Augmentin XR (Amoxicillin / Clavulanate Potassium) - Description and Clinical Pharmacology

To reduce the development of drug-resistant bacteria and maintain the effectiveness of AUGMENTIN XR (amoxicillin/clavulanate potassium) and other antibacterial drugs, AUGMENTIN XR should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

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 (2 S,5 R ,6 R)-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 [2 S -[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:

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 12.6 mg (0.32 mEq) of potassium and 29.3 mg (1.27 mEq) 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 (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, 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 below.

Table 1. Mean (SD) Pharmacokinetic Parameters for Amoxicillin and Clavulanate Following Oral Administration of Two AUGMENTIN XR Tablets (2,000 mg/125 mg) 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)*	1.50 (1.00-6.00)	1.03 (0.75-3.00)
T½ (hours)	1.27 (0.20)	1.03 (0.17)

^*Median (range).

The half-life of amoxicillin after the oral administration of AUGMENTIN XR is approximately 1.3 hours, and that of clavulanate is approximately 1.0 hour.

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.

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 ≤2 mcg/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 produceβ-lactamase, and therefore, are susceptible to amoxicillin alone. Adequate and well-controlled clinical trials have established the effectiveness of amoxicillin alone in treating certain clinical infections due to S. 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 the most effective antimicrobial.

Dilution Technique

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 procedure.^1,3 Standardized procedures are based on dilution methods (broth or agar; broth for S. pneumoniae and H. influenzae) or equivalent with standardized inoculum concentration 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 criteria provided in Table 2.

Diffusion Technique

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobials. One such standardized technique requires the use of a standardized inoculum concentration.^1,4 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 zone sizes should be interpreted according to criteria provided in Table 2.

Table 2. Susceptibility Test Result Interpretive Criteria for Amoxicillin/Clavulanate Potassium

	Minimum Inhibitory Concentration (mcg/mL)			Disk Diffusion (Zone Diameter in mm)
Pathogen	S	I	R	S	I	R
Haemophilus spp.	≤4/2	Not applicable (NA)	≥8/4	≥20	NA	≤19
Klebsiella pneumoniae	≤8/4	16/8	≥32/16	≥18	14 to 17	≤13
Staphylococcus spp.	≤4/2	NA	≥8/4	≥20	NA	≤19
Streptococcus pneumoniae	≤2/1	4/2	≥8/4	NA

NOTE: 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/clavulanate acid. An amoxicillin/clavulanate acid MIC should be determined on isolates of S. pneumoniae with oxacillin zone sizes of ≤19 mm.

NOTE: β-lactamase−negative, ampicillin-resistant H. influenzae isolates must be considered resistant to amoxicillin/clavulanic acid.

A report of S (“Susceptible”) indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of I (“Intermediate”) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible antimicrobials, 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 doses of antimicrobial 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 R (“Resistant”) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of quality control microorganisms to determine the performance of the test procedures.^1,3,4 Standard amoxicillin/clavulanate potassium powder should provide the MIC ranges for the quality control organisms in Table 3. For the disk diffusion technique, the 30 mcg amoxicillin/clavulanate potassium disk should provide the zone diameter ranges for the quality control organisms in Table 3.

Table 3. Acceptable Quality Control Ranges for Amoxicillin/Clavulanate Potassium

Quality Control Organism	Minimum Inhibitory Concentration Range (mcg/mL)	Disk Diffusion (Zone Diameter Range in mm)
Escherichia coli ATCC®* 35218† (H. influenzae quality control)	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	Not applicable (NA)
Staphylococcus aureus ATCC 25923	NA	28 to 36
Streptococcus pneumoniae ATCC 49619	0.03/0.015 to 0.12/0.06	NA
*ATCC is a trademark of the American Type Culture Collection. †When using Haemophilus Test Medium (HTM).

CLINICAL STUDIES

Acute Bacterial Sinusitis

Adults with a diagnosis of acute bacterial sinusitis (ABS) were evaluated in 3 clinical studies. In one study, 363 patients were randomized to receive either AUGMENTIN XR 2,000 mg/125 mg orally every 12 hours or levofloxacin 500 mg orally daily for 10 days in a double-blind, multicenter, prospective trial. These patients were clinically and radiologically evaluated at the test of cure (day 17-28) visit. The combined clinical and radiological responses were 83.7% for AUGMENTIN XR and 84.3% for levofloxacin at the test of cure visit in clinically evaluable patients (95% CI for the treatment difference = -9.4, 8.3). The clinical response rates at the test of cure were 87.0% and 88.6%, respectively.

The other 2 trials were non-comparative, multicenter studies designed to assess the bacteriological and clinical efficacy of AUGMENTIN XR (2,000 mg/125 mg orally q12h for 10 days) in the treatment of 2288 patients with ABS. Evaluation timepoints were the same as in the prior study. Patients underwent maxillary sinus puncture for culture prior to receiving study medication. At test of cure, the clinical success rates were 87.5% and 86.6% (intention-to-treat) and 92.5% and 92.1% (per protocol populations).

