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:

Inactive Ingredients

Powder for Oral Suspension—Colloidal silicon dioxide, flavorings (see HOW SUPPLIED), xanthan gum, and 1 or more of the following: Aspartamea, hypromellose, mannitol, silica gel, silicon dioxide, and sodium saccharin. Chewable Tablets—Colloidal silicon dioxide, flavorings (see HOW SUPPLIED), magnesium stearate, mannitol, and 1 or more of the following: Aspartamea, D&C Yellow No. 10, FD&C Red No. 40, glycine, sodium saccharin and succinic acid.

a  See PRECAUTIONS—Information for the Patient.

Each 125-mg chewable tablet and each 5 mL of reconstituted 125 mg/5 mL oral suspension of AUGMENTIN contains 0.16 mEq potassium. Each 250-mg chewable tablet and each 5 mL of reconstituted 250 mg/5 mL oral suspension of AUGMENTIN contains 0.32 mEq potassium. Each 200-mg chewable tablet and each 5 mL of reconstituted 200 mg/5 mL oral suspension of AUGMENTIN contains 0.14 mEq potassium. Each 400-mg chewable tablet and each 5 mL of reconstituted 400 mg/5 mL oral suspension of AUGMENTIN contains 0.29 mEq of 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.

Oral administration of single doses of 400-mg chewable tablets of AUGMENTIN and 400 mg/5 mL suspension to 28 adult volunteers yielded comparable pharmacokinetic data:

a  Administered at the start of a light meal.

b  Mean values of 28 normal volunteers. Peak concentrations occurred approximately 1 hour after the dose.
 

Oral administration of 5 mL of 250 mg/5 mL suspension of AUGMENTIN or the equivalent dose of 10 mL of 125 mg/5 mL suspension of AUGMENTIN provides average peak serum concentrations approximately 1 hour after dosing of 6.9 mcg/mL for amoxicillin and 1.6 mcg/mL for clavulanic acid. The areas under the serum concentration curves obtained during the first 4 hours after dosing were 12.6 mcg.hr/mL for amoxicillin and 2.9 mcg.hr/mL for clavulanic acid when 5 mL of 250 mg/5 mL suspension of AUGMENTIN or equivalent dose of 10 mL of 125 mg/5 mL suspension of AUGMENTIN was administered to adult volunteers. One 250-mg chewable tablet of AUGMENTIN or two 125-mg chewable tablets of AUGMENTIN are equivalent to 5 mL of 250 mg/5 mL suspension of AUGMENTIN and provide similar serum levels of amoxicillin and clavulanic acid.

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. Time above the minimum inhibitory concentration of 1.0 mcg/mL for amoxicillin has been shown to be similar after corresponding every 12 hours and every 8 hours dosing regimens of AUGMENTIN in adults and children.

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 10 mL of 250 mg/5 mL suspension 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.

Two hours after oral administration of a single 35 mg/kg dose of suspension of AUGMENTIN to fasting children, average concentrations of 3.0 mcg/mL of amoxicillin and 0.5 mcg/mL of clavulanic acid were detected in middle ear effusions.

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 distinctive 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 pneumoniaed; 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; MICs of 8 mcg/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.

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 faecalise

Staphylococcus epidermidis (β-lactamase and non−β-lactamase−producing)

Staphylococcus saprophyticus (β-lactamase and non−β-lactamase−producing)

Streptococcus pneumoniaee, f

Streptococcus pyogenese, f

viridans group Streptococcuse, f

Gram-Negative Aerobes

Eikenella corrodens (β-lactamase and non−β-lactamase−producing)

Neisseria gonorrhoeaee (β-lactamase and non−β-lactamase−producing)

Proteus mirabilise (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 Testing

Dilution 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:

For Staphylococcusg and Haemophilus species:

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:

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 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 laboratory procedures. Standard amoxicillin/clavulanate potassium powder should provide the following MIC values:

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 potassium (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 Staphylococcusi species and H. influenzaej:

For Other Organisms Except S.pneumoniaek and N. gonorrhoeael:

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 ≥ 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.

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:

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 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 listed 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 eva luation 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.)