To reduce the development of drug-resistant bacteria and maintain
the effectiveness of AUGMENTIN (amoxicillin/clavulanate potassium) and other
antibacterial drugs, AUGMENTIN should be used only to treat or prevent
infections that are proven or strongly suspected to be caused by bacteria.
Description
AUGMENTIN is an oral antibacterial combination consisting of the
semisynthetic antibiotic amoxicillin and the β-lactamase inhibitor, clavulanate
potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of
ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid.
The amoxicillin molecular formula is C16H19N3O5S•3H2O, and the molecular weight is 419.46. Chemically, amoxicillin
is (2S,5R,6R)-6-[(R)-(-)-2-Amino-2-(p-hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic
acid trihydrate and may be represented structurally as:
Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a β-lactam structurally
related to the penicillins and possesses the ability to inactivate a wide
variety of β-lactamases by blocking the active sites of these enzymes.
Clavulanic acid is particularly active against the clinically important
plasmid-mediated β-lactamases frequently responsible for transferred drug
resistance to penicillins and cephalosporins. The clavulanate potassium
molecular formula is C8H8KNO5, and the molecular weight is 237.25. Chemically, clavulanate
potassium is potassium (Z)-(2R,
5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate,
and may be represented structurally as:
Each tablet of AUGMENTIN contains 0.63 mEq potassium.
Clinical Pharmacology
Amoxicillin and clavulanate potassium are well absorbed from the
gastrointestinal tract after oral administration of AUGMENTIN. Dosing in the
fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin.
While AUGMENTIN can be given without regard to meals, absorption of clavulanate
potassium when taken with food is greater relative to the fasted state. In 1
study, the relative bioavailability of clavulanate was reduced when AUGMENTIN
was dosed at 30 and 150 minutes after the start of a high-fat breakfast. The
safety and efficacy of AUGMENTIN have been established in clinical trials where
AUGMENTIN was taken without regard to meals.
Meana amoxicillin and clavulanate potassium
pharmacokinetic parameters are shown in the table below:
Doseb and regimen
AUC0-24 (mcg•hr/mL)
Cmax (mcg/mL)
amoxicillin/ clavulanate potassium
amoxicillin (±S.D.)
clavulanate potassium
(±S.D.)
amoxicillin (±S.D.)
clavulanate potassium
(±S.D.)
250/125 mg q8h
26.7 ± 4.56
12.6 ± 3.25
3.3 ± 1.12
1.5 ± 0.70
500/125 mg q12h
33.4 ± 6.76
8.6 ± 1.95
6.5 ± 1.41
1.8 ± 0.61
500/125 mg q8h
53.4 ± 8.87
15.7 ± 3.86
7.2 ± 2.26
2.4 ± 0.83
875/125 mg q12h
53.5 ± 12.31
10.2 ± 3.04
11.6 ± 2.78
2.2 ±
0.99
a Mean values of 14 normal volunteers (n = 15 for
clavulanate potassium in the low-dose regimens). Peak concentrations occurred
approximately 1.5 hours after the dose.
b Administered at the start of a light meal.
Amoxicillin serum concentrations achieved with AUGMENTIN are similar to those
produced by the oral administration of equivalent doses of amoxicillin alone.
The half-life of amoxicillin after the oral administration of AUGMENTIN is 1.3
hours and that of clavulanic acid is 1.0 hour.
Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of
the clavulanic acid are excreted unchanged in urine during the first 6 hours
after administration of a single 250-mg or 500-mg tablet of AUGMENTIN.
Concurrent administration of probenecid delays amoxicillin excretion but does
not delay renal excretion of clavulanic acid.
Neither component in AUGMENTIN is highly protein-bound; clavulanic acid has
been found to be approximately 25% bound to human serum and amoxicillin
approximately 18% bound.
Amoxicillin diffuses readily into most body tissues and fluids with the
exception of the brain and spinal fluid. The results of experiments involving
the administration of clavulanic acid to animals suggest that this compound,
like amoxicillin, is well distributed in body tissues. Microbiology Amoxicillin is a semisynthetic antibiotic with a broad spectrum
of bactericidal activity against many gram-positive and gram-negative
microorganisms. Amoxicillin is, however, susceptible to degradation by
β-lactamases, and therefore, the spectrum of activity does not include organisms
which produce these enzymes. Clavulanic acid is a β-lactam, structurally related
to the penicillins, which possesses the ability to inactivate a wide range of
β-lactamase enzymes commonly found in microorganisms resistant to penicillins
and cephalosporins. In particular, it has good activity against the clinically
important plasmid-mediated β-lactamases frequently responsible for transferred
drug resistance.
