Amoxicillin,Clavulanate 875/125mg

/Amoxicillin,Clavulanate 875/125mg
Amoxicillin,Clavulanate 875/125mg2018-09-06T09:12:40+00:00

Prescription Drug Name:

Amoxicillin,Clavulanate 875/125mg

ID:

8c358cd9-f387-47d9-946f-c0551f5a6501

Code:

34391-3

Clinical Pharmacology


id: 53007657-e40b-4e9f-9a01-55e648e5a3ad
displayName: CLINICAL PHARMACOLOGY SECTION
FDA Article Code: 34090-1

Amoxicillin and clavulanate potassium are well absorbed from the
gastrointestinal tract after oral administration of Amoxicillin and Clavulanate
Potassium Tablets. Dosing in the fasted or fed state has minimal effect on the
pharmacokinetics of amoxicillin. While Amoxicillin and Clavulanate Potassium
Tablets can be given without regard to meals, absorption of clavulanate
potassium when taken with food is greater relative to the fasted state. In 1
study, the relative bioavailability of clavulanate was reduced when Amoxicillin
and Clavulanate Potassium Tablets were dosed at 30 and 150 minutes after the
start of a high-fat breakfast. The safety and efficacy of Amoxicillin and
Clavulanate Potassium Tablets have been established in clinical trials where
Amoxicillin and Clavulanate Potassium Tablets were taken without regard to
meals.
Mean* amoxicillin and clavulanate potassium pharmacokinetic parameters are
shown in the table below:

Dose and
regimen   
AUC0-24
(mcg • hr/mL) 
Cmax
(mcg/mL)
amoxicillin/clavulanate

potassium

amoxicillin (±S.D.) clavulanate
potassium
(±S.D.)
amoxicillin
(±S.D.)
clavulanate
potassium
(±S.D.) 
250 mg/125 mg q8h 26.7 ± 4.56 12.6 ± 3.25 3.3 ± 1.12 1.5 ± 0.70
500 mg/125 mg q12h 33.4 ± 6.76 8.6 ± 1.95 6.5 ± 1.41 1.8 ± 0.61
500 mg/125 mg q8h 53.4 ± 8.87 15.7 ± 3.86 7.2 ± 2.26 2.4 ± 0.83
875 mg/125 mg q12h 53.5 ± 12.31 10.2 ± 3.04 11.6 ± 2.78 2.2 ± 0.99
*Mean values of 14 normal volunteers (n = 15 for clavulanate potassium in the
low-dose regimens). Peak concentrations occurred approximately 1.5 hours after
the dose.
Administered at the start of a light meal.
Amoxicillin serum concentrations achieved with Amoxicillin and Clavulanate
Potassium Tablets are similar to those produced by the oral administration of
equivalent doses of amoxicillin alone. The half-life of amoxicillin after the
oral administration of Amoxicillin and Clavulanate Potassium Tablets is 1.3
hours and that of clavulanic acid is 1.0 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 Amoxicillin and Clavulanate Potassium tablet
250 mg/125 mg or 500 mg/125 mg.
Concurrent administration of probenecid delays amoxicillin excretion but does
not delay renal excretion of clavulanic acid.
Neither component in Amoxicillin and Clavulanate Potassium Tablets is highly
protein-bound; clavulanic acid 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, the spectrum of activity does not include organisms
which produce these enzymes. Clavulanic acid is a β-lactam, structurally related
to the penicillins, 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 responsible for transferred
drug resistance.
The formulation of amoxicillin and clavulanic acid in Amoxicillin and
Clavulanate Potassium Tablets 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. Thus, Amoxicillin and Clavulanate Potassium Tablets
possess the properties of a broad-spectrum antibiotic and a β-lactamase
inhibitor.
Amoxicillin/clavulanic acid has been shown to be active against most strains
of the following microorganisms, both in vitro and in clinical infections as
described in INDICATIONS AND USAGE.
Gram-Positive Aerobes:
Staphylococcus aureus (β-lactamase and
non-β-lactamase-producing)

