Amoxicillin

The most frequently reported adverse events for patients who received double therapy amoxicillin/lansoprazole were diarrhea (8%) and headache (7%). For more information on adverse reactions with clarithromycin or lansoprazole, refer to the Adverse Reactions section of their package inserts.

6.2 Postmarketing or Other Experience

In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of penicillins. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to amoxicillin.

• Infections and Infestations: Mucocutaneous candidiasis.
• Gastrointestinal: Black hairy tongue, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment [see Warnings and Precautions (5.2)].
• Hypersensitivity Reactions: Anaphylaxis [see Warnings and Precautions (5.1)]. Serum sickness

  7 DRUG INTERACTIONS

  7.1 Probenecid

  
  

  Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use of amoxicillin and probenecid may result in increased and prolonged blood levels of amoxicillin.

  7.2 Oral Anticoagulants

  
  

  Abnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has been reported in patients receiving amoxicillin and oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.

  7.3 Allopurinol

  
  

  The concurrent administration of allopurinol and amoxicillin increases the incidence of rashes in patients receiving both drugs as compared to patients receiving amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients.

  7.4 Oral Contraceptives

  
  

  Amoxicillin may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.

  7.5 Other Antibacterials

  
  

  Chloramphenicol, macrolides, sulfonamides, and tetracyclines may interfere with the bactericidal effects of penicillin. This has been demonstrated in vitro; however, the clinical significance of this interaction is not well documented.

  7.6 Effects on Laboratory Tests

  
  

  High urine concentrations of ampicillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST^®, Benedict

  8 USE IN SPECIFIC POPULATIONS

  8.1 Pregnancy

  
  

  Teratogenic Effects:  Pregnancy Category B. Reproduction studies have been performed in mice and rats at doses up to 2000 mg/kg (3 and 6 times the 3 g human dose, based on body surface area). There was no evidence of harm to the fetus due to amoxicillin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, amoxicillin should be used during pregnancy only if clearly needed.

  8.2 Labor and Delivery

  
  

  Oral ampicillin is poorly absorbed during labor. It is not known whether use of amoxicillin in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood of the necessity for an obstetrical intervention.

  8.3 Nursing Mothers

  
  

  Penicillins have been shown to be excreted in human milk. Amoxicillin use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin is administered to a nursing woman.

  8.4 Pediatric Use

  
  

  Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed. Dosing of amoxicillin should be modified in pediatric patients 12 weeks or younger (

  8.5 Geriatric Use

  
  

  An analysis of clinical studies of amoxicillin was conducted to determine whether subjects aged 65 and over respond differently from younger subjects. These analyses 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 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.

  8.6 Dosing in Renal Impairment

  
  

  Amoxicillin is primarily eliminated by the kidney and dosage adjustment is usually required in patients with severe renal impairment (GFR <30 mL/min). See Dosage and Administration (2.4) for specific recommendations in patients with renal impairment.

  10 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. Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin¹.
  
  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 circulation by hemodialysis.

  11 DESCRIPTION

  
  

  Formulation of amoxicillin capsules, USP contains 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. It may be represented structurally as:

  
  
  

  The amoxicillin molecular formula is C₁₆H₁₉N₃O₅S•3H₂O, and the molecular weight is 419.45.
  
  Each capsule of amoxicillin with blue cap and pink body, contains 250 mg or 500 mg amoxicillin as the trihydrate. The body of the 250 mg capsule is imprinted with

  12 CLINICAL PHARMACOLOGY

  12.1 Mechanism of Action

  
  

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

  12.3 Pharmacokinetics

  
  

  Absorption: 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; 400 mg and 875 mg formulations have been studied only when administered at the start of a light meal.
  
  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 875 mg of amoxicillin and clavulanate potassium showed that the 875 mg tablet of amoxicillin produces an AUC_0-

  12.4 Microbiology

  
  

  Mechanism of Action
  
  Amoxicillin is similar to penicillin in its bactericidal action against susceptible bacteria during the stage of active multiplication. It acts through the inhibition of cell wall biosynthesis that leads to the death of the bacteria.
  
  Method of Resistance
  
  Resistance to amoxicillin is mediated primarily through enzymes called beta-lactamases that cleave the beta-lactam ring of amoxicillin, rendering it inactive.
  
  Amoxicillin has been shown to be active against most isolates of the bacteria listed below, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

  
  

  Gram-Positive Bacteria	Gram-Negative Bacteria
  Enterococcus faecalis  Staphylococcus spp.  Streptococcus pneumoniae  Alpha and ⛚-hemolytic streptococci.	Escherichia coli  Haemophilus influenzae  Neisseria gonorrhoeae  Proteus mirabilis  Helicobacter pylori

  
  

  Susceptibility Test Methods: (susceptibility to amoxicillin can be determined using ampicillin powder and a 10 mcg ampicillin disk)
  
  When available, clinical microbiology should provide the results of in vitro susceptibility test results for antimicrobial drugs 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 antimicrobial 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 procedure. Standardized procedures are based on dilution methods (broth or agar)^2,3 or equivalent with standardized inoculum concentrations and standardized concentrations of ampicillin powder. The MIC values should be interpreted according to the criteria in Table 4.
  
  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 procedure³ requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10 mcg ampicillin to test the susceptibility of bacteria to ampicillin. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for amoxicillin. 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 criteria listed in Table 4.

