AMOXICILLIN TABLETS, USP 875 mg Rx only Revised: August 2008

To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and other antibacterial drugs, amoxicillin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Formulation of amoxicillin tablets contain amoxicillin, a semisynthetic antibiotic, an analog of ampicillin, with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms. Chemically it is (2S,5R,6R)- 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. The structural formula is:

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

Tablets of amoxicillin are intended for oral administration.

Tablets: Each film coated tablet contains 875 mg amoxicillin as the trihydrate. Each film-coated, capsule-shaped, pink tablet is scored on one side and imprinted WW951 on the other side. Inactive ingredients: carmine, colloidal silicon dioxide, crospovidone, FD&C Red #40 Lake, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol-partially hydrolyzed, polyethylene glycol, sodium starch glycolate, talc, and titanium dioxide.

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 the tablets and suspension of amoxicillin 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 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 Amoxicillin and Clavulanate Potassium Tablets 875 mg/125 mg showed that the 875-mg tablet of amoxicillin produces an AUC₀-∞ of 35.4 ± 8.1 mcg•hr/mL and a C_max of 13.8 ± 4.1 mg/mL. Dosing was at the start of a light meal following an overnight fast.

Orally administered doses of amoxicillin suspension, 125 mg/5mL 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 mcg/mL to 5 mcg/mL, respectively.

Oral administration of single doses of 400-mg/5 mL suspension of amoxicillin to 24 adult volunteers yielded the following pharmacokinetic data:

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 - 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 of ampicillin 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

Staphylococcus^a

Streptococcus (except S. pneumoniae)

S. pneumoniae^b

(Amoxicillin powder should be used to determine susceptibility.)

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

For Gram-Negative Aerobes:

Enterobacteriaceae

H. influenzae^c

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

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

c. These interpretive standards are applicable only to broth microdilution test with H. influenzae using Haemophilus Test Medium (HTM).¹

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.

Standard ampicillin powder should provide the following MIC values:

Using amoxicillin to determine susceptibility:

d. This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution procedure using HTM.¹

e. 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 2-5% lysed horse blood.

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 for ampicillin. 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

Staphylococcus^f

β -hemolytic streptococci

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

H. influenzae^g

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

g. These interpretive standards are applicable only to disk diffusion susceptibility tests with H. influenzae using Haemophilus Test Medium (HTM)².

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:

Using 1-mcg oxacillin disk:

h. This quality control range is applicable to only H. influenzae ATCC 49247 tested by a disk diffusion procedure using HTM².

i. 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.

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.

Amoxicillin is indicated in the treatment of infections due to susceptible (ONLY α -lactamase-negative) strains of the designated microorganisms in the conditions listed below:

Infections of the ear, nose and throat – due to Streptococcus spp. (α- and β –hemolytic strains only), S. pneumoniae, Staphylococcus spp., or H. influenzae.

Infections of the genitourinary tract – due to E. coli, P. mirabilis, or E. faecalis.

Infections of the skin and skin structure – due to Streptococcus spp. (α- and β -hemolytic strains only), Staphylococcus spp. or E. coli.

Infections of the lower respiratory tract – due to Streptococcus spp. (α- and β –hemolytic strains only), S. pneumoniae, Staphylococcus spp., or H. influenzae.

Gonorrhea, acute uncomplicated (ano-genital and urethral infections) – due to N. gonorrhoeae (males and females).
H. pylori eradication to reduce the risk of duodenal ulcer recurrence.

Triple Therapy: Amoxicillin/clarithromycin/lansoprazole

Amoxicillin, in combination with clarithromycin plus lansoprazole as triple therapy, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or 1-year history of a duodenal ulcer) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. (See CLINICAL STUDIES and DOSAGE AND ADMINISTRATION.)

Dual Therapy: Amoxicillin/lansoprazole

Amoxicillin, in combination with lansoprazole delayed-release capsules as dual therapy, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or 1-year history of a duodenal ulcer) who are either allergic or intolerant to clarithromycin or in whom resistance to clarithromycin is known or suspected. (See the clarithromycin package insert, MICROBIOLOGY). Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. (See CLINICAL STUDIES and DOSAGE AND ADMINISTRATION.)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and other antibacterial drugs, amoxicillin 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. 

Indicated surgical procedures should be performed.

A history of allergic reactions to any of the penicillins is a contraindication.

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY.

ALTHOUGH ANAPHYLAXIS IS MORE FREQUENT FOLLOWING PARENTERAL THERAPY, IT HAS OCCURRED IN PATIENTS ON ORAL PENICILLINS.