Staphylococci which are resistant to methicillin/oxacillin
must be considered resistant to amoxicillin/clavulanic acid. Gram-Negative Aerobes:
Enterobacter species (Although most strains of Enterobacter species are resistant in vitro, clinical
efficacy has been demonstrated with Amoxicillin and Clavulanate Potassium
Tablets in urinary tract infections caused by these organisms.)
Escherichia coli (β-lactamase and
non-β-lactamase-producing)
Haemophilus influenzae
(β-lactamase and non-β-lactamase-producing)
Klebsiella species (All known strains are
β-lactamase-producing)
Moraxella catarrhalis
(β-lactamase and non-β-lactamase-producing)
The following in vitro data are available, but
their clinical significance is unknown
.
Amoxicillin/clavulanic acid exhibits in vitro minimal inhibitory
concentrations (MICs) of 2 mcg/mL or less against most (≥90%) strains of Streptococcus
pneumoniae
§; MICs of 0.06 mcg/mL or less against most (≥90%) strains of
Neisseria gonorrhoeae; MICs of 4 mcg/mL or less
against most (≥90%) strains of staphylococci and anaerobic bacteria; and MICs of
8 mcg/mL or less against most (≥90%) strains of other listed organisms. However,
with the exception of organisms shown to respond to amoxicillin alone, the
safety and effectiveness of amoxicillin/clavulanic acid in treating clinical
infections due to these microorganisms have not been established in adequate and
well-controlled clinical trials.
§Because amoxicillin
has greater in vitro activity against S. pneumoniae
than does ampicillin or penicillin, the majority of S. pneumoniae strains with intermediate susceptibility to
ampicillin or penicillin are fully susceptible to amoxicillin.
Gram-Positive Aerobes:
Enterococcus faecalis

Staphylococcus epidermidis (β-lactamase and
non-β-lactamase-producing)
Staphylococcus saprophyticus
(β-lactamase and non-β-lactamase-producing)
Streptococcus pneumoniae
║¶

Streptococcus pyogenes
║¶

viridans group Streptococcus
║¶ Gram-Negative Aerobes:
Eikenella corrodens (β-lactamase and
non-β-lactamase-producing)
Neisseria
gonorrhoeae

(β-lactamase and
non-β-lactamase-producing)
Proteus mirabilis
(β-lactamase and non-β-lactamase-producing)
Anaerobic Bacteria:
Bacteroides species, including Bacteroides fragilis (β-lactamase and
non-β-lactamase-producing)
Fusobacterium species
(β-lactamase and non-β-lactamase-producing)
Peptostreptococcus species¶

Adequate and well-controlled clinical trials have established the
effectiveness of amoxicillin alone in treating certain clinical infections due
to these organisms.
These are
non-β-lactamase-producing organisms, and therefore, are susceptible to
amoxicillin alone.
Susceptibility Testing 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 procedure. Standardized procedures are based on
a dilution method1 (broth or agar) or equivalent with standardized inoculum
concentrations 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 the following criteria:
RECOMMENDED RANGES FOR AMOXICILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING For Gram-Negative Enteric Aerobes

MIC (mcg/mL)          Interpretation
≤8/4 Susceptible (S)           
16/8 Intermediate (I)
≥32/16 Resistant (R)
For  Staphylococcus**
and  Haemophilus  species
MIC (mcg/mL)          Interpretation              
≤4/2 Susceptible (S)
≥8/4 Resistant (R)
** Staphylococci which are susceptible to amoxicillin/clavulanic acid but
resistant to methicillin/oxacillin must be considered as resistant.


For 
S. pneumoniae
from nonmeningitis sources 

Isolates
should be tested using amoxicillin/clavulanic acid and the following criteria
should be used:

