CLAVULANATE POTASSIUM
DESCRIPTION:
Augmentin is an oral antibacterial combination consisting of the semisynthetic
antibiotic amoxicillin and the beta-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 C16H19N3 O5S.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.
Clavulanic acid is produced by the fermentation of Streptomyces Clavuligerus. It
is a beta-lactam structurally related to the penicillins and possesses the
ability to inactivate a wide variety of beta-lactamases by blocking the active
sites of these enzymes. Clavulanic acid is particularly active against the
clinically important plasmid mediated beta-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.
INACTIVE INGREDIENTS: Colloidal silicon dioxide, hydroxypropyl methylcellulose,
magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium
starch glycolate and titanium dioxide.
Each Augmentin tablet contains 0.63 mEq potassium.
ACTIONS/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 one
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.
Mean* amoxicillin and clavulanate potassium pharmacokinetic parameters are shown
in the table below:
Dose** and regimen AUC0-24 (mcgm.hr/mL) Cmax (mcgm/mL)
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amoxicillin/ clavulanate clavulanate
clavulanate amoxicillin potassium amoxicillin potassium
potassium (+/- S.D.) (+/- S.D.) (+/- S.D.) (+/- 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 +/- 11.6 +/- 2.78 2.2 +/- 0.99
3.04
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* 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.
** 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 Augmentin 250 mg or 500 mg tablet.
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 fluids. 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 beta-
lactamases and, therefore, the spectrum of activity does not include organisms
which produce these enzymes. Clavulanic acid is a beta-lactam, structurally
related to the penicillins, which possesses the ability to inactivate a wide
range of beta- lactamase enzymes commonly found in microorganisms resistant to
penicillins and cephalosporins. In particular, it has good activity against the
clinically important plasmid mediated beta-lactamases frequently responsible for
transferred drug resistance.
The formulation of amoxicillin and clavulanic acid in Augmentin protects
amoxicillin from degradation by beta-lactamase enzymes and effectively extends
the antibiotic spectrum of amoxicillin to include many bacteria normally
resistant to amoxicillin and other beta-lactam antibiotics. Thus Augmentin
possesses the properties of a broad-spectrum antibiotic and a beta-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 the INDICATIONS AND USAGE section.
GRAM-POSITIVE AEROBES
Staphylococcus Aureus (beta-lactamase and non- beta-lactamase producing)*/*
----------
*/* 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 (beta-lactamase and non-beta- lactamase producing)
Haemophilus Influenzae (beta-lactamase and non- beta-lactamase producing)
Klebsiella species (All known strains are beta- lactamase producing.)
Moraxella Catarrhalis (beta-lactamase and non- beta-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 0.5 mcgm/mL or less against most (>/=90%) strains of Streptococcus
Pneumoniae#; MICs of 0.06 mcgm/mL or less against most (>/=90%) strains of
Neisseria Gonorrhoeae; MICs of 4 mcgm/mL or less against most (>/=90%) strains
of staphylococci and anaerobic bacteria; and MICs of 8 mcgm/mL or less against
most (>/=90%) strains of other listed 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.
----------
# Because amoxicillin has greater In Vitro activity against Streptococcus
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##
Staphylococcus Epidermidis (beta-lactamase and non-beta-lactamase producing)
Staphylococcus Saprophyticus (beta-lactamase and non-beta-lactamase producing)
Streptococcus Pneumoniae## **/*
Streptococcus Pyogenes## **/*
viridans group Streptococcus## **/*
GRAM-NEGATIVE AEROBES
Eikenella Corrodens (beta-lactamase and non-beta- lactamase producing)
Neisseria Gonorrhoeae## (beta-lactamase and non- beta-lactamase producing)
Proteus Mirabilis## (beta-lactamase and non-beta- lactamase producing)
ANAEROBIC BACTERIA
Bacteroides species, including Bacteroides Fragilis (beta-lactamase and non-
beta-lactamase producing)
Fusobacterium species (beta-lactamase and non- beta-lactamase producing)
Peptostreptococcus species**/*
----------
## Adequate and well-controlled clinical trials have established the
effectiveness of amoxicillin alone in treating certain clinical infections due
to these organisms.
**/* These are non-beta-lactamase-producing organisms and, therefore, are
susceptible to amoxicillin alone.
----------
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 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 (mcgm/mL) Interpretation
=8/4 Susceptible (S)
16/8 Intermediate (I)
>/=32/16 Resistant (R)
For Staphylococcus*/** and Haemophilus species:
MIC (mcgm/mL) Interpretation
=4/2 Susceptible (S)
>/=8/4 Resistant (R)
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*/** Staphylococci which are susceptible to amoxicillin/clavulanic acid but
resistant to methicillin/oxacillin must be considered as resistant.