The formulation of amoxicillin and clavulanic acid in AUGMENTIN protects
amoxicillin from degradation by β-lactamase enzymes and effectively extends the
antibiotic spectrum of amoxicillin to include many bacteria normally resistant
to amoxicillin and other β-lactam antibiotics. Thus, AUGMENTIN possesses the
properties of a broad-spectrum antibiotic and a β-lactamase inhibitor.
Amoxicillin/clavulanic acid has been shown to be active against most strains
of the following microorganisms, both in vitro and in clinical infections as
described in INDICATIONS AND USAGE. Gram-Positive
Aerobes
Staphylococcus aureus (β-lactamase and
non−β-lactamase−producing)c
c Staphylococci which are resistant to
methicillin/oxacillin must be considered resistant to amoxicillin/clavulanic
acid. Gram-Negative
Aerobes
Enterobacter species (Although most
strains of Enterobacter species are resistant in
vitro, clinical efficacy has been demonstrated with AUGMENTIN in urinary tract
infections caused by these organisms.)
Escherichia coli (β-lactamase and
non−β-lactamase−producing)
Haemophilus influenzae (β-lactamase and
non−β-lactamase−producing)
Klebsiella species (All known strains are
β-lactamase−producing.)
Moraxella catarrhalis (β-lactamase and
non−β-lactamase−producing)
The following in vitro data are available, but their clinical significance is unknown.
Amoxicillin/clavulanic acid exhibits in vitro minimal inhibitory
concentrations (MICs) of 2 mcg/mL or less against most (≥ 90%) strains of Streptococcus pneumoniae
d; MICs of
0.06 mcg/mL or less against most (≥ 90%) strains of Neisseria gonorrhoeae ; MICs of 4 mcg/mL or less against
most (≥ 90%) strains of staphylococci and anaerobic bacteria; and MICs of
8 mcg/mL or less against most (≥ 90%) strains of other uled organisms.
However, with the exception of organisms shown to respond to amoxicillin alone,
the safety and effectiveness of amoxicillin/clavulanic acid in treating clinical
infections due to these microorganisms have not been established in adequate and
well-controlled clinical trials.
d Because amoxicillin has greater in vitro activity
against S. pneumoniae than does ampicillin or
penicillin, the majority of S. pneumoniae strains
with intermediate susceptibility to ampicillin or penicillin are fully
susceptible to amoxicillin. Gram-Positive
Aerobes
Enterococcus faecalis
e
Staphylococcus epidermidis (β-lactamase and
non−β-lactamase−producing)
Staphylococcus saprophyticus (β-lactamase and
non−β-lactamase−producing)
Streptococcus pneumoniae
e f
Streptococcus pyogenes
e f
viridans group Streptococcus
e
f Gram-Negative
Aerobes
Eikenella corrodens (β-lactamase and
non−β-lactamase−producing)
Neisseria gonorrhoeae
e
(β-lactamase and non–β-lactamase–producing)
Proteus mirabilis
e
(β-lactamase and non–β-lactamase–producing) Anaerobic
Bacteria
Bacteroides species, including Bacteroides fragilis (β-lactamase and
non–β-lactamase–producing)
Fusobacterium species (β-lactamase and
non–β-lactamase–producing)
Peptostreptococcus speciesf
e Adequate and well-controlled clinical trials have
established the effectiveness of amoxicillin alone in treating certain clinical
infections due to these organisms.
f These are non–β-lactamase−producing organisms, and
therefore, are susceptible to amoxicillin alone. Susceptibility TestingDilution
Techniques
Quantitative methods are used to determine antimicrobial 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 method1
(broth or agar) or equivalent with standardized inoculum concentrations and
standardized concentrations of amoxicillin/clavulanate potassium powder.