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, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, AMOXICILLIN SHOULD BE DISCONTINUED AND 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 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.

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. (See WARNINGS.)

Hypersensitivity Reactions: Anaphylaxis (See WARNINGS) 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 (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.

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.

In case of overdosage, discontinue medication, 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-control 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 amoxicillin. Amoxicillin may be removed from the circulation by hemodialysis.

The 875-mg tablet has 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.

Neonates and Infants Aged ≤12 weeks (≤3 months): Due to incompletely developed renal function affecting elimination of amoxicillin in this age group, the recommended upper dose of Amoxicillin is 30 mg/kg/day divided q12h.

Adults and Pediatric Patients > 3 Months:

All patients with gonorrhea should be evaluated for syphilis. (See PRECAUTIONS – Laboratory Tests).

Larger doses may be required for stubborn or severe infections.

General: It should be recognized that in the treatment of chronic urinary tract infections, frequent bacteriological and clinical appraisals are necessary. Smaller doses than those recommended above should not be used. Even higher doses may be needed at times. In stubborn infections, therapy may be required for several weeks. It may be necessary to continue clinical and/or bacteriological follow-up for several months after cessation of therapy. Except for gonorrhea, treatment should be continued for a minimum of 48 to 72 hours beyond the time the patient becomes asymptomatic or evidence of bacterial eradication has been obtained. It is recommended that there be at least 10 days’ treatment for any infection caused by Streptococcus pyogenes to prevent the occurrence of acute rheumatic fever.

H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence: Triple therapy: Amoxicillin/clarithromycin/ lansoprazole

The recommended adult oral dose is 1 gram amoxicillin, 500 mg clarithromycin, and 30 mg lansoprazole, all given twice daily (q12h) for 14 days. (See INDICATIONS AND USAGE).

Dual therapy: Amoxicillin/lansoprazole

The recommended adult oral dose is 1 gram amoxicillin and 30 mg lansoprazole, each given three times daily (q8h) for 14 days. (See INDICATIONS AND USAGE).

Please refer to clarithromycin and lansoprazole full prescribing information for CONTRAINDICATIONS and WARNINGS, and for information regarding dosing in elderly and renally impaired patients.

Dosing Recommendations for Adults with Impaired Renal Function: 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 <30 mL/min. should not receive the 875 mg tablet. Patients with a glomerular filtration rate of 10 to 30 mL/min. should receive 500 mg or 250 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 or 250 mg every 24 hours, depending on the severity of the infection. Hemodialysis patients should receive 500 mg or 250 mg every 24 hours, depending on the severity of the infection. They should receive an additional dose both during and at the end of dialysis.

There are currently no dosing recommendations for pediatric patients with impaired renal function.

Tablets of Amoxicillin: Amoxicillin Tablets USP, 875 mg are available as film-coated, capsule-shaped, pink tablets scored on one side and imprinted WW951 on the other side. They are available in bottles of 100 and 20.

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

Dispense in a tight container.

H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence:

Randomized, double-blind clinical studies performed in the United States in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) evaluated the efficacy of lansoprazole in combination with amoxicillin capsules and clarithromycin tablets as triple 14-day therapy, or in combination with amoxicillin capsules as dual 14-day therapy, for the eradication of H. pylori. Based on the results of these studies, the safety and efficacy of two different eradication regimens were established:

Triple therapy: Amoxicillin 1 gram twice daily/clarithromycin 500 mg twice daily/lansoprazole 30 mg twice daily.

Dual therapy: Amoxicillin 1 gram three times daily/lansoprazole 30 mg three times daily.

All treatments were for 14 days. H. pylori eradication was defined as two negative tests (culture and histology) at 4 to 6 weeks following the end of treatment.

Triple therapy was shown to be more effective than all possible dual therapy combinations.

Dual therapy was shown to be more effective than both monotherapies. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.

• National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically – Fourth Edition; Approved Standard. NCCLS Document M7-A4, Vol. 17, No. 2. NCCLS, Wayne, PA, January 1997.
• National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests – Sixth Edition; Approved Standard. NCCLS Document M2-A6, Vol. 17, No. 1. NCCLS, Wayne, PA, January 1997.
• 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.
CLOtest is a registered trademark of Kimberly-Clark Corporation.

Manufactured by:
Hikma Pharmaceuticals
P.O. Box 182400
Amman 11118 - Jordan

Distributed by:
West-ward Pharmaceutical Corp.
Eatontown, NJ 07724

Revised: August 2008

NDC 66336-0074-XX

NDC 66336-0074-30

NDC 66336-0074-XX