For Streptococcus Pneumoniae: Isolates should be tested using
amoxicillin/clavulanic acid and the following criteria should be used:
MIC (mcgm/mL) Interpretation
=0.5/0.25 Susceptible (S)
1/0.5 Intermediate (I)
>/=2/1 Resistant (R)
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 (mcgm/mL)#/#
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
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#/# 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 mcgm of amoxicillin/clavulanate potassium (20 mcgm
amoxicillin plus 10 mcgm 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 mcgm amoxicillin/clavulanate acid (20 mcgm
amoxicillin plus 10 mcgm clavulanate potassium) disk should be interpreted
according to the following criteria:
RECOMMENDED RANGES FOR AMOXICILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING
For Staphylococcus##/# species and H. Influenzae(a):
Zone Diameter (mm) Interpretation
>/=20 Susceptible (S)
=19 Resistant (R)
For other organisms except S. Pneumoniae(b) and N. Gonorrhoeae(c):
Zone Diameter (mm) Interpretation
>/=18 Susceptible (S)
14 to 17 Intermediate (I)
=13 Resistant (R)
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##/# Staphylococci which are resistant to methicillin/oxacillin must be
considered as resistant to amoxicillin/clavulanic acid.
(a) 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.
(b) Susceptibility of S. Pneumoniae should be determined using a 1 mcgm
oxacillin disk. Isolates with oxacillin zone sizes of >/=20 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 =19 mm.
(c) 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 mcgm
amoxicillin/clavulanate potassium (20 mcgm amoxicillin plus 10 mcgm 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 listed below:
LOWER RESPIRATORY TRACT INFECTIONS--caused by beta-lactamase-producing strains
of Haemophilus Influenzae and Moraxella (Branhamella) Catarrhalis.
OTITIS MEDIA--caused by beta-lactamase-producing strains of Haemophilus
Influenzae and Moraxella (Branhamella) Catarrhalis.
SINUSITIS--caused by beta-lactamase-producing strains of Haemophilus Influenzae
and Moraxella (Branhamella) Catarrhalis.
SKIN AND SKIN STRUCTURE INFECTIONS--caused by beta-lactamase-producing strains
of Staphylococcus Aureus, Escherichia Coli and Klebsiella spp.
URINARY TRACT INFECTIONS--caused by beta- lactamase-producing strains of
Escherichia Coli, Klebsiella spp. and Enterobacter spp.
While Augmentin is indicated only for the conditions listed above, infections
caused by ampicillin-susceptible organisms are also amenable to Augmentin
treatment due to its amoxicillin content. Therefore, mixed infections caused by
ampicillin-susceptible organisms and beta-lactamase-producing organisms
susceptible to Augmentin should not require the addition of another antibiotic.
Because amoxicillin has greater In Vitro activity against Streptococcus
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 subsection.)
Bacteriological studies, to determine the causative organisms and their
susceptibility to Augmentin, should be performed together with any indicated
surgical procedures.
Therapy may be instituted prior to obtaining the results from bacteriological
and susceptibility studies to determine the causative organisms and their
susceptibility to Augmentin when there is reason to believe the infection may
involve any of the beta-lactamase-producing organisms listed above. Once the
results are known, therapy should be adjusted, if appropriate.
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 Augmentin-associated cholestatic jaundice/hepatic dysfunction.
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.
PSEUDOMEMBRANOUS COLITIS HAS BEEN REPORTED WITH NEARLY ALL ANTIBACTERIAL AGENTS,
INCLUDING AUGMENTIN, AND HAS RANGED 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 the 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 colitis.
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.
Drug Interactions: Probenecid decreases the renal tubular secretion of
amoxicillin. Concurrent use with Augmentin may result in increased and prolonged
blood levels of amoxicillin. Co- administration of probenecid cannot be
recommended.
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(R), 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(R) or Tes-Tape(R)) 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.
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 1200 mg/kg/day (5.7
times the maximum human dose, 1480 mg/M(squared)/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.
Teratogenic Effects. Pregnancy (Category B): Reproduction studies performed in
pregnant rats and mice given Augmentin at oral dosages up to 1200 mg/kg/day,
equivalent to 7200 and 4080 mg/M(squared)/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.
Nursing Mothers: Ampicillin class antibiotics are excreted in the milk;
therefore, caution should be exercised when Augmentin is administered to a
nursing woman.
DRUG INTERACTIONS:
Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use
with Augmentin may result in increased and prolonged blood levels of
amoxicillin. Co-administration of probenecid cannot be recommended.
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.
(See Also PRECAUTIONS.)
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, enterocolitis, and hemorrhage/
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) 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 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.
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.
OVERDOSAGE:
Most patients have been asymptomatic following overdosage or 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. (REF. 3)
Interstitial nephritis resulting in oliguric renal failure has been reported in
a small number of patients after overdosage with amoxicillin. 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 AUGMENTIN 250 MG AND 500 MG TABLETS CONTAIN THE SAME AMOUNT OF
CLAVULANIC ACID (125 MG, AS THE POTASSIUM SALT), 2 AUGMENTIN 250 MG TABLETS ARE
NOT EQUIVALENT TO 1 AUGMENTIN 500 MG TABLET. THEREFORE, 2 AUGMENTIN 250 MG
TABLETS SHOULD NOT BE SUBSTITUTED FOR 1 AUGMENTIN 500 MG TABLET.