The recommended dilution pattern utilizes a constant amoxicillin/clavulanate
potassium ratio of 2 to 1 in all tubes with varying amounts of amoxicillin. MICs
are expressed in terms of the amoxicillin concentration in the presence of
clavulanic acid at a constant 2 parts amoxicillin to 1 part clavulanic acid. The
MIC values should be interpreted according to the following criteria:
RECOMMENDED RANGES FOR AMOXICILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING
For Gram-Negative Enteric Aerobes:
MIC
(mcg/mL)
Interpretation
≤ 8/4
Susceptible (S)
16/8
Intermediate (I)
≥ 32/16
Resistant
(R)
For Staphylococcus
g and Haemophilus species:
MIC
(mcg/mL)
Interpretation
≤ 4/2
Susceptible (S)
≥ 8/4
Resistant
(R)
g Staphylococci which are susceptible to
amoxicillin/clavulanic acid but resistant to methicillin/oxacillin must be
considered as resistant.
For S. pneumoniae from
non-meningitis sources:
Isolates should be tested using amoxicillin/clavulanic acid and the following
criteria should be used:
MIC
(mcg/mL)
Interpretation
≤ 2/1
Susceptible (S)
4/2
Intermediate (I)
≥ 8/4
Resistant
(R)
NOTE: These interpretive criteria are based on the
recommended doses for respiratory tract infections.
A report of “Susceptible” indicates that the pathogen is likely to be
inhibited if the antimicrobial compound in the blood reaches the concentration
usually achievable. A report of “Intermediate” indicates that the result should
be considered equivocal, and, if the microorganism is not fully susceptible to
alternative, clinically feasible drugs, the test should be repeated. This
category implies possible clinical applicability in body sites where the drug is
physiologically concentrated or in situations where high dosage of drug can be
used. This category also provides a buffer zone, which prevents small
uncontrolled technical factors from causing major discrepancies in
interpretation. A report of “Resistant” indicates that the pathogen is not
likely to be inhibited if the antimicrobial compound in the blood reaches the
concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory
control microorganisms to control the technical aspects of the laboratory
procedures. Standard amoxicillin/clavulanate potassium powder should provide the
following MIC values:
Microorganism
MIC Range (mcg/mL)h
Escherichia coli ATCC
25922
2 to 8
Escherichia coli ATCC
35218
4 to 16
Enterococcus faecalis ATCC
29212
0.25 to 1.0
Haemophilus influenzae ATCC
49247
2 to 16
Staphylococcus aureus ATCC
29213
0.12 to 0.5
Streptococcus
pneumoniae ATCC 49619
0.03 to 0.12
h Expressed as concentration of amoxicillin in the
presence of clavulanic acid at a constant 2 parts amoxicillin to 1 part
clavulanic acid. Diffusion
Techniques
Quantitative methods that require measurement of zone diameters
also provide reproducible estimates of the susceptibility of bacteria to
antimicrobial compounds. One such standardized procedure2
requires the use of standardized inoculum concentrations. This procedure uses
paper disks impregnated with 30 mcg of amoxicillin/clavulanate potassium (20 mcg
amoxicillin plus 10 mcg clavulanate potassium) to test the susceptibility of
microorganisms to amoxicillin/clavulanic acid.
Reports from the laboratory providing results of the standard single-disk
susceptibility test with a 30-mcg amoxicillin/clavulanate acid (20 mcg
amoxicillin plus 10 mcg clavulanate potassium) disk should be interpreted
according to the following criteria: RECOMMENDED RANGES FOR
AMOXICILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING
For Staphylococcus
i species and H. influenzae
j:
Zone Diameter
(mm)
Interpretation
≥ 20
Susceptible (S)
≤ 19
Resistant
(R)
For Other Organisms Except S.
pneumoniae
k and N.
gonorrhoeae
l:
Zone Diameter
(mm)
Interpretation
≥ 18
Susceptible (S)
14 to 17
Intermediate (I)
≤ 13
Resistant
(R)
i Staphylococci which are resistant to
methicillin/oxacillin must be considered as resistant to amoxicillin/clavulanic
acid.
j A broth microdilution method should be used for
testing H. influenzae. Beta-lactamase−negative,
ampicillin-resistant strains must be considered resistant to
amoxicillin/clavulanic acid.
k Susceptibility of S.
pneumoniae should be determined using a 1-mcg oxacillin disk. Isolates
with oxacillin zone sizes of ≥2 0 mm are susceptible to amoxicillin/clavulanic
acid. An amoxicillin/clavulanic acid MIC should be determined on isolates of
S. pneumoniae with oxacillin zone sizes of ≤1
9 mm.
l A broth microdilution method should be used for
testing N. gonorrhoeae and interpreted according to
penicillin breakpoints.
