Amoxicillin and Clavulanate Potassium Extended Release (Page 4 of 6)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Amoxicillin and Clavulanate Potassium Extended Release Tablet is an antibacterial drug. [see Microbiology (12.4)]

12.3 Pharmacokinetics

Amoxicillin and Clavulanate Potassium Extended Release Tablet is an extended-release formulation which provides sustained plasma concentrations of amoxicillin. Amoxicillin systemic exposure achieved with Amoxicillin and Clavulanate Potassium Extended Release Tablets is similar to that produced by the oral administration of equivalent doses of amoxicillin alone.

Absorption: Amoxicillin and Clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of Amoxicillin and Clavulanate Potassium Extended Release Tablets.

In a study of healthy adult volunteers, the pharmacokinetics of Amoxicillin and Clavulanate Potassium Extended Release Tablets were compared when administered in a fasted state, at the start of a standardized meal (612 kcal, 89.3 g carb, 24.9 g fat, and 14.0 g protein), or 30 minutes after a high‑fat meal. When the systemic exposure to both amoxicillin and clavulanate is taken into consideration, Amoxicillin and Clavulanate Potassium Extended Release Tablets is optimally administered at the start of a standardized meal. Absorption of amoxicillin is decreased in the fasted state. Amoxicillin and Clavulanate Potassium Extended Release Tablet is not recommended to be taken with a high‑fat meal, because clavulanate absorption is decreased. The pharmacokinetics of the components of Amoxicillin and Clavulanate Potassium Extended Release Tablets following administration of two Amoxicillin and Clavulanate Potassium Extended Release Tablets at the start of a standardized meal are presented in Table 1.

Table 1: Mean (SD) Pharmacokinetic Parameter for Amoxicillin and Clavulanate Following Oral Administration of Two Amoxicillin and Clavulanate Potassium Extended Release Tablets (2,000 mg/125 mg) to Healthy Adult Volunteers (n = 55) Fed a Standar dized 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)
T1/2 (hours)	1.27 (0.20)	1.03 (0.17)

^a Median (range).

The half-life of amoxicillin after the oral administration of Amoxicillin and Clavulanate Potassium Extended Release Tablets is approximately 1.3 hours, and that of clavulanate is approximately 1.0 hour.

Distribution:Neither component in Amoxicillin and Clavulanate Potassium Extended Release Tablets 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.

Excretion: 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.

Drug Interactions

Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanate [see Drug Interactions (7.1)].

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 Amoxicillin and Clavulanate Potassium Extended Release Tablets.

Pediatrics

In a study of pediatric patients with acute bacterial sinusitis, 7 to 15 years of age, and weighing at least 40 kg, the pharmacokinetics of amoxicillin and clavulanate were assessed following administration of Amoxicillin and Clavulanate Potassium Extended Release Tablets 2000 mg/125 mg (as two 1000 mg/62.5 mg tablets) every 12 hours with food (Table 2).

Table 2: Mean (SD) Pharmacokinetic Parameters for Amoxicillin and Clavulanate Following Oral Administration of Two Amoxicillin and Clavulanate Potassium Extended Release Tablets (2,000 mg/125 mg) 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)
T1/2 (hours)	3.32 (2.21)b	0.94 (0.13)c

^a Median (range).

^b n=18.

^c n=17.

12.4 Microbiology

Mechanism of Action

Amoxicillin binds to penicillin-binding proteins within the bacterial cell wall and inhibits bacterial cell wall synthesis.

Clavulanic acid is a β‑lactam, structurally related to penicillin, that may inactivate certain β‑lactamase enzymes.

Mechanism of Resistance

Resistance to penicillins may be mediated by destruction of the beta-lactam ring by a beta-lactamase, altered affinity of penicillin for target, or decreased penetration of the antibiotic to reach the target site. Amoxicillin alone is susceptible to degradation by β‑lactamases, and therefore its spectrum of activity does not include bacteria that produce these enzymes.

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 (1).

Gram-positive bacteria:

Staphylococcus aureus

Streptococcus pneumoniae

Gram-negative bacteria:

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella pneumoniae

Moraxella catarrhalis

The following in vitro data are available, but their clinical significance is unknown.

At least 90 percent of the following bacteria exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoint for amoxicillin/clavulanic acid.¹ However, the safety and effectiveness of amoxicillin/clavulanic acid in treating clinical infections due to these bacteria have not been established in adequate and well‑controlled clinical trials.

Gram-positive bacteria:

Streptococcus pyogenes

Susceptibility Test Methods: When available, the clinical microbiology laboratory should provide cumulative results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community‑acquired pathogens.

These reports should aid the physician in selecting an antibacterial drug product for treatment.

Dilution Techniques:

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method^1,2 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 3.

Diffusion Techniques:

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.^1,3 This procedure uses paper disks impregnated with 30 mcg amoxicillin/clavulanate potassium (20 mcg amoxicillin plus 10 mcg clavulanate potassium) to test susceptibility of microorganisms to amoxicillin/clavulanate potassium. Disk diffusion interpretive criteria should be interpreted according to criteria provided in Table 3.

Table 3: Susceptibility Interpretive Criteria for Amoxicillin/ Clavulanate Potassium

	Minimum Inhibitory Concentration (mcg/mL)			Disk Diffusion (Zone Diameter in mm)
Pathogen	S	I	R	S	I	R
Streptococcus pneumoniae (nonmeningitis isolates)	≤ 2/1	4/2	≥ 8/4	–	–	–
Haemophilus spp.	≤ 4/2	–	≥ 8/4	≥ 20	–	≤ 19
Klebsiella pneumoni	≤ 8/4	16/8	≥ 32/16	≥ 18	14 to 17	≤ 13

S= Susceptible, I=Intermediate, R=Resistant

NOTE: Susceptibility of staphylococci to amoxicillin/clavulanate may be deduced from testing only penicillin and either cefoxitin or oxacillin.

NOTE: Susceptibility of S. pneumoniae by disk diffusion should be determined using a 1mcg oxacillin disk.

NOTE: For nonmeningitis isolates, a penicillin MIC of ≤ 0.06 mcg/ml (or oxacillin zone ≥ 20 mm) can predict susceptibility to amoxicillin/clavulanate.¹

NOTE: Beta‑lactamase–negative, ampicillin‑resistant (BLNAR) H. influenzae isolates should be considered resistant to amoxicillin/clavulanic acid, despite apparent in vitro susceptibility of some BLNAR isolates to these agents. ¹

A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentrations at the site of infection necessary to inhibit growth of the pathogen. 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. 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 antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control:

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.^1,2,3 Standard amoxicillin/clavulanate potassium powder should provide the following range of MIC noted in Table 4. For the disk diffusion technique using the 30 mcg amoxicillin/clavulanate potassium disk, the criteria in Table 4 should be achieved.

Table 4: Acceptable Quality Control Ranges for Susceptibility Testing

Quality Control Organism	Minimum Inhibitory Concentration Range (mcg/mL)	Disk Diffusion Zone Diameters (mm)
Escherichia coli ATCC®abc 35218	4/2 to 16/8	17 to 22
Escherichia coli ATCC 25922	2/1 to 8/4	18 to 24
Haemophilus influenzae ATCC 49247	2/1 to 16/8	15 to 23
Staphylococcus aureus ATCC 29213	0.12/0.06 to 0.5/0.25	–
Staphylococcus aureus ATCC 25923	–	28 to 36
Streptococcus pneumoniae ATCC 49619	0.03/0.015 to 0.12/0.06	–