Amoxicillin and Clavulanate Tablets

Name: Amoxicillin and Clavulanate Tablets

Overdosage


In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures as required. A prospective study of 51 pediatric patients at a poison-control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms 1.

Interstitial nephritis resulting in oliguric renal failure has been reported in patients after overdosage with amoxicillin and clavulanate potassium.

Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin and clavulanate potassium overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin and clavulanate potassium crystalluria.

Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of amoxicillin and clavulanate potassium. Amoxicillin and clavulanate potassium may be removed from circulation by hemodialysis. [see Dosage and Administration (2.3)]

Amoxicillin and Clavulanate Tablets - Clinical Pharmacology

Mechanism of Action


Amoxicillin and clavulanate potassium is an antibacterial drug. [see Microbiology 12.4]

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.


Table 3: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters ab With Amoxicillin and Clavulanate Potassium Tablets
Dose and Regimen
C max (mcg/mL)
AUC 0 to 24 (mcg*h/mL)
Amoxicillin and 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
a
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.
b
Amoxicillin and clavulanate potassium administered at the start of a light meal.

Table 4: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters a,b with Amoxicillin and Clavulanate Potassium Powder 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
400/57 mg (5 mL of suspension)
6.94 ± 1.24
1.10 ± 0.42
17.29 ± 2.28
2.34 ± 0.94
400/57 mg (1 chewable tablet)
6.67 ± 1.37
1.03 ± 0.33
17.24 ± 2.64
2.17 ± 0.73

a Mean (± standard deviation) values of 28 normal adults. Peak concentrations occurred approximately 1 hour after the dose.

b Amoxicillin/clavulanate potassium administered at the start of a light meal.


Oral administration of 5 mL of 250 mg/62.5 mg per 5 mL suspension of amoxicillin and clavulanate potassium or the equivalent dose of 10 mL of 125 mg/31.5 mg per 5 mL suspension of amoxicillin and 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/5 mL suspension of amoxicillin and clavulanate potassium or equivalent dose of 10 mL of 125 mg/5 mL suspension of amoxicillin and clavulanate potassium were administered to normal adults. One 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium or two  125 mg/31.25 mg chewable tablet of amoxicillin and clavulanate potassium are equivalent to 5 mL of 250 mg/5 mL suspension of amoxicillin and clavulanate potassium and provide similar serum concentrations of amoxicillin and clavulanic acid.


Amoxicillin serum concentrations achieved with amoxicillin and 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 and clavulanate potassium in adults and children.


Absorption:


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

 

Distribution:


Neither component in amoxicillin and 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 and 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 and 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 and clavulanate potassium.

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 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 Test Methods


When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals 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 2,3 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 5.


Diffusion techniques:  


Quantitative methods that require measurement of zone diameters can 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 3,4. This procedure uses paper disks impregnated with 30 mcg amoxicillin/clavulanic acid (20 mcg amoxicillin plus 10 mcg clavulanic acid) to test the susceptibility of bacteria to amoxicillin/clavulanic acid. The disc diffusion interpretive criteria are provided in Table 5.


Table 5: Susceptibility Test Interpretive Criteria for Amoxicillin Clavulanic Acid
Minimum Inhibitory Concentrations (mcg/mL)
Disk Diffusion (zone diameters in mm)
Pathogen
S      
I
R
S
I
R
Enterobacteriaceae
8/4
16/8
32/16
≥ 18
14 to 17
≤ 13
Haemophilus influenzae and Staphylococcus aureus
4/2
---
8/4
≥ 20
----
≤ 19

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 2,3,4. Standard amoxicillin/clavulanic acid powder should provide the following range of MIC values noted in Table 6 for the diffusion technique using the 30 mcg amoxicillin/clavulanic acid (20 mcg amoxicillin plus 10 mcg clavulanic acid) disk, the criteria in Table 6 should be achieved.


