DESCRIPTION
AUGMENTIN XR is an oral antibacterial combination consisting of the semisynthetic antibiotic amoxicillin (present as amoxicillin trihydrate and amoxicillin sodium) 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 trihydrate molecular formula is C16H19N3O5S•3H2O, and the molecular weight is 419.45. Chemically, amoxicillin trihydrate 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:
The amoxicillin sodium molecular formula is C16H18N3NaO5S, and the molecular weight is 387.39. Chemically, amoxicillin sodium is [2S-[2α,5α,6β(S *)]]-6-[[Amino(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid monosodium salt 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
Citric acid, colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, titanium dioxide, and xanthan gum.
Each tablet of AUGMENTIN XR contains 12.6mg (0.32mEq) of potassium and 29.3mg (1.27mEq) of sodium.
CLINICAL PHARMACOLOGY
Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of AUGMENTIN XR.
AUGMENTIN XR is an extended-release formulation which provides sustained plasma concentrations of amoxicillin. Amoxicillin systemic exposure achieved with AUGMENTIN XR is similar to that produced by the oral administration of equivalent doses of amoxicillin alone. In a study of healthy adult volunteers, the pharmacokinetics of AUGMENTIN XR were compared when administered in a fasted state, at the start of a standardized meal (612kcal, 89.3g carb, 24.9g fat, and 14.0g protein), or 30minutes after a high-fat meal. When the systemic exposure to both amoxicillin and clavulanate is taken into consideration, AUGMENTIN XR is optimally administered at the start of a standardized meal. Absorption of amoxicillin is decreased in the fasted state. AUGMENTIN XR is not recommended to be taken with a high-fat meal, because clavulanate absorption is decreased. The pharmacokinetics of the components of AUGMENTIN XR following administration of two AUGMENTIN XR tablets at the start of a standardized meal are presented in Table 1.
Table 1. Mean (SD) Pharmacokinetic Parameters for Amoxicillin and Clavulanate Following Oral Administration of Two AUGMENTIN XR Tablets (2,000mg/125mg) to Healthy Adult Volunteers (n = 55) Fed a Standardized Meal
|
Parameter (units) |
Amoxicillin |
Clavulanate |
|
AUC(0-inf) (mcg•hr/mL) |
71.6 (16.5) |
5.29 (1.55) |
|
Cmax (mcg/mL) |
17.0 (4.0) |
2.05 (0.80) |
|
Tmax (hours)a |
1.50 (1.00 - 6.00) |
1.03 (0.75 - 3.00) |
|
T½ (hours) |
1.27 (0.20) |
1.03 (0.17) |
aMedian (range).
The half-life of amoxicillin after the oral administration of AUGMENTIN XR is approximately 1.3hours, and that of clavulanate is approximately 1.0hour.
Clearance of amoxicillin is predominantly renal, with approximately 60% to 80% of the dose being excreted unchanged in urine, whereas clearance of clavulanate has both a renal (30% to 50%) and a non-renal component.
Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanate.
In a study of adults, the pharmacokinetics of amoxicillin and clavulanate were not affected by administration of an antacid (MAALOX®), either simultaneously with or 2 hours after AUGMENTIN XR.
Neither component in AUGMENTIN XR is highly protein-bound; clavulanate 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.
In a study of pediatric patients with acute bacterial sinusitis, 7 to 15 years of age, and weighing at least 40kg, the pharmacokinetics of amoxicillin and clavulanate were assessed following administration of AUGMENTINXR 2000mg/125mg (as two 1000mg/62.5mg tablets) every 12 hours with food (Table2).
Table2. Mean (SD) Pharmacokinetic Parameters for Amoxicillin and Clavulanate Following Oral Administration of Two AUGMENTINXR Tablets (2,000mg/125mg) Every 12 Hours With Food to Pediatric Patients (7 to 15 Years of Age and Weighing ≥ 40kg) With Acute Bacterial Sinusitis
|
Parameter (units) |
Amoxicillin
(n=24) |
Clavulanate
(n=23) |
|
AUC(0-τ) (mcg•hr/mL) |
57.8 (15.6) |
3.18 (1.37) |
|
Cmax (mcg/mL) |
11.0 (3.34) |
1.17 (0.67) |
|
Tmax (hours)a |
2.0 (1.0 – 5.0) |
2.0 (1.0 – 4.0) |
|
T½ (hours) |
3.32 (2.21)b |
0.94 (0.13)c |
aMedian (range).
bn=18.
cn=17.
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, its spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a β-lactam, structurally related to penicillin, 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 found responsible for transferred drug resistance.
The clavulanic acid component of AUGMENTIN XR 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.
Amoxicillin/clavulanic acid has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.
Aerobic Gram-Positive Microorganisms
Streptococcus pneumoniae (including isolates with penicillin MICs ≤2mcg/mL)
Staphylococcus aureus (including β-lactamase−producing isolates)
NOTE: Staphylococci which are resistant to methicillin/oxacillin must be considered resistant to amoxicillin/clavulanic acid.
Aerobic Gram-Negative Microorganisms
Haemophilus influenzae (including β-lactamase−producing isolates)
Moraxella catarrhalis (including β-lactamase−producing isolates)
Haemophilus parainfluenzae (including β-lactamase−producing isolates)
Klebsiella pneumoniae (all known isolates are β-lactamase−producing)
The following in vitro data are available, but their clinical significance is unknown.
At least 90% of the following microorganisms exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoint for amoxicillin/clavulanic acid.1,2 However, the safety and efficacy of amoxicillin/clavulanic acid in treating infections due to these microorganisms have not been established in adequate and well-controlled trials.
Aerobic Gram-Positive Microorganisms
Streptococcus pyogenes
Anaerobic Microorganisms
Bacteroides fragilis (including β-lactamase−producing isolates)
Fusobacterium nucleatum (including β-lactamase−producing isolates)
Peptostreptococcus magnus
Peptostreptococcus micros
NOTE:S. pyogenes, P. magnus, and P. micros do not produce β-lactamase, and therefore, are susceptible to amoxicillin alone. Adequate and well-controlled clinical trials have established the effectiveness of amoxicillin alone in treating certain clin
