ADVERSE REACTIONS

As with other penicillins, it may be expected that untoward reactions will be essentially limited to sensitivity phenomena. They are more likely to occur in individuals who have previously demonstrated hypersensitivity to penicillins and in those with a history of allergy, asthma, hay fever, or urticaria. The following adverse reactions have been reported as associated with the use of penicillins:

Infections and Infestations: Mucocutaneous candidiasis.

Gastrointestinal: Nausea, vomiting, diarrhea, black hairy tongue, and hemorrhagic/ pseudomembranous colitis.

Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment (seeWARNINGS).

Hypersensitivity Reactions: Anaphylaxis (seeWARNINGS)

Serum sickness-like reactions, erythematous maculopapular rashes, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, hypersensitivity vasculitis and urticaria have been reported.

NOTE: These hypersensitivity reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids. Whenever such reactions occur, amoxicillin should be discontinued unless, in the opinion of the physician, the condition being treated is life-threatening and amenable only to amoxicillin therapy.

Liver: A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted, but the significance of this finding is unknown. Hepatic dysfunction including cholestatic jaundice, hepatic cholestasis and acute cytolytic hepatitis have been reported.

Renal:Crystalluria has also been reported (seeOVERDOSAGE).

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.

Central Nervous System: Reversible hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, behavioral changes, and/or dizziness 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.

Combination Therapy With Clarithromycin and Lansoprazole

In clinical trials using combination therapy with amoxicillin plus clarithromycin and lansoprazole, and amoxicillin plus lansoprazole, no adverse reactions peculiar to these drug combinations were observed. Adverse reactions that have occurred have been limited to those that had been previously reported with amoxicillin, clarithromycin, or lansoprazole.

Triple Therapy

Amoxicillin/clarithromycin/lansoprazole

The most frequently reported adverse events for patients who received triple therapy were diarrhea (7%), headache (6%), and taste perversion (5%). No treatment-emergent adverse events were observed at significantly higher rates with triple therapy than with any dual therapy regimen.

Dual Therapy

Amoxicillin/lansoprazole

The most frequently reported adverse events for patients who received amoxicillin three times daily plus lansoprazole three times daily dual therapy were diarrhea (8%) and headache (7%). No treatment-emergent adverse events were observed at significantly higher rates with amoxicillin three times daily plus lansoprazole three times daily dual therapy than with lansoprazole alone.

For more information on adverse reactions with clarithromycin or lansoprazole, refer to their package inserts,ADVERSE REACTIONS.

CLINICAL PHARMACOLOGY

Amoxicillin is stable in the presence of gastric acid and is rapidly absorbed after oral administration. The effect of food on the absorption of amoxicillin from amoxicillin tablets and amoxicillin suspension has been partially investigated. The 400 mg and 875 mg formulations have been studied only when administered at the start of a light meal. However, food effect studies have not been performed with the 200 mg and 500 mg formulations. Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when meninges are inflamed. The half-life of amoxicillin is 61.3 minutes. Most of the amoxicillin is excreted unchanged in the urine; its excretion can be delayed by concurrent administration of probenecid. In blood serum, amoxicillin is approximately 20% protein-bound.

Orally administered doses of 250 mg and 500 mg amoxicillin capsules result in average peak blood levels 1 to 2 hours after administration in the range of 3.5 mcg/mL to 5.0 mcg/mL and 5.5 mcg/mL to 7.5 mcg/mL, respectively.

Mean amoxicillin pharmacokinetic parameters from an open, two-part, single- dose crossover bioequivalence study in 27 adults comparing 875 mg of amoxicillin with 875 mg of amoxicillin/clavulanate potassium showed that the 875 mg tablet of amoxicillin produces an AUC0-∞ of 35.4 ± 8.1 mcg•hr/mL and a Cmax of 13.8 ± 4.1 mcg/mL. Dosing was at the start of a light meal following an overnight fast.