MIC (mcg/mL)          Interpretation              
≤2/1 Susceptible (S)
4/2 Intermediate (I)
≥8/4 Resistant (R)
Note: These interpretive criteria are based on the
recommended doses for respiratory tract infections.
A report of “Susceptible” indicates that the pathogen is likely to be
inhibited if the antimicrobial compound in the blood reaches the concentration
usually achievable. 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 or in situations where high dosage of drug can be
used. This category also provides a buffer zone, which prevents small
uncontrolled technical factors from causing major discrepancies in
interpretation. A report of “Resistant” indicates that the pathogen is not
likely to be inhibited if the antimicrobial compound in the blood reaches the
concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory
control microorganisms to control the technical aspects of the laboratory
procedures. Standard amoxicillin/clavulanate potassium powder should provide the
following MIC values:
Microorganism MIC Range (mcg/mL)††       
Escherichia
coli ATCC 25922
2 to 8
Escherichia coli ATCC 35218 4 to 16
Enterococcus faecalis ATCC
29212
0.25 to 1.0
Haemophilus influenzae ATCC
49247
2 to 16
Staphylococcus aureus ATCC
29213
0.12 to 0.5
Streptococcus pneumoniae
ATCC 49619     
0.03 to 0.12
††  Expressed as concentration of amoxicillin in the
presence of clavulanic acid at a constant 2 parts amoxicillin to 1 part
clavulanic acid.
Diffusion Techniques: 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 standardized inoculum
concentrations. This procedure uses paper disks impregnated with 30 mcg of
amoxicillin/clavulanate potassium (20 mcg amoxicillin plus 10 mcg clavulanate
potassium) to test the susceptibility of microorganisms to
amoxicillin/clavulanic acid.
Reports from the laboratory providing results of the standard single-disk
susceptibility test with a 30-mcg amoxicillin/clavulanate acid (20 mcg
amoxicillin plus 10 mcg clavulanate potassium) disk should be interpreted
according to the following criteria:
RECOMMENDED RANGES FOR AMOXICILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING For Staphylococcus
‡‡

species and H. influenzae
a
Zone Diameter (mm)   Interpretation             
≥20 Susceptible (S)
≤19 Resistant (R)
For  Other Organisms Except 
S.  pneumoniae
b and 
N. gonorrhoeae
c
Zone Diameter (mm)   Interpretation             
≥18 Susceptible (S)
14 to 17 Intermediate (I)
≤13 Resistant (R)
‡‡
Staphylococci which are
resistant to methicillin/oxacillin must be considered as resistant to
amoxicillin/clavulanic acid.
a A broth microdilution
method should be used for testing H. influenzae.  Beta-lactamase-negative,
ampicillin-resistant strains must be considered resistant to
amoxicillin/clavulanic acid. 
b 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/clavulanic acid. 
An amoxicillin/clavulanic acid MIC should be determined on isolates of S.
pneumoniae with oxacillin zone sizes of ≤19 mm. 
c A
broth microdilution method should be used for testing N. gonorrhoeae and
interpreted according to penicillin breakpoints.
Interpretation should be as stated above for results using dilution
techniques. Interpretation involves correlation of the diameter obtained in the
disk test with the MIC for amoxicillin/clavulanic acid.
As with standardized dilution techniques, diffusion methods require the use
of laboratory control microorganisms that are used to control the technical
aspects of the laboratory procedures. For the diffusion technique, the 30 mcg
amoxicillin/clavulanate potassium (20 mcg amoxicillin plus 10 mcg clavulanate
potassium) disk should provide the following zone diameters in these laboratory
quality control strains:
Microorganism Zone Diameter (mm)               
Escherichia
coli ATCC 25922
19 to 25
Escherichia
coli ATCC 35218
18 to 22
Staphylococcus
aureus ATCC 25923      
28 to 36 

Indication and Usage


id: f981a2e0-06b7-499e-b5fe-b8db93baa0fb
displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9

Amoxicillin and Clavulanate Potassium Tablets are indicated in
the treatment of infections caused by susceptible strains of the designated
organisms in the conditions listed below:
Lower Respiratory
Tract Infections
– caused by β-lactamase-producing strains of H. influenzae and M.
catarrhalis
.
Otitis Media – caused by
β-lactamase-producing strains of H. influenzae and
M. catarrhalis.
Sinusitis
– caused by β-lactamase-producing strains of H. influenzae
and M. catarrhalis.
Skin
and Skin Structure Infections
– caused by β-lactamase-producing strains
of S. aureus, E. coli, and
Klebsiella spp.
Urinary Tract
Infections
– caused by β-lactamase-producing strains of E. coli, Klebsiella spp., and
Enterobacter spp.
While Amoxicillin and Clavulanate Potassium Tablets are indicated only for
the conditions listed above, infections caused by ampicillin-susceptible
organisms are also amenable to treatment with Amoxicillin and Clavulanate
Potassium Tablets due to their amoxicillin content; therefore, mixed infections
caused by ampicillin-susceptible organisms and β-lactamase-producing organisms
susceptible to Amoxicillin and Clavulanate Potassium Tablets should not require
the addition of another antibiotic. Because amoxicillin has greater in vitro activity against S. pneumoniae
than does ampicillin or penicillin, the majority of S. pneumoniae strains with intermediate susceptibility to
ampicillin or penicillin are fully susceptible to amoxicillin and Amoxicillin
and Clavulanate Potassium Tablets. (See Microbiology)
To reduce the development of drug-resistant bacteria and maintain the
effectiveness of Amoxicillin and Clavulanate Potassium Tablets and other
antibacterial drugs, Amoxicillin and Clavulanate Potassium Tablets should be
used only to treat or prevent infections that are proven or strongly suspected
to be caused by susceptible bacteria. When culture and susceptibility
information are available, they should be considered in selecting or modifying
antibacterial therapy. In the absence of such data, local epidemiology and
susceptibility patterns may contribute to the empiric selection of therapy.
Bacteriological studies, to determine the causative organisms and their
susceptibility to Amoxicillin and Clavulanate Potassium Tablets, should be
performed together with any indicated surgical procedures.

