiting 1.1%
INCIDENCE LESS THAN 1%:
Cardiovascular: Chest pain, hypotension.
Dermatologic: Fungal skin infection, skin scaling/peeling.
Endocrine: Menstrual irregularity.
Genital: Pruritus.
Gastrointestinal: Flatulence, decreased salivation, candidiasis,
pseudomembranous colitis.
Hypersensitivity: Anaphylactic shock.
Metabolic: Decreased appetite.
Miscellaneous: Malaise, fever.
Central Nervous System: Dizziness, fatigue, anxiety, insomnia, flushing,
nightmares, weakness.
Respiratory: Cough, epistaxis.
Special Senses: Taste alteration, eye itching, tinnitus.
GRANULES FOR ORAL SUSPENSION (MULTIPLE DOSE):
In clinical trials using multiple doses of cefpodoxime proxetil granules for
oral suspension, 1586 pediatric patients (90% of whom were less than 12 years of
age) were treated with the recommended dosages of cefpodoxime (10 mg/kg/day Q 24
hours or divided Q 12 hours to a maximum equivalent adult dose). There were no
deaths or permanent disabilities in any of the patients in these studies.
Twenty-three patients (1.5%) discontinued medication due to adverse events
thought possibly- or probably-related to study drug. Primarily, these
discontinuations were for gastrointestinal disturbances, usually diarrhea,
vomiting, or diaper area rashes.
ADVERSE EVENTS thought possibly- or probably- related to cefpodoxime proxetil
for oral suspension in multiple dose clinical trials (N=1586 cefpodoxime treated
patients) were:
INCIDENCE GREATER THAN 1%:
Diarrhea 5.7%
The incidence of diarrhea in infants and toddlers (age 6 months to 2 years) was
15.4%.
Diaper Rash/Fungal Skin Rash 2.3%
The incidence of diaper rash in infants and toddlers was 12.1%
Other skin rashes 1.8%
Vomiting 2.1%
INCIDENCE LESS THAN 1%:
Central Nervous System: Headache, irritability.
Dermatologic: Exacerbation of acne, exfoliative dermatitis.
Genital: Pruritus or vaginitis.
Gastrointestinal: Nausea, abdominal pain, candidiasis, decreased salivation,
pseudomembranous colitis.
Metabolic: Decreased appetite.
Miscellaneous: Fever.
Psychiatric: Hyperactivity/nervousness.
Respiratory: Epistaxis, rhinitis.
FILM-COATED TABLETS (SINGLE DOSE):
In clinical trials using a single dose of cefpodoxime proxetil film-coated
tablets, 509 patients were treated with the recommended dosage of cefpodoxime
(200 mg). There were no deaths or permanent disabilities thought related to drug
toxicity in these studies.
ADVERSE EVENTS thought possibly- or probably- related to cefpodoxime in single
dose clinical trials conducted in the United States were:
INCIDENCE GREATER THAN 1%:
Nausea 1.4%
Diarrhea 1.2%
INCIDENCE LESS THAN 1%:
Central Nervous System: Dizziness, headache, syncope.
Dermatologic: Rash.
Genital: Vaginitis.
Gastrointestinal: Abdominal pain.
Psychiatric: Anxiety.
LABORATORY CHANGES (ADULT PATIENTS):
Significant laboratory changes that have been reported in adult patients in
clinical trials of cefpodoxime proxetil, without regard to drug relationship,
were:
Hepatic: Transient increases in AST (SGOT), ALT (SGPT), GGT, alkaline
phosphatase, bilirubin, and LDH.
Hematologic: Eosinophilia, leukocytosis, lymphocytosis, granulocytosis,
basophilia, monocytosis, thrombocytosis, decreased hemoglobin, leukopenia,
neutropenia, lymphocytopenia, thrombocytopenia, positive Coombs' test, and
prolonged PT, and PTT.
Serum Chemistry: Increases in glucose, decreases in glucose, decreases in serum
albumin, decreases in serum total protein.
Renal: Increases in BUN and creatinine.
Most of these abnormalities were transient and not clinically significant.
LABORATORY CHANGES (PEDIATRIC PATIENTS):
Significant laboratory changes that have been reported in pediatric patients in
clinical trials of cefpodoxime proxetil, without regard to drug relationship,
were:
Hematologic: Eosinophilia, decreased hemoglobin, decreased hematocrit.
Hepatic: Transiently increased ALT (SGPT)
Most of these abnormalities were transient and not clinically significant.
POST-MARKETING EXPERIENCE:
The following serious adverse experiences have been reported: allergic reactions
including Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema
multiforme and serum sickness-like reactions, pseudomembranous colitis, bloody
diarrhea with abdominal pain, ulcerative colitis, rectorrhagia with hypotension,
anaphylactic shock, acute liver injury, in utero exposure with miscarriage,
purpuric nephritis, pulmonary infiltrate with eosinophilia, and eyelid
dermatitis.
One death was attributed to pseudomembranous colitis and disseminated
intravascular coagulation.
CEPHALOSPORIN CLASS LABELING:
In addition to the adverse reactions listed above which have been observed in
patients treated with cefpodoxime proxetil, the following adverse reactions and
altered laboratory tests have been reported for cephalosporin class antibiotics:
ADVERSE REACTIONS AND ABNORMAL LABORATORY TESTS: Renal dysfunction, toxic
nephropathy, hepatic dysfunction including cholestasis, aplastic anemia,
hemolytic anemia, serum sickness-like reaction, hemorrhage, agranulocytosis, and
pancytopenia.