Table 6: Acceptable Quality Control Ranges for Amoxicillin/Clavulanic Acid
QC Strain
Minimum Inhibitory
Concentration (mcg/mL)
Disk Diffusion (zone
diameter in mm)
Escherichia coli ATCC 25922
2/1 to 8/4
18 to 24
Escherichia coli ATCC 35218
4/2 to 16/8
17 to 22
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 29523
-
28 to 36

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility


Long-term studies in animals have not been performed to evaluate carcinogenic potential.

Amoxicillin and clavulanate potassium (4:1 ratio formulation of amoxicillin:clavulanate) was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and clavulanate potassium 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. Amoxicillin and clavulanate potassium 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.

Amoxicillin and clavulanate potassium tablets (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses of up to 1,200 mg/kg/day was found to have no effect on fertility and reproductive performance in rats. Based on body surface area, this dose of amoxicillin is approximately 4 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, the dose multiple is approximately 9 times higher than the maximum recommended adult human oral dose (125 mg every 8 hours), also based on body surface area.

How Supplied/Storage and Handling


Amoxicillin and Clavulanate Potassium Tablets USP are supplied as follows:

Amoxicillin and clavulanate potassium tablets USP, 250 mg/125 mg

are white to off-white colored, capsule shaped, biconvex, film-coated tablets, debossed with “I 05” on one side and plain on the other side. Each tablet contains 250 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt.  They are available as follows.

Bottles of 30                                               NDC 42571-160-30
Bottles of 100                                             NDC 42571-160-01
Carton of 100 (10x10 Unit-dose)           NDC 42571-160-11

Amoxicillin and clavulanate potassium tablets USP, 500 mg/125 mg are white to off-white colored, capsule shaped, biconvex, film-coated tablets debossed with “I 06” on one side and plain on the other side. Each tablet contains 500 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt.  They are available as follows.

Bottles of 20                                               NDC 42571-161-42
Bottles of 100                                             NDC 42571-161-01
Carton of 100 (10x10 Unit-dose)           NDC 42571-161-11

Amoxicillin and clavulanate potassium tablets USP, 875 mg/125 mg are white to off-white colored, capsule shaped, biconvex, film-coated tablets debossed with “I 07” on one side score line on the other side. Each tablet contains 875 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt.  They are available as follows.

Bottles of 20                                               NDC 42571-162-42
Bottles of 100                                             NDC 42571-162-01
Carton of 40 (4x10 Unit-dose)                NDC 42571-162-44

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Advise patients to keep in a closed container.

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

Package label.principal display panel


NDC 42571-160-30
Amoxicillin and Clavulanate
Potassium Tablets, USP
250 mg/125 mg*
Rx Only
30 Tablets
MICRO LABS




NDC 42571-160-11
Amoxicillin and Clavulante
Potassium Tablets, USP
250 mg/125 mg*
Rx Only
100 Tablets (10x10 Unit-dose)
MICRO LABS





NDC 42571-161-42
Amoxicillin and Clavulante
Potassium Tablets, USP
500 mg/125 mg*
Rx Only
20 Tablets
MICRO LABS




NDC 42571-161-11
Amoxicillin and Clavulante
Potassium Tablets, USP
500 mg/125 mg*
Rx Only
100 Tablets (10x10 Unit-dose)




NDC 42571-162-42
Amoxicillin and Clavulanate
Potassium Tablets, USP
875 mg/125 mg*
Rx Only
20 Tablets
MICRO LABS LIMITED





NDC 42571-162-44
Amoxicillin and Clavulanate
Potassium Tablets, USP
875 mg/125 mg*
Rx Only
40 Tablets (4 x 10 Unit-dose)
MICRO LABS LIMITED 