Contraindications


id: 2eff168e-fba1-4024-8509-c66118cc60ef
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3

Amoxicillin and Clavulanate Potassium Tablets are contraindicated in patients
with a history of allergic reactions to any penicillin. It is also
contraindicated in patients with a previous history of cholestatic
jaundice/hepatic dysfunction associated with Amoxicillin and Clavulanate
Potassium Tablets.

Warnings


id: 2f7258a0-e061-4c51-9090-40ba90ac6ebe
displayName: WARNINGS SECTION
FDA Article Code: 34071-1

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC)
REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS
ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN
HYPERSENSITIVITY AND/OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE
HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY
WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE
INITIATING THERAPY WITH AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS, CAREFUL
INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO
PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS,
AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS SHOULD BE DISCONTINUED AND THE
APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC REACTIONS
REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS
STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE
ADMINISTERED AS INDICATED.
Clostridium difficile

associated diarrhea (CDAD) has been reported with use of nearly all
antibacterial agents, including Amoxicillin and Clavulanate Potassium Tablets,
and may range in severity from mild diarrhea to fatal colitis. Treatment with
antibacterial agents alters the normal flora of the colon leading to overgrowth
of

C. difficile
.
C. difficile produces toxins A and B which
contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as
these infections can be refractory to antimicrobial therapy and may require
colectomy. CDAD must be considered in all patients who present with diarrhea
following antibiotic use. Careful medical history is necessary since CDAD has
been reported to occur over two months after the administration of antibacterial
agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed
against C. difficile may need to be discontinued.
Appropriate fluid and electrolyte management, protein supplementation,
antibiotic treatment of C. difficile, and surgical
evaluation should be instituted as clinically indicated.
Amoxicillin and Clavulanate Potassium Tablets should be used with caution in
patients with evidence of hepatic dysfunction. Hepatic toxicity associated with
the use of Amoxicillin and Clavulanate Potassium Tablets is usually reversible.
On rare occasions, deaths have been reported (less than 1 death reported per
estimated 4 million prescriptions worldwide). These have generally been cases
associated with serious underlying diseases or concomitant medications. (See
CONTRAINDICATIONS and ADVERSE
REACTIONS-Liver
)

Precautions


id: acf723cc-c5db-4f8f-9426-80a386faa9c3
displayName: PRECAUTIONS SECTION
FDA Article Code: 42232-9

