(amoxicillin/clavulanate potassium)
Tablets
DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED
CLINICAL STUDIES
REFERENCES
Augmentin is an oral antibacterial combination consisting of the semisynthetic antibiotic amoxicillin and the Beta-lactamase inhibitor, clavulanate potassium (the potassium salt 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 Beta-lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of B-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid mediated B-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:
Inactive Ingredients: Collodial silicon dioxide, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate and titanium dioxide.
Each Augmentin tablet contains 0.63 mEq potassium
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:
DoseT and regimen AUC0-24 (µg/hr/mL) Cmax µg/mL
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+/-0.7 500/125 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
* 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. T 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 approximateley 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 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 B-lactamases and, therefore, the spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a B-lactam, structurally related to the penicillins, which possesses the ability to inactivate a wide range of B-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalorsporins. In particular, it has good activity against the clinically important plasmid mediated B-lactamases frequently responsible for transferred drug resistance.
The formulation of amoxicillin and clavulanic acid in Augmentin protects amoxicillin from degradation by B-lactamase enzymes and effectively extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin and other B-lactam antibiotics. Thus, Augmentin possesses the distinctive properties of broad-spectrum antiobiotic and a B-lactamase inhibitor.
Amoxicillin/clavulanic acid has been shown to be active against most strains of the following microorganiams, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.
GRAM-POSITIVE AEROBES
Staphylococcus aureus (B-lactamase producing and non-B-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 (B-lactamase and non-B-lactamase producing)
Haemophilus influenzae (B-lactamase and non-B-lactamase producing)
Klebsiella species (All known strains are B-lactamase producing.)
Moraxella catarrhalis (B-lactamase and non-B-lactamase producing)
The following in vitro data are available, but their clinical significance is unkown.
Amoxicillin/clavulanic acid exhibits in vitro minimal inhibitory concentrations (MICs) of 0.5 µg/mL or less against most (>/=90%) strains of Streptococcus pneumoniae**, MICs of 0.06 µg/mL or less against most (>/=90%) strains of Neisseria gonorrhoeae, MICs of 4 µg/mL or less against most (>/=90%) strains of staphylococci and anaerobic bacteria; and MICs of 8 µg/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 (B-lactamase producing and non-B-lactamase producing)
Staphylococcus saprophyticus (B- lactamase producing and non-B-lactamase producing)
Staphylococcus pneumoniae*#
Streptococcus pyogenes*#
viridans group Streptococcus*#
GRAM-NEGATIVE AEROBES
Eikenella corrodens (B-lactamase and non-B-lactamase producing)
Neisseria gonorrhoeae* (B-lactamase and non-B-lactamase producing)
Proteus mirabils* (B-lactamase and non-B-lactamase producing)
ANAEROBIC BACTERIA
Bacteroides species including Bacteroides fragilis (B-lactamase producing and non-B-lactamase producing)
Fusobacterium species (B-lactamase and non-B-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-B-lactamase producing organisms and, therefore, are susceptible to amoxicillin alone.
SUCCEPTIBILITY TESTING
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth 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 (µg/mL) Interpretation
< /= 8/4 Susceptible (S)
16/8 Intermediate (I)
>/= 32/16 Resistant (R)
For Staphylooccus** and Haemophilus
species:
MIC (µg/mL) Interpretation
< /= 4/2 Susceptible (S)
> /= 8/4 Resistant (R)
** Staphylococci which are susceptible to
amoxicillin/clavulanic acid but resistant
to methicillin/oxacillin must be
considered as resistant.