Interpretation should be as stated above for results using dilution
techniques. Interpretation involves correlation of the diameter obtained in the
disk test with the MIC for amoxicillin/clavulanic acid.
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-mcg
amoxicillin/clavulanate potassium (20-mcg amoxicillin plus 10-mcg clavulanate
potassium) disk should provide the following zone diameters in these laboratory
quality control strains:
Microorganism
Zone Diameter
(mm)
Escherichia coli ATCC
25922
19 to 25
Escherichia coli ATCC
35218
18 to 22
Staphylococcus
aureus ATCC 25923
28 to 36
Indications And Usage
AUGMENTIN is indicated in the treatment of infections caused by
susceptible strains of the designated organisms in the conditions uled
below: Lower Respiratory Tract Infections − caused by β-lactamase−producing strains of H. influenzae and M.
catarrhalis. Otitis Media − caused by β-lactamase−producing strains of H. influenzae and M.
catarrhalis. Sinusitis − caused by β-lactamase−producing strains of H. influenzae and M.
catarrhalis. Skin and Skin Structure Infections − caused by β-lactamase−producing strains of S. aureus, E. coli, and Klebsiella spp. Urinary Tract Infections − caused by β-lactamase−producing strains of E. coli, Klebsiella spp., and
Enterobacter spp.
While AUGMENTIN is indicated only for the conditions uled above, infections
caused by ampicillin-susceptible organisms are also amenable to treatment with
AUGMENTIN due to its amoxicillin content; therefore, mixed infections caused by
ampicillin-susceptible organisms and β-lactamase−producing organisms susceptible
to AUGMENTIN should not require the addition of another antibiotic. Because
amoxicillin has greater in vitro activity against S.
pneumoniae than does ampicillin or penicillin, the majority of S. pneumoniae strains with intermediate susceptibility to
ampicillin or penicillin are fully susceptible to amoxicillin and AUGMENTIN.
(See Microbiology.)
To reduce the development of drug-resistant bacteria and maintain the
effectiveness of AUGMENTIN and other antibacterial drugs, AUGMENTIN should be
used only to treat or prevent infections that are proven or strongly suspected
to be caused by susceptible bacteria. When culture and susceptibility
information are available, they should be considered in selecting or modifying
antibacterial therapy. In the absence of such data, local epidemiology and
susceptibility patterns may contribute to the empiric selection of therapy.
Bacteriological studies, to determine the causative organisms and their
susceptibility to AUGMENTIN, should be performed together with any indicated
surgical procedures.
Contraindications
AUGMENTIN is contraindicated in patients with a history of
allergic reactions to any penicillin. It is also contraindicated in patients
with a previous history of cholestatic jaundice/hepatic dysfunction associated
with AUGMENTIN.
Warnings
SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC)
REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS
ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN
HYPERSENSITIVITY AND/OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE
HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY
WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE
INITIATING THERAPY WITH AUGMENTIN, CAREFUL INQUIRY SHOULD BE MADE CONCERNING
PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER
ALLERGENS. IF AN ALLERGIC REACTION OCCURS, AUGMENTIN SHOULD BE DISCONTINUED AND
THE APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC
REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN,
INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO
BE ADMINISTERED AS INDICATED.
Clostridium difficile associated diarrhea (CDAD)
has been reported with use of nearly all antibacterial agents, including
AUGMENTIN, and may range in severity from mild diarrhea to fatal colitis.
Treatment with antibacterial agents alters the normal flora of the colon leading
to overgrowth of C. difficile.
C. difficile produces toxins A and B which
contribute to the development of CDAD. Hypertoxin producing strains of C. difficile. cause increased morbidity and mortality, as
these infections can be refractory to antimicrobial therapy and may require
colectomy. CDAD must be considered in all patients who present with diarrhea
following antibiotic use. Careful medical history is necessary since CDAD has
been reported to occur over two months after the administration of antibacterial
agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed
against C. difficile. may need to be discontinued.