General While Amoxicillin and Clavulanate Potassium Tablets possess the
characteristic low toxicity of the penicillin group of antibiotics, periodic
assessment of organ system functions, including renal, hepatic, and
hematopoietic function, is advisable during prolonged therapy.
A high percentage of patients with mononucleosis who receive ampicillin
develop an erythematous skin rash. Thus, ampicillin-class antibiotics should not
be administered to patients with mononucleosis.
The possibility of superinfections with mycotic or bacterial pathogens should
be kept in mind during therapy. If superinfections occur (usually involving
Pseudomonas or Candida),
the drug should be discontinued and/or appropriate therapy instituted.
Prescribing Amoxicillin and Clavulanate Potassium Tablets in the absence of a
proven or strongly suspected bacterial infection or a prophylactic indication is
unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
Drug Interaction Probenecid decreases the renal tubular secretion of amoxicillin.
Concurrent use with Amoxicillin and Clavulanate Potassium Tablets may result in
increased and prolonged blood levels of amoxicillin. Coadministration of
probenecid cannot be recommended.
The concurrent administration of allopurinol and ampicillin increases
substantially the incidence of rashes in patients receiving both drugs as
compared to patients receiving ampicillin alone. It is not known whether this
potentiation of ampicillin rashes is due to allopurinol or the hyperuricemia
present in these patients. There are no data with Amoxicillin and Clavulanate
Potassium Tablets and allopurinol administered concurrently.
In common with other broad-spectrum antibiotics, Amoxicillin and Clavulanate
Potassium Tablets may reduce the efficacy of oral contraceptives.
Drug/Laboratory Test Interaction Oral administration of Amoxicillin and Clavulanate Potassium
Tablets will result in high urine concentrations of amoxicillin. High urine
concentrations of ampicillin may result in false-positive reactions when testing
for the presence of glucose in urine using CLINITEST®,
Benedict’s Solution, or Fehling’s Solution. Since this effect may also occur
with amoxicillin and therefore Amoxicillin and Clavulanate Potassium Tablets, it
is recommended that glucose tests based on enzymatic glucose oxidase reactions
(such as CLINISTIX®) be used.
Following administration of ampicillin to pregnant women, a transient
decrease in plasma concentration of total conjugated estriol,
estriol-glucuronide, conjugated estrone and estradiol has been noted. This
effect may also occur with amoxicillin and therefore Amoxicillin and Clavulanate
Potassium Tablets.
Information for patients Patients should be counseled that antibacterial drugs including
Amoxicillin and Clavulanate Potassium Tablets, should only be used to treat
bacterial infections. They do not treat viral infections (e.g., the common
cold). When Amoxicillin and Clavulanate Potassium Tablets are prescribed to
treat a bacterial infection, patients should be told that although it is common
to feel better early in the course of therapy, the medication should be taken
exactly as directed. Skipping doses or not completing the full course of therapy
may: (1) decrease the effectiveness of the immediate treatment, and (2) increase
the likelihood that bacteria will develop resistance and will not be treatable
by Amoxicillin and Clavulanate Potassium Tablets or other antibacterial drugs in
the future.
Diarrhea is a common problem caused by antibiotics which usually ends when
the antibiotic is discontinued. Sometimes after starting treatment with
antibiotics, patients can develop watery and bloody stools (with or without
stomach cramps and fever) even as late as two or more months after having taken
the last dose of the antibiotic. If this occurs, patients should contact their
physician as soon as possible.
Labor and Delivery Oral ampicillin-class antibiotics are generally poorly absorbed during labor.
Studies in guinea pigs have shown that intravenous administration of ampicillin
decreased the uterine tone, frequency of contractions, height of contractions,
and duration of contractions; however, it is not known whether the use of
Amoxicillin and Clavulanate Potassium Tablets in humans during labor or delivery
has immediate or delayed adverse effects on the fetus, prolongs the duration of
labor, or increases the likelihood that forceps delivery or other obstetrical
intervention or resuscitation of the newborn will be necessary. In a single
study in women with premature rupture of fetal membranes, it was reported that
prophylactic treatment with Amoxicillin and Clavulanate Potassium Tablets may be
associated with an increased risk of necrotizing enterocolitis in neonates.
Nursing Mothers Ampicillin-class antibiotics are excreted in the milk; therefore, caution should
be exercised when Amoxicillin and Clavulanate Potassium Tablets are administered
to a nursing woman.
Pediatric Use Pediatric patients weighing 40 kg or more should be dosed according to the adult
recommendations (see DOSAGE AND ADMINISTRATION: Pediatric
Patients
). Safety and effectiveness of Amoxicillin and Clavulanate
Potassium Tablets in pediatric patients weighing less than 40 kg have not been
established.
Geriatric use An analysis of clinical studies of Amoxicillin and Clavulanate
Potassium Tablets was conducted to determine whether subjects aged 65 and over
respond differently from younger subjects. Of the 3,119 patients in this
analysis, 68% were LT 65 years old, 32% were GE 65 years old and 14% were  LE 75
years old. This analysis and other reported clinical experience have not
identified differences in responses between the elderly and younger patients,
but a greater sensitivity of some older individuals cannot be ruled out.
This drug is known to be substantially excreted by the kidney, and the risk
of dose dependant toxic reactions to this drug may be greater in patients with
impaired renal function. Because elderly patients are more likely to have
decreased renal function, care should be taken in dose selection, and it may be
useful to monitor renal function.