For Streptoccocus pneumoniae: Isolates
should be tested using amoxiciliin/clauvanic
acid and the following criteria should be used:
MIC (µg/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 that 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 laboratrory procedures. Standard amoxicillin/clavulanate potassium powder should provide the following MIC values:
Microorganism MIC Range (ug/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 Staphylococus aureus ATCC 29213 0.12 to 0.5 Streptococcus pneumonia ATCC 49619 0.03 to 0.12 ++ 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 procedure requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 µg of amoxicillin/clavulanate potassium (20 µg amoxicillin plus 10 µg 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 µg amoxicillin/clavulanate acid (20 µg amoxicillin plus 10 µg 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 organims except S. pneumoniae b and N. gonorrhoeae c
Zone Diameter (mm) Interpretation
> /=1 8 Susceptible (S)
14 to 17 Intermediate (I)
< /= 13 Resistant (R)
++ Staphylocci 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 µg oxacillin disk.
Isolates with oxacillin zone sizes of
>/= 20 mm are susceptible to amoxicillin/
clavulanic acid. An amoxicillin/clavulanic
acid MIC should be determinded 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 µg amoxicillin/clavulanate potassium (20 µg amoxicillin plus 10 µg 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
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.
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.
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 ANAPHLACTIC 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 admisistration 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.)
General: While Augmentin possesses the characteristic low toxicity of the penicillin group of antibiotics, periodic assessment of organ system functions, inlcuding 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 of 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 administred concurrently.
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 Dolution. 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® or Tes-Tape®) 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, Impariment 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 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/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:clavulanante.
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/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 resusciation 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.
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 requently 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, mucocutaneous candidiasis and 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 unkown. Hepatic dysfunction, inlcuding increases in serum transaminases (AST and/or ALT), serum bilirubin and or alkaline phosphatase, has been infrequently reported with Augmentin. 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, 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.
Central Nervous System: Reversible hyperactivity, agitation, anxiety, insomnia, confusion, behavioral changes, and/or dizziness have been reported rarely.
Amoxicillin may be removed from circulation by hemodialysis.
The molecular weight, degree of protein binding and pharmacokinetic profile of clavulanic acid together with information from a single patient with renal insufficiency all suggest that this compound may also be removed by hemodialysis.
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. Severly 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 the severity of the infection. Patients with a less than 10 mL/minute glomerular filtration rate should receive 500 mg or 250 mg every 24 hous, 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, absorpition of clavulanate potassium is enhanced when Augmentin is administered at the start of a meal. To minimzie the potential for gastrointestinal intolerance, Augmentin should be taken at the start of a meal.
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.
NDC 0029-6075-27………………………………..bottles of 30
NDC 0029-6075-31………………..Unit Dose (10 x 10) 100 tablets
AUGMENTIN 500 MG TABLETS: Each white oval filmcoated tablet, debossed with AUGMENTIN on 1 side and 500/125 on the other side, contains 500 mg amoxicillin as the tryihydrate and 125 mg clavulanic acid as the potassium salt.
NDC 0029-6080-12………………………………..bottles of 20
NDC 0029-6080-27………………………………..bottles of 30
NDC 0029-6080-31………………..Unit Dose (10 X 10) 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 (10 X 10) 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 0029-6085-22………………………………..150 mL bottle
AUGMENTIN 250 MG/5 ML (250 mg amoxicillin/62.5 mg clavulanic acid) FOR ORAL SUSPENSION:
NDC 0029-6090-39…………………………………75 mL bottle
NDC 0029-6090-23………………………………..100 mL bottle
NDC 0029-6090-22………………………………..150 mL bottle
AUGMENTIN 125 MG (125 mg amoxicillin/31.25 mg clavulanic acid) CHEWABLE TABLETS:
NDC 0029-6073-47…………………….carton of 30 (5×6) tablets
AUGMENTIN 250 MG (250 mg amoxicillin/62.5 mg clavulanic acid) CHEWABLE TABLETS:
NDC 0029-6074-47…………………….carton of 30 (5×6) tablets
Store tablets and dry powder at or below 25oC (77oF). Dispense in tightly closed, moisture-proof containers.
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 (5-9 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.
1. National Committee for Clinical Laboratory Standards. Method 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.
DATE OF ISSUANCE MAR. 1996
©SmithKline Beecham, 1996
Printed in U.S.A.
SmithKline Beecham Pharmaceuticals
Philadelphia, PA 19101