Appropriate fluid and electrolyte management, protein supplementation,
antibiotic treatment of C. difficile, and surgical
evaluation should be instituted as clinically indicated.
AUGMENTIN should be used with caution in patients with evidence of hepatic
dysfunction. Hepatic toxicity associated with the use of AUGMENTIN is usually
reversible. On rare occasions, deaths have been reported (less than 1 death
reported per estimated 4 million prescriptions worldwide). These have generally
been cases associated with serious underlying diseases or concomitant
medications. (See CONTRAINDICATIONS and ADVERSE REACTIONS: Liver.)
Precautions
General While AUGMENTIN possesses the characteristic low toxicity of the
penicillin group of antibiotics, periodic assessment of organ system functions,
including renal, hepatic, and hematopoietic function, is advisable during
prolonged therapy.
A high percentage of patients with mononucleosis who receive ampicillin
develop an erythematous skin rash. Thus, ampicillin-class antibiotics should not
be administered to patients with mononucleosis.
The possibility of superinfections with mycotic or bacterial pathogens should
be kept in mind during therapy. If superinfections occur (usually involving
Pseudomonas or Candida),
the drug should be discontinued and/or appropriate therapy instituted.
Prescribing AUGMENTIN in the absence of a proven or strongly suspected
bacterial infection or a prophylactic indication is unlikely to provide benefit
to the patient and increases the risk of the development of drug-resistant
bacteria. Drug Interactions Probenecid decreases the renal tubular secretion of amoxicillin.
Concurrent use with AUGMENTIN may result in increased and prolonged blood levels
of amoxicillin. Coadministration of probenecid cannot be recommended.
Abnormal prolongation of prothrombin time (increased international normalized
ratio [INR]) has been reported rarely in patients receiving amoxicillin and oral
anticoagulants. Appropriate monitoring should be undertaken when anticoagulants
are prescribed concurrently. Adjustments in the dose of oral anticoagulants may
be necessary to maintain the desired level of anticoagulation.
The concurrent administration of allopurinol and ampicillin increases
substantially the incidence of rashes in patients receiving both drugs as
compared to patients receiving ampicillin alone. It is not known whether this
potentiation of ampicillin rashes is due to allopurinol or the hyperuricemia
present in these patients. There are no data with AUGMENTIN and allopurinol
administered concurrently.
In common with other broad-spectrum antibiotics, AUGMENTIN may reduce the
efficacy of oral contraceptives. Drug/Laboratory Test Interactions Oral administration of AUGMENTIN will result in high urine
concentrations of amoxicillin. High urine concentrations of ampicillin may
result in false-positive reactions when testing for the presence of glucose in
urine using CLINITEST®, Benedict’s Solution, or Fehling’s
Solution. Since this effect may also occur with amoxicillin and therefore
AUGMENTIN, it is recommended that glucose tests based on enzymatic glucose
oxidase reactions (such as CLINISTIX®) be used.
Following administration of ampicillin to pregnant women, a transient
decrease in plasma concentration of total conjugated estriol,
estriol-glucuronide, conjugated estrone and estradiol has been noted. This
effect may also occur with amoxicillin and therefore AUGMENTIN. Information for Patients Patients should be counseled that antibacterial drugs including
AUGMENTIN, should only be used to treat bacterial infections. They do not treat
viral infections (e.g., the common cold). When AUGMENTIN is prescribed to treat
a bacterial infection, patients should be told that although it is common to
feel better early in the course of therapy, the medication should be taken
exactly as directed. Skipping doses or not completing the full course of therapy
may: (1) decrease the effectiveness of the immediate treatment, and (2) increase
the likelihood that bacteria will develop resistance and will not be treatable
by AUGMENTIN or other antibacterial drugs in the future.