Adverse Reaction


id: bce0a75e-cb2f-450a-aaa0-2fe22e34f857
displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4

Amoxicillin and Clavulanate Potassium Tablets are generally well
tolerated. The majority of side effects observed in clinical trials were of a
mild and transient nature and less than 3% of patients discontinued therapy
because of drug-related side effects. The most frequently reported adverse
effects were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria
(3%), vomiting (1%) and vaginitis (1%). The overall incidence of side effects,
and in particular diarrhea, increased with the higher recommended dose. Other
less frequently reported reactions include: Abdominal discomfort, flatulence,
and headache.
The following adverse reactions have been reported for ampicillin-class
antibiotics:
Gastrointestinal: Diarrhea, nausea, vomiting,
indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue,
mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous
colitis. Onset of pseudomembranous colitis symptoms may occur during or after
antibiotic treatment. (See WARNINGS)
Hypersensitivity Reactions: Skin rashes, pruritus,
urticaria, angioedema, serum sickness-like reactions (urticaria or skin rash
accompanied by arthritis, arthralgia, myalgia, and frequently fever), erythema
multiforme (rarely Stevens-Johnson syndrome), acute generalized exanthematous
pustulosis, hypersensitivity vasculitis, and an occasional case of exfoliative
dermatitis (including toxic epidermal necrolysis) have been reported. These
reactions may be controlled with antihistamines and, if necessary, systemic
corticosteroids. Whenever such reactions occur, the drug should be discontinued,
unless the opinion of the physician dictates otherwise. Serious and occasional
fatal hypersensitivity (anaphylactic) reactions can occur with oral penicillin.
(See WARNINGS)
Liver: A moderate rise in AST (SGOT) and/or ALT
(SGPT) has been noted in patients treated with ampicillin-class antibiotics but
the significance of these findings is unknown. Hepatic dysfunction, including
hepatitis and cholestatic jaundice, [see CONTRAINDICATIONS], increases in serum transaminases (AST
and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been infrequently
reported with Amoxicillin and Clavulanate Potassium Tablets. It has been
reported more commonly in the elderly, in males, or in patients on prolonged
treatment. The histologic findings on liver biopsy have consisted of
predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular
changes. The onset of signs/symptoms of hepatic dysfunction may occur during or
several weeks after therapy has been discontinued. The hepatic dysfunction,
which may be severe, is usually reversible. On rare occasions, deaths have been
reported (less than 1 death reported per estimated 4 million prescriptions
worldwide). These have generally been cases associated with serious underlying
diseases or concomitant medications.
Renal: Interstitial nephritis and hematuria have been
reported rarely. Crystalluria has also been reported (see OVERDOSAGE).
Hemic and Lymphatic Systems: Anemia, including
hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia,
leukopenia, and agranulocytosis have been reported during therapy with
penicillins. These reactions are usually reversible on discontinuation of
therapy and are believed to be hypersensitivity phenomena. A slight
thrombocytosis was noted in less than 1% of the patients treated with
Amoxicillin and Clavulanate Potassium Tablets. There have been reports of
increased prothrombin time in patients receiving Amoxicillin and Clavulanate
Potassium Tablets and anticoagulant therapy concomitantly.
Central Nervous System: Agitation, anxiety,
behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible
hyperactivity have been reported rarely.
Miscellaneous: Tooth discoloration (brown, yellow, or
gray staining) has been rarely reported. Most reports occurred in pediatric
patients. Discoloration was reduced or eliminated with brushing or dental
cleaning in most cases.