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:
In acute rodent toxicity studies, a single 5 g/kg oral dose produced no adverse
effects.
In the event of serious toxic reaction from overdosage, hemodialysis or
peritoneal dialysis may aid in the removal of cefpodoxime from the body,
particularly if renal function is compromised.
The toxic symptoms following an overdose of (beta)-lactam antibiotics may
include nausea, vomiting, epigastric distress, and diarrhea.
DOSAGE AND ADMINISTRATION:
(SEE INDICATIONS AND USAGE FOR INDICATED PATHOGENS.)
FILM-COATED TABLETS:
CEPODEM Tablets should be administered orally with food to enhance absorption.
(See CLINICAL PHARMACOLOGY.)
The recommended dosages, durations of treatment, and applicable patient
population are as described in the following chart:
ADULTS (AGE 13 YEARS AND OLDER):
-------------------------------------------------------------------------------------------------------------------------------------------------
TYPE OF INFECTION DAILY DOSE DOSE FREQUENCY DURATION
DOSE
----------------------------- -------------- -------------------- ---------------------------------------------------------------------------
Acute community-acquired 400 mg 200 mg Q 12 hours 14 days
pneumonia
Acute bacterial exacerbations 400 mg 200 mg Q 12 hours 10 days
of chronic bronchitis
Uncomplicated gonorrhea 200 mg single dose
(men and women) and rectal
gonococcal infections (women)
Skin and skin structure 800 mg 400 mg Q 12 hours 7 to 14
days
Pharyngitis and/or tonsillitis 200 mg 100 mg Q 12 hours 5 to 10
days
Uncomplicated urinary tract 200 mg 100 mg Q 12 hours 7 days
infection
GRANULES FOR ORAL SUSPENSION:
CEPODEM for Oral Suspension may be given without regard to food. The recommended
dosages, durations of treatment, and applicable patient populations are as
described in the following chart:
ADULTS (AGE 13 YEARS AND OLDER):
TYPE OF INFECTION TOTAL DAILY DOSE FREQUENCY DURATION
DOSE
----------------------------- ------------- ------------------- --------------------------------------------------------------------------------
Acute community-acquired 400 mg 200 mg Q 12 hours 14 days
pneumonia
Uncomplicated gonorrhea 200 mg single dose
(men and women) and rectal
gonococcal infections (women)
Skin and skin structure 800 mg 400 mg Q 12 hours 7 to 14
days
Pharyngitis and/or tonsillitis 200 mg 100 mg Q 12 hours 5 to 10
days
Uncomplicated urinary tract 200 mg 100 mg Q 12 hours 7 days
infection
CHILDREN (AGE 5 MONTHS THROUGH 12 YEARS):
TYPE OF INFECTION TOTAL DAILY DOSE FREQUENCY DURATION
DOSE
----------------------------- --------------- ------------------- ----------------------------------------------------------------------------------------
Acute otitis media 10 mg/kg/day 10 mg/kg Q 24 h 10 days
(Max 400 mg/day) (Max 400 mg/dose)
or
5 mg/kg Q 12 h
(Max 200 mg/dose)
Pharyngitis and/or tonsillitis 10 mg/kg/day 5 mg/kg/dose Q 12 h 5 to 10
(Max 200 mg/day) (Max 100 mg/dose) days
PATIENTS WITH RENAL DYSFUNCTION:
For patients with severe renal impairment (<30 mL/min creatinine clearance), the
dosing intervals should be increased to Q 24 hours. In patients maintained on
hemodialysis, the dose frequency should be 3 times/week after hemodialysis.
When only the serum creatinine level is available, the following formula (based
on sex, weight, and age of the patient) may be used to estimate creatinine
clearance (mL/min). For this estimate to be valid, the serum creatinine level
should represent a steady state of renal function.
WEIGHT (KG) X (140-AGE)
MALES: -----------------------
(mL/min) 72 x serum creatinine (mg/100 mL)
FEMALES: 0.85 x above value
(mL/min)
PATIENTS WITH CIRRHOSIS:
Cefpodoxime pharmacokinetics in cirrhotic patients (with or without ascites) are
similar to those in healthy subjects.
Dose adjustment is not necessary in this population.
PREPARATION OF SUSPENSION:
Constitution Directions For Oral Suspension
------------------------------------------------------------------------------
Bottle Final
Size Concentration Directions
--------- --------------- ---------------------------------------------------------------------------------------------------------------------
100 mL 50 mg per 5 mL Suspend in a total of 58 mL of water.
Method: First, tap the bottle to loosen
granules.
Then add the water in two portions, shaking
well after each aliquot of water.
100 mL 100 mg per 5 mL Suspend in a total of 57 mL of water.
Method: First, tap the bottle to loosen
granules.
Then add the water in two portions, shaking
well after each aliquot of water.
After mixing, the suspension should be stored in a refrigerator, 2 deg to 8 deg
C (36 deg to 46 deg F). Shake well before using. Keep container tightly closed.
The mixture may be used for 14 days. Discard unused portion after 14 days.
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