Diarrhea is a common problem caused by antibiotics which usually ends when
the antibiotic is discontinued. Sometimes after starting treatment with
antibiotics, patients can develop watery and bloody stools (with or without
stomach cramps and fever) even as late as two or more months after having taken
the last dose of the antibiotic. If this occurs, patients should contact their
physician as soon as possible. Carcinogenesis, Mutagenesis, Impairment of
Fertility Long-term studies in animals have not been performed to evaluate
carcinogenic potential. Mutagenesis
The mutagenic potential of AUGMENTIN was investigated in vitro
with an Ames test, a human lymphocyte cytogenetic assay, a yeast test and a
mouse lymphoma forward mutation assay, and in vivo with mouse micronucleus tests
and a dominant lethal test. All were negative apart from the in vitro mouse
lymphoma assay where weak activity was found at very high, cytotoxic
concentrations. Impairment of
Fertility
AUGMENTIN at oral doses of up to 1,200 mg/kg/day (5.7 times the
maximum human dose, 1,480 mg/m2/day, based on body
surface area) was found to have no effect on fertility and reproductive
performance in rats, dosed with a 2:1 ratio formulation of
amoxicillin:clavulanate. PregnancyTeratogenic
Effects
Pregnancy (Category B). Reproduction studies performed in
pregnant rats and mice given AUGMENTIN at oral dosages up to 1,200 mg/kg/day,
equivalent to 7,200 and 4,080 mg/m2/day, respectively
(4.9 and 2.8 times the maximum human oral dose based on body surface area),
revealed no evidence of harm to the fetus due to AUGMENTIN. There are, however,
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 Oral ampicillin-class antibiotics are generally poorly absorbed
during labor. Studies in guinea pigs have shown that intravenous administration
of ampicillin decreased the uterine tone, frequency of contractions, height of
contractions, and duration of contractions; however, it is not known whether the
use of AUGMENTIN in humans during labor or delivery has immediate or delayed
adverse effects on the fetus, prolongs the duration of labor, or increases the
likelihood that forceps delivery or other obstetrical intervention or
resuscitation of the newborn will be necessary. In a single study in women with
premature rupture of fetal membranes, it was reported that prophylactic
treatment with AUGMENTIN may be associated with an increased risk of necrotizing
enterocolitis in neonates. Nursing Mothers Ampicillin-class antibiotics are excreted in the milk; therefore,
caution should be exercised when AUGMENTIN is administered to a nursing
woman. Pediatric Use Pediatric patients weighing 40 kg or more should be dosed
according to the adult recommendations (see DOSAGE AND ADMINISTRATION: Pediatric
Patients). Safety and effectiveness of AUGMENTIN Tablets in pediatric patients
weighing less than 40 kg have not been established. (See prescribing information
for AUGMENTIN Powder for Oral Suspension and Chewable Tablets.) Geriatric Use An analysis of clinical studies of AUGMENTIN was conducted to
determine whether subjects aged 65 and over respond differently from younger
subjects. Of the 3,119 patients in this analysis, 68% were <65 years old, 32%
were >65 years old and 14% were >75 years old. This analysis and other reported
clinical experience have not identified differences in responses between the
elderly and younger patients, but a greater sensitivity of some older
individuals cannot be ruled out.
This drug is known to be substantially excreted by the kidney, and the risk
of toxic reactions to this drug may be greater in patients with impaired renal
function. Because elderly patients are more likely to have decreased renal
function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
AUGMENTIN is generally well tolerated. The majority of side
effects observed in clinical trials were of a mild and transient nature and less
than 3% of patients discontinued therapy because of drug-related side effects.
The most frequently reported adverse effects were diarrhea/loose stools (9%),
nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%).
The overall incidence of side effects, and in particular diarrhea, increased
with the higher recommended dose. Other less frequently reported reactions
include: Abdominal discomfort, flatulence, and headache.
The following adverse reactions have been reported for ampicillin-class
antibiotics: Gastrointestinal Diarrhea, nausea, vomiting, indigestion, gastritis, stomatitis,
glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and
hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms
may occur during or after antibiotic treatment. (See WARNINGS.) Hypersensitivity Reactions Skin rashes, pruritus, urticaria, angioedema, serum sickness−like
reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia,
and frequently fever), erythema multiforme (rarely Stevens-Johnson syndrome),
acute generalized exanthematous pustulosis, hypersensitivity vasculitis, and an
occasional case of exfoliative dermatitis (including toxic epidermal necrolysis)
have been reported. These reactions may be controlled with antihistamines and,
if necessary, systemic corticosteroids. Whenever such reactions occur, the drug
should be discontinued, unless the opinion of the physician dictates otherwise.