AMOXICILLIN AND CLAVULANATE POTASSIUM  
amoxicillin and clavulanate potassium tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:42571-160
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
AMOXICILLIN (AMOXICILLIN ANHYDROUS) AMOXICILLIN ANHYDROUS 250 mg
CLAVULANATE POTASSIUM (CLAVULANIC ACID) CLAVULANIC ACID 125 mg
Inactive Ingredients
Ingredient Name Strength
SILICON DIOXIDE  
HYPROMELLOSE 2910 (5 MPA.S)  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
POLYETHYLENE GLYCOL 400  
SODIUM STARCH GLYCOLATE TYPE A POTATO  
TITANIUM DIOXIDE  
ETHYLCELLULOSE (10 MPA.S)  
TALC  
Product Characteristics
Color white (white to off-white) Score no score
Shape CAPSULE (biconvex) Size 17mm
Flavor Imprint Code I05
Contains     
Packaging
# Item Code Package Description
1 NDC:42571-160-30 30 TABLET, FILM COATED in 1 BOTTLE
2 NDC:42571-160-01 100 TABLET, FILM COATED in 1 BOTTLE
3 NDC:42571-160-11 10 BLISTER PACK in 1 CARTON
3 NDC:42571-160-32 10 TABLET, FILM COATED in 1 BLISTER PACK
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA205707 03/01/2017
AMOXICILLIN AND CLAVULANATE POTASSIUM  
amoxicillin and clavulanate potassium tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:42571-161
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
AMOXICILLIN (AMOXICILLIN ANHYDROUS) AMOXICILLIN ANHYDROUS 500 mg
CLAVULANATE POTASSIUM (CLAVULANIC ACID) CLAVULANIC ACID 125 mg
Inactive Ingredients
Ingredient Name Strength
SILICON DIOXIDE  
HYPROMELLOSE 2910 (5 MPA.S)  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
POLYETHYLENE GLYCOL 400  
SODIUM STARCH GLYCOLATE TYPE A POTATO  
TITANIUM DIOXIDE  
ETHYLCELLULOSE (10 MPA.S)  
TALC  
Product Characteristics
Color white (white to off-white) Score no score
Shape CAPSULE (biconvex) Size 19mm
Flavor Imprint Code I06
Contains     
Packaging
# Item Code Package Description
1 NDC:42571-161-42 20 TABLET, FILM COATED in 1 BOTTLE
2 NDC:42571-161-01 100 TABLET, FILM COATED in 1 BOTTLE
3 NDC:42571-161-11 10 BLISTER PACK in 1 CARTON
3 NDC:42571-161-32 10 TABLET, FILM COATED in 1 BLISTER PACK
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA205707 03/01/2017
AMOXICILLIN AND CLAVULANATE POTASSIUM  
amoxicillin and clavulanate potassium tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:42571-162
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
AMOXICILLIN (AMOXICILLIN ANHYDROUS) AMOXICILLIN ANHYDROUS 875 mg
CLAVULANATE POTASSIUM (CLAVULANIC ACID) CLAVULANIC ACID 125 mg
Inactive Ingredients
Ingredient Name Strength
SILICON DIOXIDE  
HYPROMELLOSE 2910 (5 MPA.S)  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
POLYETHYLENE GLYCOL 400  
SODIUM STARCH GLYCOLATE TYPE A POTATO  
TITANIUM DIOXIDE  
ETHYLCELLULOSE (10 MPA.S)  
TALC  
Product Characteristics
Color white (white to off-white) Score 2 pieces
Shape CAPSULE (biconvex) Size 22mm
Flavor Imprint Code I07
Contains     
Packaging
# Item Code Package Description
1 NDC:42571-162-42 20 TABLET, FILM COATED in 1 BOTTLE
2 NDC:42571-162-01 100 TABLET, FILM COATED in 1 BOTTLE
3 NDC:42571-162-44 4 BLISTER PACK in 1 CARTON
3 NDC:42571-162-43 4 TABLET, FILM COATED in 1 BLISTER PACK
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA204755 03/01/2017
Labeler - Micro Labs Limited (862174955)
Registrant - Micro Labs Limited (862174955)
Revised: 09/2017   Micro Labs Limited
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