Patients with acute bacterial sinusitis due to S. pneumoniae with reduced susceptibility to penicillin were accrued through enrollment in these 2 open-label non-comparative clinical trials. Microbiologic eradication rates for key pathogens in these studies are shown in the following table:

Clinical Outcome for ABS
Penicillin MICs of S. pneumoniae Isolates	Intent-To-Treat			Clinically Evaluable
	n/N *	%	95% CI †	n/N *	%	95% CI †
All S. pneumoniae	344/370	93.0	—	318/326	97.5	—
MIC ≥2.0 mcg/mL‡	35/36	97.2	85.5, 99.9	30/31	95.8	83.3, 99.9
MIC = 2.0 mcg/mL	23/24	95.8	78.9, 99.9	19/20	95.0	75.1, 99.9
MIC ≥4.0 mcg/mL§	12/12	100	73.5, 100	11/11	100	71.5, 100
H. influenzae	265/305	86.9	—	242/259	93.4	—
M. catarrhalis	94/105	89.5	—	86/90	95.6	—

^*n/N = patients with pathogen eradicated or presumed eradicated/total number of patients.

^†Confidence limits calculated using exact probabilities.

^‡ S. pneumoniae strains with penicillin MICs of ≥2 mcg/mL are considered resistant to penicillin.

^§Includes one patient each with S. pneumoniae penicillin MICs of 8 and 16 mcg/mL.

Community-Acquired Pneumonia

Four randomized, controlled, double-blind clinical studies and one non-comparative study were conducted in adults with community-acquired pneumonia (CAP). In comparative studies, 904 patients received AUGMENTIN XR at a dose of 2,000 mg/125 mg orally every 12 hours for 7 or 10 days. In the non-comparative study to assess both clinical and bacteriological efficacy, 1,122 patients received AUGMENTIN XR 2,000 mg/125 mg orally every 12 hours for 7 days. In the 4 comparative studies, the combined clinical success rate at test of cure ranged from 86.3% to 94.7% in clinically evaluable patients who received AUGMENTIN XR; in the non-comparative study, the clinical success rate was 85.6%.

Data on the efficacy of AUGMENTIN XR in the treatment of community-acquired pneumonia due to S. pneumoniae with reduced susceptibility to penicillin were accrued from the 4 controlled clinical studies and the 1 non-comparative study. The majority of these cases were accrued from the non-comparative study.

Clinical Outcome for CAP due to S. pneumoniae
Penicillin MICs of S. pneumoniae Isolates	Intent-To-Treat			Clinically Evaluable
	n/N *	%	95% CI †	n/N *	%	95% CI †
All S. pneumoniae	318/367	86.6	—	275/297	92.6	—
MIC ≥2.0 mcg/mL‡	30/35	85.7	69.7, 95.2	24/25	96.0	79.6, 99.9
MIC = 2.0 mcg/mL	22/24	91.7	73.0, 99.0	18/18	100	81.5, 100
MIC ≥ 4.0 mcg/mL§	8/11	72.7	39.0, 94.0	6/7	85.7	42.1, 99.6

^*n/N = patients with pathogen eradicated or presumed eradicated/total number of patients.

^†Confidence limits calculated using exact probabilities.

^‡ S. pneumoniae strains with penicillin MICs of ≥2 mcg/mL are considered resistant to penicillin.

^§Includes one patient each with S. pneumoniae penicillin MICs of 8 and 16 mcg/mL in the Intent-To-Treat group only.

Safety

In 2 randomized, double-blind, multicenter studies, AUGMENTIN XR (2,000 mg/125 mg orally q12h, n = 577) was compared to AUGMENTIN (875 mg/125 mg orally q12h, n = 570), administered for 7 days for the treatment of community-acquired pneumonia. Adverse events, regardless of relationship to test drug, were reported by 44.4% of patients who received AUGMENTIN XR (versus 46.3% in comparator group). Treatment-related adverse events were reported in 21.7% of patients who received AUGMENTIN XR (versus 21.2% in comparator group); most were mild and transient in nature. Adverse events which led to withdrawal were reported by 2.8% of patients who received AUGMENTIN XR (versus 5.3% in comparator group). In each group, the most frequently reported adverse events were diarrhea (14.4% versus 13.0%, p = 0.47), nausea (3.5 % versus 4.4%), and headache (3.5% versus 3.2%). Only 2 patients (0.3%) who received AUGMENTIN XR and 3 patients (0.5%) in the comparator group withdrew due to diarrhea. Serious adverse events considered suspected or probably related to test drug were reported in 0.3% of patients (versus 0.5% in comparator).