Serious and occasional fatal hypersensitivity (anaphylactic) reactions can occur
with oral penicillin. (See WARNINGS.) Liver A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted in
patients treated with ampicillin-class antibiotics but the significance of these
findings is unknown. Hepatic dysfunction, including hepatitis and cholestatic
jaundice, [see CONTRAINDICATIONS], increases in serum transaminases (AST and/or
ALT), serum bilirubin, and/or alkaline phosphatase, has been infrequently
reported with AUGMENTIN. It has been reported more commonly in the elderly, in
males, or in patients on prolonged treatment. The histologic findings on liver
biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed
cholestatic-hepatocellular changes. The onset of signs/symptoms of hepatic
dysfunction may occur during or several weeks after therapy has been
discontinued. The hepatic dysfunction, which may be severe, is usually
reversible. On rare occasions, deaths have been reported (less than 1 death
reported per estimated 4 million prescriptions worldwide). These have generally
been cases associated with serious underlying diseases or concomitant
medications. Renal Interstitial nephritis and hematuria have been reported rarely.
Crystalluria has also been reported (see OVERDOSAGE). Hemic and Lymphatic Systems Anemia, including hemolytic anemia, thrombocytopenia,
thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have
been reported during therapy with penicillins. These reactions are usually
reversible on discontinuation of therapy and are believed to be hypersensitivity
phenomena. A slight thrombocytosis was noted in less than 1% of the patients
treated with AUGMENTIN. There have been reports of increased prothrombin time in
patients receiving AUGMENTIN and anticoagulant therapy concomitantly. Central Nervous System Agitation, anxiety, behavioral changes, confusion, convulsions,
dizziness, insomnia, and reversible hyperactivity have been reported
rarely. Miscellaneous Tooth discoloration (brown, yellow, or gray staining) has been
rarely reported. Most reports occurred in pediatric patients. Discoloration was
reduced or eliminated with brushing or dental cleaning in most cases.
Overdosage
Following overdosage, patients have experienced primarily
gastrointestinal symptoms including stomach and abdominal pain, vomiting, and
diarrhea. Rash, hyperactivity, or drowsiness have also been observed in a small
number of patients.
In the case of overdosage, discontinue AUGMENTIN, treat symptomatically, and
institute supportive measures as required. If the overdosage is very recent and
there is no contraindication, an attempt at emesis or other means of removal of
drug from the stomach may be performed. A prospective study of 51 pediatric
patients at a poison center suggested that overdosages of less than 250 mg/kg of
amoxicillin are not associated with significant clinical symptoms and do not
require gastric emptying.3
Interstitial nephritis resulting in oliguric renal failure has been reported
in a small number of patients after overdosage with amoxicillin.
Crystalluria, in some cases leading to renal failure, has also been reported
after amoxicillin overdosage in adult and pediatric patients. In case of
overdosage, adequate fluid intake and diuresis should be maintained to reduce
the risk of amoxicillin crystalluria.
Renal impairment appears to be reversible with cessation of drug
administration. High blood levels may occur more readily in patients with
impaired renal function because of decreased renal clearance of both amoxicillin
and clavulanate. Both amoxicillin and clavulanate are removed from the
circulation by hemodialysis. (See DOSAGE AND ADMINISTRATION for recommended
dosing for patients with impaired renal function.)
Dosage And Administration
Since both the 250-mg and 500-mg tablets of
AUGMENTIN contain the same amount of clavulanic acid (125 mg, as the potassium
salt), two 250-mg tablets of AUGMENTIN are not equivalent to one 500-mg tablet
of AUGMENTIN; therefore, two 250-mg tablets of AUGMENTIN should not be
substituted for one 500-mg tablet of AUGMENTIN. DosageAdults The usual adult dose is one 500-mg tablet of AUGMENTIN every
12 hours or one 250-mg tablet of AUGMENTIN every 8 hours. For more severe
infections and infections of the respiratory tract, the dose should be one
875-mg tablet of AUGMENTIN every 12 hours or one 500-mg tablet of AUGMENTIN
every 8 hours.
Patients with impaired renal function do not generally require a reduction in
dose unless the impairment is severe. Severely impaired patients with a
glomerular filtration rate of <30 mL/min. should not receive the 875-mg
tablet. Patients with a glomerular filtration rate of 10 to 30 mL/min. should
receive 500 mg or 250 mg every 12 hours, depending on the severity of the
infection. Patients with a less than 10 mL/min. glomerular filtration rate
should receive 500 mg or 250 mg every 24 hours, depending on severity of the
infection.
