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Moxatag (Amoxicillin) - Description and Clinical Pharmacology

 
 



DESCRIPTION

MOXATAG (amoxicillin extended-release) tablets for oral administration are provided as blue film-coated tablets that contain 775 mg of amoxicillin as the trihydrate and are printed with ”MB-111” on one side in black edible ink.

Amoxicillin is a semi-synthetic antibiotic, an analog of ampicillin, with bactericidal activity against gram-positive and gram-negative microorganisms.

Chemically, amoxicillin 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. Its chemical name is amoxicillin. It may be represented structurally as:

The amoxicillin molecular formula is C16H19N3O5S·3H2O, and the molecular weight is 419.45.

MOXATAG is an extended release tablet formulation consisting of three components, one immediate-release and two delayed-release, each containing amoxicillin. The three components are combined in a specific ratio to prolong the release of amoxicillin from MOXATAG compared to immediate-release amoxicillin.

Each tablet contains amoxicillin, crospovidone, FD&C Blue #2 lake, hypromellose, hypromellose acetate succinate, iron oxide, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, polyethylene glycol 400, polyoxyl 35 castor oil, shellac, colloidal silicon dioxide, sodium lauryl sulfate, talc, titanium dioxide, and triethyl citrate.

CLINICAL PHARMACOLOGY

Mechanism of Action

Amoxicillin is an antibacterial drug. [see Clinical Pharmacology (12.4)]

Pharmacokinetics

MOXATAG is an extended-release formulation of amoxicillin intended to provide once-daily dosing. Following the administration of MOXATAG with a low-fat meal in healthy subjects, mean amoxicillin AUC0-∞, Cmax, and Tmax values were 29.8 μg•h/mL, 6.6 μg/mL and 3.1 hours, respectively. The mean plasma concentration-time curve is shown below in Figure 1.

Figure 1. Mean Amoxicillin Plasma Concentrations Following a Single Oral Dose of MOXATAG With a Low-Fat Meal in Healthy Subjects (N=20)

Figure 1. Mean Amoxicillin Plasma Concentrations Following a Single Oral Dose of MOXATAG With a Low-Fat Meal in Healthy Subjects (N=20)

Administration of MOXATAG with food decreases the rate, but not the extent of amoxicillin absorption. Compared to immediate-release amoxicillin suspension, the rate of amoxicillin absorption following administration of MOXATAG was slower, resulting in a lower Cmax and longer Tmax. Total amoxicillin exposure (AUC) achieved with MOXATAG is similar to that observed after oral administration of a comparable dose of immediate-release amoxicillin suspension.

Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when meninges are inflamed. Amoxicillin is approximately 20% protein bound in human serum.

Amoxicillin is primarily cleared by renal excretion. Approximately 60% of an oral dose of immediate-release amoxicillin is eliminated unchanged in urine. The half-life of amoxicillin after oral administration of MOXATAG is approximately 1.5 hours, similar to that of immediate-release amoxicillin. No accumulation of amoxicillin was observed after once-daily dosing of 775 mg of MOXATAG for 7 days.

Drug Interactions

In a study of healthy adult subjects, amoxicillin AUC was similar whereas Cmax increased approximately 35% following the administration of lansoprazole with MOXATAG given with food.

Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use of MOXATAG and probenecid may result in increased and prolonged blood levels of amoxicillin. The clinical relevance of this finding has not been evaluated.

Microbiology

Amoxicillin is a semi-synthetic antimicrobial belonging to the penicillin class of antimicrobials with activity against gram-positive bacteria.

Mechanism of Action

Amoxicillin exerts its bactericidal action against susceptible organisms during the stage of multiplication. It acts through the inhibition of biosynthesis of cell wall mucopeptide.

Mechanism of Resistance

To date there are no known mechanisms of resistance to penicillin or amoxicillin in Streptococcus pyogenes.

MOXATAG has been shown to be active in vitro against isolates of the microorganism S. pyogenes and in clinical infections as described in the INDICATIONS AND USAGE section.

Facultative Gram-Positive Bacteria:

Streptococcus pyogenes

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptibility breakpoint of amoxicillin (as determined by susceptibility tests using the class representative agents penicillin or ampicillin).