Over Dosage


id: 842edd15-1858-4696-8063-942e54102480
displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5

Following overdosage, patients have experienced primarily
gastrointestinal symptoms including stomach and abdominal pain, vomiting, and
diarrhea. Rash, hyperactivity, or drowsiness have also been observed in a small
number of patients.
In the case of overdosage, discontinue Amoxicillin and Clavulanate Potassium
Tablets, treat symptomatically, and institute supportive measures as required.
If the overdosage is very recent and there is no contraindication, an attempt at
emesis or other means of removal of drug from the stomach may be performed. A
prospective study of 51 pediatric patients at a poison center suggested that
overdosages of less than 250 mg/kg of amoxicillin are not associated with
significant clinical symptoms and do not require gastric emptying.3
Interstitial nephritis resulting in oliguric renal
failure has been reported in a small number of patients after overdosage with
amoxicillin.
Crystalluria, in some cases leading to renal failure, has also been reported
after amoxicillin overdosage in adult and pediatric patients. In case of
overdosage, adequate fluid intake and diuresis should be maintained to reduce
the risk of amoxicillin 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 both amoxicillin
and clavulanate. Both amoxicillin and clavulanate are removed from the
circulation by hemodialysis. (See DOSAGE AND
ADMINISTRATION
for recommended dosing for patients with impaired renal
function)

Dosage and Administration


id: a3897f2c-3f48-4aef-bf0c-12b4858cde0c
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

Since both the 250 mg/125 mg and 500 mg/125 mg
tablets of Amoxicillin and Clavulanate Potassium contain the same amount of
clavulanic acid (125 mg, as the potassium salt), two 250 mg/125 mg tablets of
Amoxicillin and Clavulanate Potassium are not equivalent to one 500 mg/125 mg
tablet of Amoxicillin and Clavulanate Potassium; therefore, two 250 mg/125 mg
tablets of Amoxicillin and Clavulanate Potassium should not be substituted for
one 500 mg/125 mg tablet of Amoxicillin and Clavulanate Potassium.
Dosage

Adults: The
usual adult dose is one 500 mg/125 mg tablet of Amoxicillin and Clavulanate
Potassium every 12 hours or one 250 mg/125 mg tablet of Amoxicillin and
Clavulanate Potassium every 8 hours. For more severe infections and infections
of the respiratory tract, the dose should be one 875 mg/125 mg tablet of
Amoxicillin and Clavulanate Potassium every 12 hours or one 500 mg/125 mg tablet
of Amoxicillin and Clavulanate Potassium every 8 hours. Patients with impaired renal function do not generally require a reduction in
dose unless the impairment is severe. Severely impaired patients with a
glomerular filtration rate of LT 30 mL/min. should not receive the 875 mg/125
mg tablet. Patients with a glomerular filtration rate of 10 to 30 mL/min. should
receive 500 mg/125 mg or 250 mg/125 mg every 12 hours, depending on the severity
of the infection. Patients with a less than 10 mL/min. glomerular filtration
rate should receive 500 mg/125 mg or 250 mg/125 mg every 24 hours, depending on
severity of the infection.
Hemodialysis patients should receive 500 mg/125 mg or 250 mg/125 mg every 24
hours, depending on severity of the infection. They should receive an additional
dose both during and at the end of dialysis.
Hepatically impaired patients should be dosed with caution and hepatic
function monitored at regular intervals.  (See WARNINGS)
Pediatric Patients: Pediatric patients
weighing 40 kg or more should be dosed according to the adult
recommendations.
Due to the different amoxicillin to clavulanic acid ratios
in the 250 mg/125 mg tablet of Amoxicillin and Clavulanate Potassium (250/125)
versus the 250 mg/62.5 mg chewable tablet of Amoxicillin and Clavulanate
Potassium (250/62.5), the 250 mg/125 mg tablet of Amoxicillin and Clavulanate
Potassium should not be used until the pediatric patient weighs at least 40 kg
or more.
Administration

Amoxicillin and Clavulanate
Potassium Tablets may be taken without regard to meals; however, absorption of
clavulanate potassium is enhanced when Amoxicillin and Clavulanate Potassium
Tablets are administered at the start of a meal. To minimize the potential for
gastrointestinal intolerance, Amoxicillin and Clavulanate Potassium Tablets
should be taken at the start of a meal.