  
  

  Table 4. Susceptibility Test Interpretive Criteria for Amoxicillin

  	Minimum Inhibitory Concentration (mcg/mL)			Disk Diffusion (zone diameter in mm)
  	Susceptible	Intermediate	Resistant	Susceptible	Intermediate	Resistant
  * S. pneumoniae should be tested using a 1 mcg oxacillin disk. Isolates with oxacillin zone sizes of 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate carcinogenic potential. Studies to detect mutagenic potential of amoxicillin alone have not been conducted; however, the following information is available from tests on a 4:1 mixture of amoxicillin and potassium clavulanate. Amoxicillin and potassium clavulanate was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and potassium clavulanate 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 potassium clavulanate was negative in the mouse micronucleus test and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays. In a multi-generation reproduction study in rats, no impairment of fertility or other adverse reproductive effects were seen at doses up to 500 mg/kg (approximately 2 times the 3 g human dose based on body surface area). 14 CLINICAL STUDIES 14.1 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 1 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 2 different eradication regimens were established: Triple Therapy: Amoxicillin 1 gram twice daily/clarithromycin 500 mg twice daily/lansoprazole 30 mg twice daily (see Table 6). Dual Therapy: Amoxicillin 1 gram three times daily/lansoprazole 30 mg three times daily (see Table 7). All treatments were for 14 days. H. pylori eradication was defined as 2 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. Table 6. H. pylori Eradication Rates When Amoxicillin is Administered as Part of a Triple Therapy Regimen Study Triple Therapy Triple Therapy Evaluable Analysisa [95% Confidence Interval] (number of patients) Intent-to-Treat Analysisb [95% Confidence Interval] (number of patients) a This analysis was based on evaluable patients with confirmed duodenal ulcer (active or within 1 year) and H. pylori infection at baseline defined as at least 2 of 3 positive endoscopic tests from CLOtest®, histology, and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy. b Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within 1 year). All dropouts were included as failures of therapy.  Study 1 92 [80 - 97.7] (n = 48) 86 [73.3 - 93.5] (n = 55)  Study 2 86 [75.7 - 93.6] (n = 66) 83 [72 - 90.8] (n = 70) Table 7. H. pylori Eradication Rates When Amoxicillin is Administered as Part of a Dual Therapy Regimen Study Dual Therapy Dual Therapy Evaluable Analysisa [95% Confidence Interval] (number of patients) Intent-to-Treat Analysisb [95% Confidence Interval] (number of patients) a This analysis was based on evaluable patients with confirmed duodenal ulcer (active or within 1 year) and H. pylori infection at baseline defined as at least 2 of 3 positive endoscopic tests from CLOtest®, histology, and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy. b Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within 1 year). All dropouts were included as failures of therapy. Study 1 77 [62.5 - 87.2] (n = 51) 70 [56.8 - 81.2] (n = 60) Study 2 66 [51.9 - 77.5] (n = 58) 61 [48.5 - 72.9] (n = 67) 15 REFERENCES 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. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard 16 HOW SUPPLIED/STORAGE AND HANDLING Amoxicillin Capsules, USP contains 250 mg or 500 mg amoxicillin as the trihydrate.                                           250 mg Capsule Blue/Pink size 17 PATIENT COUNSELING INFORMATION 17.1 Information for Patients Patients should be advised that amoxicillin may be taken every 8 hours or every 12 hours, depending on the dose prescribed. Patients should be counseled that antibacterial drugs, including amoxicillin, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When amoxicillin is 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 or other antibacterial drugs in the future. Patients should be counseled that diarrhea is a common problem caused by antibiotics, and it 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 2 or more months after having taken their last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Patients should be aware that amoxicillin contains a penicillin class drug product that can cause allergic reactions in some individuals. CLINITEST® is a registered trademark of Siemens Medical Solutions Diagnostics, and Ames Company, Inc. CLINISTIX® is a registered trademark of Bayer Healthcare Llc, and Ames Company, Inc. CLOtest® is a registered trademark of  Kimberly-Clark Worldwide, Inc. GREENSTONE® BRAND Distributed by:            Greenstone LLC Peapack, NJ 07977 Code No.: DRUGS/AP/57/2003 Revised: 03/2012 PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 250 mg (100 Capsule Bottle) NDC 59762-1020-1 100 Capsules GREENSTONE® BRAND amoxicillin capsules, USP 250 mg Rx only  PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 500 mg (100 Capsule Bottle) NDC 59762-1021-7 100 Capsules GREENSTONE® BRAND amoxicillin capsules, USP 500 mg Rx only Amoxicillin Amoxicillin CAPSULE Product Information Product Type Human prescription drug label Item Code (Source) NDC:59762-1020 Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength AMOXICILLIN amoxicillin anhydrous 250 mg Inactive Ingredients Ingredient Name Strength cellulose, microcrystalline D&C RED NO. 28 FD&C BLUE NO. 1 FD&C RED NO. 40 GELATIN MAGNESIUM STEARATE titanium dioxide SODIUM LAURYL SULFATE Product Characteristics Color Size Imprint Code Shape PINK 19 mm A44 CAPSULE Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:59762-1020-1 100 in 1 BOTTLE 2 NDC:59762-1020-3 500 in 1 BOTTLE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065271 2005-09-11 Amoxicillin Amoxicillin CAPSULE Product Information Product Type Human prescription drug label Item Code (Source) NDC:59762-1021 Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength AMOXICILLIN amoxicillin anhydrous 500 mg Inactive Ingredients Ingredient Name Strength cellulose, microcrystalline D&C RED NO. 28 FD&C BLUE NO. 1 FD&C RED NO. 40 GELATIN MAGNESIUM STEARATE titanium dioxide SODIUM LAURYL SULFATE Product Characteristics Color Size Imprint Code Shape PINK 23 mm A45 CAPSULE Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:59762-1021-7 100 in 1 BOTTLE 2 NDC:59762-1021-1 500 in 1 BOTTLE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065271 2005-09-11 PLEASE, BE CAREFUL! 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