Facultative Gram-Positive Bacteria:

Streptococcus spp. (Group B, C, and G; β-hemolytic)

Susceptibility Test Methods:

When available, the clinical microbiology laboratory should provide cumulative results of the 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.

Susceptibility testing of penicillins (such as amoxicillin) and other β-lactams approved by FDA for the treatment of Group A streptococcus (S. pyogenes) is not routinely necessary for clinical purposes. Isolates of Group A streptococcus resistant to amoxicillin have not been recognized and therefore all isolates can be considered susceptible to amoxicillin However, susceptibility tests can be conducted using dilution or diffusion techniques employing penicillin or ampicillin to predict susceptibility to amoxicillin.

Dilution Techniques

Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure1,3. Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of penicillin or ampicillin. The susceptibility of Group A streptococcus to penicillin or amoxicillin should be interpreted according to the criteria in Table 2.

Diffusion Technique

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of a standardized inoculum concentration. This procedure uses paper disks impregnated with 10 units penicillin or 10 mcg ampicillin to test the susceptibility of S. pyogenes to penicillin or amoxicillin. Reports from the laboratory providing results of the standard single-disk susceptibility test should be interpreted according to the criteria in Table 2

Table 2. Susceptibility Test Results Interpretive Criteria for Beta-Hemolytic Streptococci including Streptococcus pyogenes
AntimicrobialMinimum Inhibitory
Concentration (mcg/mL)
Disk Diffusion
(zone diameter in mm)
Penicillin≤0.12 = Susceptible≥24 = Susceptible
Ampicillin≤0.25 = Susceptible≥24 = Susceptible

The current absence of data on resistant isolates precludes defining any categories other than “Susceptible”. Isolates yielding results suggestive of a “nonsusceptible” category should be retested, and if the result is confirmed, the isolate should be submitted to a reference laboratory for further testing.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test. Standard penicillin or ampicillin powders should provide the MIC ranges provided in Table 3. For the disk diffusion technique using the 10 unit penicillin disk or 10 μg ampicillin disk the criteria in Table 3 should be achieved.

Table 3. Acceptable Quality Control Ranges for Susceptibility Testing

ATCC = American Type Culture Collection

QC OrganismAntimicrobialMinimum Inhibitory
Concentration (mcg/mL)
Disk Diffusion
(zone diameter in mm)
Streptococcus pneumoniae Penicillin0.25 – 124 – 30
ATCC 49619Ampicillin0.06 – 0.2530 - 36

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. Studies to detect mutagenic potential of amoxicillin alone have not been conducted; however, the following information is available from tests on a 4:1 mixture of amoxicillin and potassium clavulanate (Augmentin). Augmentin was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Augmentin was weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at doses that were also associated with decreased cell survival. Augmentin was negative in the mouse micronucleus test, and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays. In a multi-generation reproduction study in rats, no impairment of fertility or other adverse reproductive effects were seen at doses up to 500 mg/kg (approximately 6 times the human dose in mg/m2).

CLINICAL STUDIES

In a randomized, parallel-group, multi-center, double-blind, double-dummy study in adults and pediatrics (age≥ 12 years) with tonsillitis and/or pharyngitis secondary to S. pyogenes, MOXATAG 775 mg QD for 10 days was non-inferior to penicillin VK 250 mg QID for 10 days.

Using strict evaluability and microbiologic response criteria 4-8 days post-therapy, the following bacteriological eradication rates and statistical outcomes in the per-protocol (PPb) and modified intent-to-treat (mITT) populations were obtained (Table 4). The mITT population included all randomized patients with a positive throat culture for S. pyogenes at baseline. The PPb population included mITT patients who had post-therapy cultures, were compliant with treatment, and didn't have major protocol violations.

Table 4. Bacteriological Eradication Rates in Patients with Tonsillitis and/or Pharyngitis
Study
Population
MOXATAG Penicillin VK Rate Difference
95% CI (%)
PPb198/233
(85.0%)
191/229
(83.4%)
1.6 (-5.1, 8.2)
mITT204/256
(79.7%)
206/264
(78.0%)
1.7 (-5.4, 8.7)

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