Orally administered doses of amoxicillin suspension, 125 mg/5 mL and 250 mg/5 mL, result in average peak blood levels 1 to 2 hours after administration in the range of 1.5 mcg/mL to 3.0 mcg/mL and 3.5 mcg/mL to 5.0 mcg/mL, respectively.

Oral administration of single doses of 400 mg chewable tablets and 400 mg/5 mL suspension of amoxicillin to 24 adult volunteers yielded comparable pharmacokinetic data:

Administered at the start of a light meal. † Mean values of 24 normal volunteers. Peak concentrations occurred approximately 1 hour after the dose.
Dose*	AUC0-∞ (mcg•hr/mL)	Cmax (mcg/mL)†
Amoxicillin	amoxicillin (± S.D.)	amoxicillin (± S.D.)
400 mg (5 mL of suspension)	17.1 (3.1)	5.92 (1.62)
400 mg (1 chewable tablet)	17.9 (2.4)	5.18 (1.64)

Detectable serum levels are observed up to 8 hours after an orally administered dose of amoxicillin. Following a 1 gram dose and utilizing a special skin window technique to determine levels of the antibiotic, it was noted that therapeutic levels were found in the interstitial fluid. Approximately 60% of an orally administered dose of amoxicillin is excreted in the urine within 6 to 8 hours.

Microbiology

Amoxicillin is similar to ampicillin in its bactericidal action against susceptible organisms during the stage of active multiplication. It acts through the inhibition of biosynthesis of cell wall mucopeptide. Amoxicillin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic Gram-Positive Microorganisms

Enterococcus faecalis

Staphylococcus spp. (β-lactamase-negative strains only)

Streptococcus pneumoniae

Streptococcus spp. (α- and β-hemolytic strains only)

• Staphylococci which are susceptible to amoxicillin but resistant to methicillin/oxacillin should be considered as resistant to amoxicillin.

Aerobic Gram-Negative Microorganisms

Escherichia coli (β-lactamase-negative strains only)

Haemophilus influenzae (β-lactamase-negative strains only)

Neisseria gonorrhoeae (β-lactamase-negative strains only)

Proteus mirabilis (β-lactamase-negative strains only)

Helicobacter

Helicobacter pylori

Susceptibility Tests

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 procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations ofampicillin powder. Ampicillin is sometimes used to predict susceptibility of S. pneumoniae to amoxicillin; however, some intermediate strains have been shown to be susceptible to amoxicillin. Therefore, S. pneumoniae susceptibility should be tested using amoxicillin powder. The MIC values should be interpreted according to the following criteria:

For Gram-Positive Aerobes

Enterococcus

MIC (mcg/mL)	Interpretation
≤ 8	Susceptible (S)
≥ 16	Resistant (R)

Staphylococcus*

Staphylococci which are susceptible to amoxicillin but resistant to methicillin/oxacillin should be considered as resistant to amoxicillin.
MIC (mcg/mL)	Interpretation
≤ 0.25	Susceptible (S)
≥ 0.5	Resistant (R)

Streptococcus (except S. pneumoniae)

MIC (mcg/mL)	Interpretation
≤ 0.25	Susceptible (S)
0.5 to 4	Intermediate (I)
≥ 8	Resistant (R)

S. pneumoniae*from non-meningitis sources.

• These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.

(Amoxicillin powder should be used to determine susceptibility.)

MIC (mcg/mL)	Interpretation
≤ 2	Susceptible (S)
4	Intermediate (I)
≥ 8	Resistant (R)

NOTE: These interpretive criteria are based on the recommended doses for respiratory tract infections.

