Amoxicillin and Clavulanate Potassium Extended Release (Page 5 of 6)

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^a ATCC = American Type Culture Collection.

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^b QC strain recommended for testing beta-lactam/beta-lactamase inhibitor combinations.^c This strain may lose its plasmid and develop susceptibility to beta-lactam antimicrobial agents after repeated transfers onto media. Minimize by removing new culture from storage at least monthly, or whenever the strain begins to show increased zone diameters to ampicillin, piperacillin or ticarcillin.¹

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long‑term studies in animals have not been performed to evaluate carcinogenic potential. The mutagenic potential of Amoxicillin and Clavulanate Potassium was investigated in vitro with an Ames test, a human lymphocyte cytogenetic assay, a yeast test, and a mouse lymphoma forward mutation assay, and in vivo with mouse micronucleus tests and a dominant lethal test. All were negative apart from the in vitro mouse lymphoma assay, where weak activity was found at very high, cytotoxic concentrations. Amoxicillin and Clavulanate Potassium at oral doses of up to 1,200 mg/kg/day (1.9 times the maximum human dose of amoxicillin and 15 times the maximum human dose of clavulanate based on body surface area) was found to have no effect on fertility and reproductive performance in rats dosed with a 2:1 ratio formulation of amoxicillin:clavulanate.

14 CLINICAL STUDIES

14.1 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 Amoxicillin and Clavulanate Potassium Extended Release Tablets 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 84% for Amoxicillin and Clavulanate Potassium Extended Release Tablets and 84% 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% and 89%, respectively.

The other 2 trials were non‑comparative, multicenter studies designed to assess the bacteriological and clinical efficacy of Amoxicillin and Clavulanate Potassium Extended Release Tablets (2,000 mg/125 mg orally every 12 hours 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. 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 Table 5.

Table 5: Clinical Outcome for ABS

* c
Penicillin MICs of S. pneumoniae Isolates	Intent-To-Treat			Clinically Evaluable
	n/Na	%	95% CIb	n/Na	%	95% CIb
All S. pneumonia	344/370	93	—	318/326	98	—
MIC ≥ 2.0 mcg/mL *	35/36	97	85.5, 99.9	30/31	96	83.3, 99.9
MIC = 2.0 mcg/mL	23/24	96	78.9, 99.9	19/20	95	75.1, 99.9
MIC ≥ 4.0 mcg/mLd	12/12	100	73.5, 100	11/11	100	71.5, 100
H. influenza	265/305	87	—	242/259	93	—
M. catarrhalis	94/105	90	—	86/90	96	—

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

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^b Confidence limits calculated using exact probabilities.^c S. pneumoniae strains with penicillin MICs of ≥ 2 mcg/mL are considered resistant to penicillin.^d Includes one patient each with S. pneumoniae penicillin MICs of 8 and 16 mcg/mL.

14.2 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 Amoxicillin and Clavulanate Potassium Extended Release Tablets 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 Amoxicillin and Clavulanate Potassium Extended Release Tablets 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% to 95% in clinically evaluable patients who received Amoxicillin and Clavulanate Potassium Extended Release Tablets.

Data on the efficacy of Amoxicillin and Clavulanate Potassium Extended Release Tablets 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. Results are shown in Table 6.

Table 6: Clinical Outcome for CAP due to S. pneumoniae

* c
Penicillin MICs of S. pneumonia Isolates	Intent-To-Treat			Clinically Evaluable
	n/Na	%	95% CIb	n/Na	%	95% CIb
All S. pneumonia	318/367	87	—	275/297	93	—
MIC ≥ 2.0 mcg/mL *	30/35	86	69.7, 95.2	24/25	96	79.6, 99.9
MIC = 2.0 mcg/mL	22/24	92	73.0, 99.0	18/18	100	81.5, 100
MIC ≥ 4.0 mcg/mLd	8/11	73	39.0, 94.0	6/7	86	42.1, 99.6