Clinical Studies


id: 92904acb-70ec-4ded-8ad5-1e81afcb4aba
displayName: CLINICAL STUDIES SECTION
FDA Article Code: 34092-7

Data from 2 pivotal studies in 1.191 patients treated for either
lower respiratory tract infections or complicated urinary tract infections
compared a regimen of 875 mg/125 mg amoxicillin/clavulanate potassium tablets
q12h to 500 mg/125 mg amoxicillin/clavulanate potassium tablets dosed q8h (584
and 607 patients, respectively). Comparable efficacy was demonstrated between
the q12h and q8h dosing regimens. There was no significant difference in the
percentage of adverse events in each group. The most frequently reported adverse
event was diarrhea; incidence rates were similar for the 875 mg/125 mg q12h and
500 mg/125 mg q8h dosing regimens (14.9% and 14.3%, respectively); however,
there was a statistically significant difference (p LT 0.05) in rates of severe
diarrhea or withdrawals with diarrhea between the regimens: 1.0% for 875 mg/125
mg q12h dosing versus 2.5% for the 500 mg/125 mg q8h dosing.
In one of these pivotal studies, 629 patients with either pyelonephritis or a
complicated urinary tract infection (i.e., patients
with abnormalities of the urinary tract that predispose to relapse of
bacteriuria following eradication) were randomized to receive either 875 mg/125
mg amoxicillin/clavulanate potassium tablets q12h or 500 mg/125 mg
amoxicillin/clavulanate potassium tablets q8h in the following
distribution:

875 mg/125 mg q12 h 500 mg/125 mg
q8h
Pyelonephritis 173 patients 188 patients
Complicated UTI 135 patients 133 patients
Total patients 308 321
The number of bacteriologically evaluable patients was comparable between the
two dosing regimens. Amoxicillin/clavulanate potassium produced comparable
bacteriological success rates in patients assessed 2 to 4 days immediately
following end of therapy. The bacteriologic efficacy rates were comparable at
one of the follow-up visits (5 to 9 days post-therapy) and at a late
post-therapy visit (in the majority of cases, this was 2 to 4 weeks
post-therapy), as seen in the table below:
875 mg/125 mg
q12h
500 mg/125 mg
q8h
2 to 4 days 81%, n=58 80%, n=54
5 to 9 days 58.5%, n=41 51.9%, n=52
2 to 4 weeks 52.5%, n=101 54.8%, n=104
As noted before, though there was no significant difference in the percentage
of adverse events in each group, there was a statistically significant
difference in rates of severe diarrhea or withdrawals with diarrhea between the
regimens.

How Supplied


id: 8ba311c6-396d-4812-b614-49c799cdc90e
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5

Amoxicillin and Clavulanate Potassium Tablets,
USP 500/125 mg 
are white to off-white, oblong film coated tablets with
beveled edges, debossed with 500/125 on one side and AMC on the other side.
They are supplied in plastic bottles of 20, 30 and 100 (with desiccant). Amoxicillin and Clavulanate Potassium Tablets, USP 875/125
mg 
are white to off-white, oblong film coated tablets with beveled edges,
scored and debossed with 875/125 on one side and AMC on the other side.
They are supplied in plastic bottles of 20 and 100 (with desiccant). Store tablets at 20 – 25°C (68 – 77°F) [See USP Controlled Room Temperature].
Dispense in tightly closed, moisture-proof containers.

References


id: 00d71c94-2a60-409a-87a9-36033d259bd0
displayName: REFERENCES SECTION
FDA Article Code: 34093-5

1. National Committee for Clinical Laboratory
Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria
That Grow Aerobically—Third Edition. Approved Standard NCCLS Document M7-A3,
Vol. 13, No. 25. NCCLS, Villanova, PA, December 1993.
2. National Committee for Clinical Laboratory
Standards. Performance Standards for Antimicrobial Disk Susceptibility
Tests―Fifth Edition. Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24.
NCCLS, Villanova, PA, December 1993.
3. Swanson-Biearman B, Dean BS, Lopez G, Krenzelok
EP. The effects of penicillin and cephalosporin ingestions in children less than
six years of age. Vet Hum Toxicol 1988;30:66-67.
CLINITEST is a registered trademark of Miles, Inc. CLINISTIX is a registered trademark of Bayer Corporation  Manufactured in Slovenia By Lek Pharmaceuticals d.d. Distributed by Lek Pharmaceuticals Inc. An affiliate of Sandoz Inc., Princeton, NJ 08540 January 2006 Revised: 02/2008
Lek
Pharmaceuticals Inc.