For Gram-Negative Aerobes

Enterobacteriaceae

MIC (mcg/mL)	Interpretation
≤ 8	Susceptible (S)
16	Intermediate (I)
≥ 32	Resistant (R)

H. influenzae*

These interpretive standards are applicable only to broth microdilution test with H. influenzaeusing Haemophilus Test Medium (HTM).1
MIC (mcg/mL)	Interpretation
≤ 1	Susceptible (S)
2	Intermediate (I)
≥ 4	Resistant (R)

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations 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. Standardampicillin powder should provide the following MIC values:

This quality control range is applicable to only****H. influenzae ATCC 49247 tested by a broth microdilution procedure using HTM.1
Microorganism	MIC Range (mcg/mL)
E. coli	ATCC 25922	2 to 8
E. faecalis	ATCC 29212	0.5 to 2
H. influenzae	ATCC 49247*	2 to 8
S. aureus	ATCC 29213	0.25 to 1

Usingamoxicillin to determine susceptibility:

This quality control range is applicable to only S. pneumoniae ATCC 49619 tested by the broth microdilution procedure using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.
Microorganism	MIC Range (mcg/mL)
S. pneumoniae	ATCC 49619*	0.03 to 0.12

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 10 mcg ampicillin to test the susceptibility of microorganisms, except S. pneumoniae, to amoxicillin. Interpretation involves correlation of the diameter obtained in the disk test with the MIC forampicillin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10 mcg ampicillin disk should be interpreted according to the following criteria:

For Gram-Positive Aerobes

Enterococcus

Zone Diameter (mm)	Interpretation
≥ 17	Susceptible (S)
≤ 16	Resistant (R)

Staphylococcus*

Staphylococci which are susceptible to amoxicillin but resistant to methicillin/oxacillin should be considered as resistant to amoxicillin.
Zone Diameter (mm)	Interpretation
≥ 29	Susceptible (S)
≤ 28	Resistant (R)

β-hemolytic streptococci

Zone Diameter (mm)	Interpretation
≥ 26	Susceptible (S)
19 to 25	Intermediate (I)
≤ 18	Resistant (R)

**NOTE:**For streptococci (other than β-hemolytic streptococci and S. pneumoniae), an ampicillin MIC should be determined.

S. pneumoniae

S. pneumoniae should be tested using a 1 mcg oxacillin disk. Isolates with oxacillin zone sizes of ≥ 20 mm are susceptible to amoxicillin. An amoxicillin MIC should be determined on isolates of S. pneumoniae with oxacillin zone sizes of ≤ 19 mm.

For Gram-Negative Aerobes

Enterobacteriaceae

Zone Diameter (mm)	Interpretation
≥ 17	Susceptible (S)
14 to 16	Intermediate (I)
≤ 13	Resistant (R)

H. influenzae*

These interpretive standards are applicable only to disk diffusion susceptibility tests with H. influenzae using Haemophilus Test Medium (HTM).2
Zone Diameter (mm)	Interpretation
≥ 22	Susceptible (S)
19 to 21	Intermediate (I)
≤ 18	Resistant (R)

Interpretation should be as stated above for results using dilution techniques.

As with standard dilution techniques, disk diffusion susceptibility test procedures require the use of laboratory control microorganisms. The 10 mcg ampicillin disk should provide the following zone diameters in these laboratory test quality control strains:

This quality control range is applicable to only H. influenzae ATCC 49247 tested by a disk diffusion procedure using HTM.2
Microorganism	Zone Diameter (mm)
E. coli	ATCC 25922	16 to 22
H. influenzae	ATCC 49247*	13 to 21
S. aureus	ATCC 25923	27 to 35

Using 1 mcgoxacillin disk:

This quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a disk diffusion procedure using Mueller-Hinton agar supplemented with 5% sheep blood and incubated in 5% CO2.
Microorganism	Zone Diameter (mm)
S. pneumoniae	ATCC 49619*	8 to 12

Susceptibility Testing for Helicobacter pylori

In vitro susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory concentrations (MICs) and zone sizes have not been standardized, validated, or approved for testing H. pylori microorganisms.

Culture and susceptibility testing should be obtained in patients who fail triple therapy. If clarithromycin resistance is found, a non-clarithromycin- containing regimen should be used.