Hemodialysis patients should receive 500 mg or 250 mg every 24 hours,
depending on severity of the infection. They should receive an additional dose
both during and at the end of dialysis.
Hepatically impaired patients should be dosed with caution and hepatic
function monitored at regular intervals. (See WARNINGS.) Pediatric
Patients Pediatric patients weighing 40 kg or more should be dosed
according to the adult recommendations.
Due to the different amoxicillin to clavulanic acid ratios
in the 250-mg tablet of AUGMENTIN (250/125) versus the 250-mg chewable tablet of
AUGMENTIN (250/62.5), the 250-mg tablet of AUGMENTIN should not be used until
the pediatric patient weighs at least 40 kg or more. Administration AUGMENTIN may be taken without regard to meals; however,
absorption of clavulanate potassium is enhanced when AUGMENTIN is administered
at the start of a meal. To minimize the potential for gastrointestinal
intolerance, AUGMENTIN should be taken at the start of a meal.
How Supplied
AUGMENTIN 250-mg Tablets Each white oval filmcoated tablet, debossed with AUGMENTIN on 1
side and 250/125 on the other side, contains 250 mg amoxicillin as the
trihydrate and 125 mg clavulanic acid as the potassium salt.
Bottles of 30
NDC 54868-0387-1
Store tablets at or below 25°C (77°F). Dispense in original
container.
Clinical Studies
Data from 2 pivotal studies in 1,191 patients treated for either
lower respiratory tract infections or complicated urinary tract infections
compared a regimen of 875-mg tablets of AUGMENTIN every 12 hours to 500-mg
tablets of AUGMENTIN dosed every 8 hours (584 and 607 patients, respectively).
Comparable efficacy was demonstrated between the every 12 hours and every 8
hours dosing regimens. There was no significant difference in the percentage of
adverse events in each group. The most frequently reported adverse event was
diarrhea; incidence rates were similar for the 875-mg every 12 hours and 500-mg
every 8 hours dosing regimens (14.9% and 14.3%, respectively); however, there
was a statistically significant difference (P < 0.05) in rates of severe diarrhea or withdrawals
with diarrhea between the regimens: 1.0% for 875-mg every 12 hours dosing versus
2.5% for the 500-mg every 8 hours dosing.
In 1 of these pivotal studies, 629 patients with either pyelonephritis or a
complicated urinary tract infection (i.e., patients with abnormalities of the
urinary tract that predispose to relapse of bacteriuria following eradication)
were randomized to receive either 875-mg tablets of AUGMENTIN every 12 hours or
500-mg tablets of AUGMENTIN every 8 hours in the following distribution:
875 mg q12h
500 mg
q8h
Pyelonephritis
173 patients
188 patients
Complicated UTI
135 patients
133 patients
Total patients
308
321
The number of bacteriologically evaluable patients was comparable between the
2 dosing regimens. AUGMENTIN produced comparable bacteriological success rates
in patients assessed 2 to 4 days immediately following end of therapy. The
bacteriologic efficacy rates were comparable at 1 of the follow-up visits (5 to
9 days post-therapy) and at a late post-therapy visit (in the majority of cases,
this was 2 to 4 weeks post-therapy), as seen in the table below:
875 mg q12h
500 mg
q8h
2 to 4 days
81%, n = 58
80%, n = 54
5 to 9 days
58.5%, n = 41
51.9%, n = 52
2 to 4 weeks
52.5%, n = 101
54.8%, n =
104
As noted before, though there was no significant difference in the percentage
of adverse events in each group, there was a statistically significant
difference in rates of severe diarrhea or withdrawals with diarrhea between the
regimens.
References
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.
Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of
penicillin and cephalosporin ingestions in children less than six years of age.
Vet Hum Toxicol. 1988;30:66-67.
AUGMENTIN is a registered trademark of GlaxoSmithKline.
CLINITEST is a registered trademark of Miles, Inc.
CLINISTIX is a registered trademark of Bayer Corporation.
Relabeling and Repackaging by:
Physicians Total Care, Inc.Tulsa, OK 74146
Principal Display Panel
Augmentin
250 mg
500 mg
875 mg
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