DOSAGE:
ADULTS: The usual adult dose is 1 Augmentin 500 mg tablet every 12 hours or 1
Augmentin 250 mg tablet every 8 hours. For more severe infections and infections
of the respiratory tract, the dose should be 1 Augmentin 875 mg tablet every 12
hours or 1 Augmentin 500 mg tablet 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/minute should not receive the 875 mg
tablet. Patients with a glomerular filtration rate of 10 to 30 mL/minute should
receive 500 mg or 250 mg every 12 hours, depending on severity of the infection.
Patients with a less than 10 mL/minute 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 the 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 AUGMENTIN 250
MG TABLET (250/125) VERSUS THE AUGMENTIN 250 MG CHEWABLE TABLET (250/62.5), THE
AUGMENTIN 250 MG TABLET 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 film- coated 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.
NDC 0029-6075-27 .............................. bottles of 30
NDC 0029-6075-31 .................. Unit Dose (10x10) 100 tablets
AUGMENTIN 500 MG TABLETS: Each white oval film- coated tablet, debossed with
AUGMENTIN on 1 side and 500/125 on the other side, contains 500 mg amoxicillin
as the trihydrate and 125 mg clavulanic acid as the potassium salt.
NDC 0029-6080-12 ............................... bottles of 20
NDC 0029-6080-31 ...................Unit Dose (10x10) 100 tablets
AUGMENTIN 875 MG TABLETS: Each scored white capsule-shaped tablet, debossed
with AUGMENTIN 875 on 1 side and SB on the other side, contains 875 mg
amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt.
NDC 0029-6086-12 .............................. bottles of 20
NDC 0029-6086-21 ................. Unit Dose (10x10) 100 tablets
AUGMENTIN Is Also Supplied As:
AUGMENTIN 125 MG/5 ML (125 mg amoxicillin/31.25 mg clavulanic acid) FOR ORAL
SUSPENSION:
NDC 0029-6085-39 .................................... 75 mL bottle
NDC 0029-6085-23 ................................... 100 mL bottle
NDC 0029-6085-23 ................................... 150 mL bottle
AUGMENTIN 200 MG/5 ML (200 mg amoxicillin/28.5 mg clavulanic acid) FOR ORAL
SUSPENSION:
NDC 0029-6085-29 .................................... 50 mL bottle
NDC 0029-6085-39 ................................... 75 mL bottle
NDC 0029-6085-51 ................................... 100 mL bottle
AUGMENTIN 250 MG/5 ML (250 mg amoxicillin/62.5 mg clavulanic acid) FOR ORAL
SUSPENSION: NDC 0029-6085-39 .................................... 75 mL bottle
NDC 0029-6085-23 ................................... 100 mL bottle
NDC 0029-6085-22 ................................... 150 mL bottle
AUGMENTIN 400 MG/5 ML (400 mg amoxicillin/57 mg clavulanic acid) FOR ORAL
SUSPENSION: NDC 0029-6085-29 .................................... 50 mL bottle
NDC 0029-6085-39 .................................... 75 mL bottle
NDC 0029-6085-51 ................................... 100 mL bottle
AUGMENTIN 125 MG (125 mg amoxicillin/31.25 mg clavulanic acid) CHEWABLE TABLETS:
NDC 00029-6073-47 ........................ carton of 30 (5x6) tablets
AUGMENTIN 200 MG (200 mg amoxicillin/28.5 mg clavulanic acid) CHEWABLE TABLETS:
NDC 00029-6071-12 ........................ carton of 20 tablets
AUGMENTIN 250 MG (250 mg amoxicillin/62.5 mg clavulanic acid) CHEWABLE TABLETS:
NDC 00029-6074-47 ........................ carton of 30 (5x6) tablets
AUGMENTIN 400 MG (400 mg amoxicillin/57.0 mg clavulanic acid) CHEWABLE TABLETS:
NDC 00029-6072-12 ........................ carton of 20 tablets
Store tablets and dry powder at or below 25 DEG C (77 DEG F). Dispense in
tightly closed, moisture- proof containers.
AG:AL5
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CLINICAL STUDIES:
Data from two pivotal studies in 1,191 patients treated for either lower
respiratory tract infections or complicated urinary tract infections compared a
regimen of 875 mg Augmentin tablets q12h to 500 mg Augmentin tablets dosed q8h
(584 and 607 patients, respectively). Comparable efficacy was demonstrated
between the q12h and q8h 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 q12h and
500 mg q8h 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 q12h dosing
versus 2.5% for the 500 mg q8h dosing.
In one 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 Augmentin tablets q12h or 500 mg
Augmentin tablets q8h 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
two 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 one 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:
1. 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.
2. 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.
3. 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.
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