Prescription Drug Information: Amoxicillin and Clavulanate Potassium (Page 4 of 5)

12.3 Pharmacokinetics

Mean amoxicillin and clavulanate potassium pharmacokinetic parameters in normal adults following administration of amoxicillin and clavulanate potassium tablets are shown in Table 3 and following administration of amoxicillin and clavulanate potassium for oral suspension and chewable tablets are shown in Table 4.

* Mean (± standard deviation) values of 14 normal adults (N = 15 for clavulanate potassium in the low-dose regimens). Peak concentrations occurred approximately 1.5 hours after the dose. † Amoxicillin/clavulanate potassium administered at the start of a light meal.
Table 3: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters * † With Amoxicillin and Clavulanate Potassium Tablets
Dose and Regimen	C max (mcg/mL)		AUC 0 to 24 (mcg*h/mL)
Amoxicillin/Clavulanate Potassium	Amoxicillin	Clavulanate Potassium	Amoxicillin	Clavulanate Potassium
250 mg/125 mg every 8 hours	3.3 ± 1.12	1.5 ± 0.70	26.7 ± 4.56	12.6 ± 3.25
500 mg/125 mg every 12 hours	6.5 ± 1.41	1.8 ± 0.61	33.4 ± 6.76	8.6 ± 1.95
500 mg/125 mg every 8 hours	7.2 ± 2.26	2.4 ± 0.83	53.4 ± 8.87	15.7 ± 3.86
875 mg/125 mg every 12 hours	11.6 ± 2.78	2.2 ± 0.99	53.5 ± 12.31	10.2 ± 3.04

* Mean ( ± standard deviation) values of 28 normal adults. Peak concentrations occurred approximately 1 hour after the dose. † Amoxicillin/clavulanate potassium administered at the start of a light meal.
Table 4: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters * † With Amoxicillin and Clavulanate Potassium for Oral Suspension and Chewable Tablets
Dose	C max (mcg/mL)		AUC 0 to 24 (mcg*h/mL)
Amoxicillin/Clavulanate Potassium	Amoxicillin	Clavulanate Potassium	Amoxicillin	Clavulanate Potassium
400 mg/57 mg (5 mL of suspension)	6.94 ± 1.24	1.10 ± 0.42	17.29 ± 2.28	2.34 ± 0.94
400 mg/57 mg (1 chewable tablet)	6.67 ± 1.37	1.03 ± 0.33	17.24 ± 2.64	2.17 ± 0.73

Oral administration of 5 mL of 250 mg/62.5 mg per 5 mL suspension of amoxicillin/clavulanate potassium or the equivalent dose of 10 mL of 125 mg/31.25 mg per 5 mL suspension of amoxicillin/clavulanate potassium 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*h/mL for amoxicillin and 2.9 mcg*h/mL for clavulanic acid when 5 mL of 250 mg/62.5 mg per 5 mL suspension of amoxicillin/clavulanate potassium or equivalent dose of 10 mL of 125 mg/31.25 mg per 5 mL suspension of amoxicillin/clavulanate potassium were administered to normal adults. One 250 mg/62.5 mg chewable tablet of amoxicillin/clavulanate potassium or two 125 mg/31.25 mg chewable tablets of amoxicillin/clavulanate potassium are equivalent to 5 mL of 250 mg/62.5 mg per 5 mL suspension of amoxicillin/clavulanate potassium and provide similar serum concentrations of amoxicillin and clavulanic acid.

Amoxicillin serum concentrations achieved with amoxicillin/clavulanate potassium are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. Time above the minimum inhibitory concentration of 1 mcg/mL for amoxicillin has been shown to be similar after corresponding every 12 hour and every 8 hour dosing regimens of amoxicillin/clavulanate potassium in adults and children.

Absorption

Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While amoxicillin/clavulanate potassium 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 amoxicillin/clavulanate potassium was dosed at 30 and 150 minutes after the start of a high-fat breakfast.

Distribution

Neither component in amoxicillin/clavulanate potassium is highly protein-bound; clavulanic acid is 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.

Two hours after oral administration of a single 35 mg/kg dose of suspension of amoxicillin/clavulanate potassium to fasting children, average concentrations of 3 mcg/mL of amoxicillin and 0.5 mcg/mL of clavulanic acid were detected in middle ear effusions.

Metabolism and Excretion

The half-life of amoxicillin after the oral administration of amoxicillin/clavulanate potassium 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 250 mg/125 mg or 500 mg/125 mg tablet of amoxicillin/clavulanate potassium.

12.4 Microbiology

Amoxicillin is a semisynthetic antibiotic with in vitro bactericidal activity against Gram-positive and Gram-negative bacteria. 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 some 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 amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) protects amoxicillin from degradation by some beta-lactamase enzymes and extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin.

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

Gram-Positive Bacteria

Staphylococcus aureus

Gram-Negative Bacteria

Enterobacter species

Escherichia coli

Haemophilus influenzae

Klebsiella species

Moraxella catarrhalis

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for amoxicillin/clavulanic acid. However, the efficacy of amoxicillin/clavulanic acid in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-Positive Bacteria

Enterococcus faecalis

Staphylococcus epidermidis

Staphylococcus saprophyticus

Streptococcus pneumoniae

Streptococcus pyogenes

Viridans group Streptococcus

Gram-Negative Bacteria

Eikenella corrodens

Proteus mirabilis

Anaerobic Bacteria

Bacteroides species including Bacteroides fragilis

Fusobacterium species

Peptostreptococcus species

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

13 NONCLINICAL TOXICOLOGY