Amoxicillin and Clavulanate Potassium

AMOXICILLIN AND CLAVULANATE POTASSIUM — amoxicillin and clavulanate potassium tablet, film coated
State of Florida DOH Central Pharmacy

Rx only

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Amoxicillin and Clavulanate Potassium Tablets and other antibacterial drugs, Amoxicillin and Clavulanate Potassium Tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Amoxicillin and Clavulanate Potassium Tablets are 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 C16 H19 N3 O5 S • 3H2 O, 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 has the following structural formula:

Structural Formula 1
(click image for full-size original)

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 C8 H8 KNO5 , 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 has the following structural formula:

Structural Formula 2

Each film coated tablet for oral administration contains 250 mg, 500 mg, or 875 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt. Each Amoxicillin and Clavulanate Potassium Tablet 250 mg/125 mg, 500 mg/125 mg, or 875 mg/125 mg contains 0.63 mEq potassium.

Inactive Ingredients: colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, talc, titanium dioxide and triethyl citrate. In addition, the 250 mg/125 mg tablet contains cetyl alcohol and sodium lauryl sulphate; the 500 mg/125 mg tablet contains ethylcellulose aqueous dispersion; and the 875 mg/125 mg tablet contains crospovidone and ethylcellulose aqueous dispersion.

CLINICAL PHARMACOLOGY

Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of Amoxicillin and Clavulanate Potassium Tablets. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While Amoxicillin and Clavulanate Potassium Tablets 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 Amoxicillin and Clavulanate Potassium Tablets were dosed at 30 and 150 minutes after the start of a high fat breakfast. The safety and efficacy of Amoxicillin and Clavulanate Potassium Tablets have been established in clinical trials where Amoxicillin and Clavulanate Potassium Tablets were taken without regard to meals.

*
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.
Mean * amoxicillin and clavulanate potassium pharmacokinetic parameters are shown in the table below:
Dose and regimen AUC0-24 (mcg∙hr/mL) Cmax (mcg/mL)
amoxicillin/clavulanate potassium amoxicillin(±S.D.) clavulanate potassium(±S.D.) amoxicillin(±S.D.) clavulanate potassium(±S.D.)
250 mg/125 mg q8h 26.7 ± 4.56 12.6 ± 3.25 3.3 ± 1.12 1.5 ± 0.70
500 mg/125 mg q12h 33.4 ± 6.76 8.6 ± 1.95 6.5 ± 1.41 1.8 ± 0.61
500 mg/125 mg q8h 53.4 ± 8.87 15.7 ± 3.86 7.2 ± 2.26 2.4 ± 0.83
875 mg/125 mg q12h 53.5 ± 12.31 10.2 ± 3.04 11.6 ± 2.78 2.2 ± 0.99

Amoxicillin serum concentrations achieved with Amoxicillin and Clavulanate Potassium Tablets 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 Amoxicillin and Clavulanate Potassium Tablets is 1.3 hours and that of clavulanic acid is 1 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 Amoxicillin and Clavulanate Potassium 250 mg/125 mg or 500 mg/125 mg Tablet.

Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid.

Neither component in Amoxicillin and Clavulanate Potassium Tablets is highly protein-bound; clavulanic acid has been found to be approximately 25% bound to human serum and amoxicillin approximately 18% bound.

Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like amoxicillin, is well distributed in body tissues.

Microbiology

Amoxicillin is a semisynthetic antibiotic with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms. Amoxicillin is, however, susceptible to degradation by β-lactamases, and therefore, the spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a β-lactam, structurally related to the penicillins, which possesses the ability to inactivate a wide range of β-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid-mediated β-lactamases frequently responsible for transferred drug resistance.

The formulation of amoxicillin and clavulanic acid in Amoxicillin and Clavulanate Potassium Tablets 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, Amoxicillin and Clavulanate Potassium Tablets possess the properties of a broad-spectrum antibiotic and a β-lactamase inhibitor.

Amoxicillin/clavulanic acid has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in INDICATIONS AND USAGE.

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