1.1 Infections of the Ear, Nose, and Throat

Amoxicillin for oral suspension is indicated in the treatment of infections due to susceptible (ONLY β-lactamase–negative) isolates of species. (α- and   β-hemolytic isolates only), , spp., or . StreptococcusStreptococcus pneumoniaeStaphylococcusHaemophilus influenzae

1.2 Infections of the Genitourinary Tract

Amoxicillin for oral suspension is indicated in the treatment of infections due to susceptible (ONLY β-lactamase–negative) isolates of , or . Escherichia coli, Proteus mirabilisEnterococcus faecalis

1.3 Infections of the Skin and Skin Structure

Amoxicillin for oral suspension is indicated in the treatment of infections due to susceptible (ONLY β-lactamase–negative) isolates of spp. (α- and β-hemolytic isolates only), spp., or . StreptococcusStaphylococcusE. coli

1.4 Infections of the Lower Respiratory Tract

Amoxicillin for oral suspension is indicated in the treatment of infections due to susceptible (ONLY β-lactamase–negative) isolates of spp. (α- and β-hemolytic isolates only), spp., or . StreptococcusS. pneumoniae, StaphylococcusH. influenzae

1.5 Helicobacter pylori Infection

Triple therapy for with clarithromycin and lansoprazole: Helicobacter pylori

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

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

1.6 Usage

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

2.1 Dosing for Adult and Pediatric Patients > 3 Months of Age

Treatment should be continued for a minimum of 48 to 72 hours beyond the time that 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 to prevent the occurrence of acute rheumatic fever. In some 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. Streptococcus pyogenes

2.2 Dosing in Neonates and Infants Aged ≤ 12 Weeks (≤ 3 Months)

Treatment should be continued for a minimum of 48 to 72 hours beyond the time that 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 to prevent the occurrence of acute rheumatic fever.  Due to incompletely developed renal function affecting elimination of amoxicillin in this age group, the recommended upper dose of amoxicillin for oral suspension is 30 mg/kg/day divided every 12 hours.  There are currently no dosing recommendations for pediatric patients with impaired renal function. Streptococcus pyogenes

2.3 Dosing for H. pylori Infection

The recommended adult oral dose is 1 gram amoxicillin for oral suspension, 500 mg clarithromycin, and 30 mg lansoprazole, all given twice daily (every 12 hours) for 14 days. The recommended adult oral dose is 1 gram amoxicillin for oral suspension and 30 mg lansoprazole, each given three times daily (every 8 hours) for 14 days. Please refer to clarithromycin and lansoprazole full prescribing information. Triple therapy:

Dual therapy:

2.4 Dosing in Renal Impairment

• 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 a 875 mg dose.
• 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 glomerular filtration rate less than 10 mL/min should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection.
• Hemodialysis patients should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection. They should receive an additional dose both during and at the end of dialysis.

2.5 Directions for Mixing Oral Suspension

Tap bottle until all powder flows freely. Add approximately 1/3 of the total amount of water for reconstitution (see Table 2) and shake vigorously to wet powder. Add remainder of the water and again shake vigorously.

After reconstitution, the required amount of suspension should be placed directly on the child’s tongue for swallowing. Alternate means of administration are to add the required amount of suspension to formula, milk, fruit juice, water, ginger ale, or cold drinks. These preparations should then be taken immediately. SHAKE ORAL SUSPENSION WELL BEFORE USING. Keep bottle tightly closed. Any unused portion of the reconstituted suspension must be discarded after 14 days. Refrigeration is preferable, but not required.
NOTE:

5.1 Anaphylactic Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy including amoxicillin. 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 regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, amoxicillin should be discontinued and appropriate therapy instituted.

5.2 Clostridium difficile Associated Diarrhea

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 Clostridium difficileC. difficile.

produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of 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 antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. C. difficileC. difficile

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of , and surgical evaluation should be instituted as clinically indicated. C. difficileC. difficile

5.3 Development of Drug-Resistant Bacteria

Prescribing amoxicillin in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

5.4 Use in Patients With Mononucleosis

A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Thus amoxicillin should not be administered to patients with mononucleosis.

5.5 Phenylketonurics

The oral suspension of amoxicillin do not contain phenylalanine and can be used by phenylketonurics.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (> 1%) observed in clinical trials of amoxicillin for oral suspension were diarrhea, rash, vomiting, and nausea. The most frequently reported adverse events for patients who received triple therapy (amoxicillin/clarithromycin/lansoprazole) were diarrhea (7%), headache (6%), and taste perversion (5%). 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.



Triple therapy:

Dual therapy:

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.

• Mucocutaneous candidiasis. Infections and Infestations:
• Black hairy tongue, and hemorrhagic/pseudomembranous colitis.  Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment . Gastrointestinal:[see ] Warnings and Precautions (5.2)
• Anaphylaxis . 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 Hypersensitivity Reactions:[see ] Warnings and Precautions (5.1)have been reported.
• A moderate rise in AST and/or ALT has been noted, but the significance of this finding is unknown. Hepatic dysfunction including cholestatic jaundice, hepatic cholestasis and acute cytolytic hepatitis Liver:have been reported.
• Crystalluria Renal:has been reported[see ]. Overdosage (10)
• Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Hemic and Lymphatic Systems:have been reported.
• Reversible hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, behavioral changes, and/or dizziness Central Nervous System:have been reported.
• Tooth discoloration (brown, yellow, or gray staining) Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases. Miscellaneous:has been reported.

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 ; however, the clinical significance of this interaction is not well documented. in vitro

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’s Solution, or Fehling’s Solution. Since this effect may also occur with amoxicillin, it is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as CLINISTIX ) be used. Following administration of ampicillin or amoxicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted. ®®

8.1 Pregnancy

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. Teratogenic Effects:

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 (≤ 3 months). [See .] Dosage and Administration (2.2)

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  for specific recommendations in patients with renal impairment. Dosing in Renal Impairment (2.4)

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

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. Absorption:

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, , single-dose study in 27 adults showed that the 875 mg tablet of amoxicillin produces an AUC of 35.4 ± 8.1 mcg•hr/mL and a C of 13.8 ± 4.1 mcg/mL. Dosing was at the start of a light meal following an overnight fast. two-partcrossover bioequivalencecomparing 875 mg of amoxicillin with 875 mg of amoxicillin/clavulanate potassium0-∞max

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 mcg/mL and 3.5 mcg/mL to 5 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:  

Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when meninges are inflamed. In blood serum, amoxicillin is approximately 20% protein-bound. 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.  Distribution:

The half-life of amoxicillin is 61.3 minutes. Approximately 60% of an orally administered dose of amoxicillin is excreted in the urine within 6 to 8 hours. Detectable serum levels are observed up to 8 hours after an orally administered dose of amoxicillin. Since most of the amoxicillin is excreted unchanged in the urine, its excretion can be delayed by concurrent administration of probenecid . Metabolism and Excretion:[see ] Drug Interactions (7.1)

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.

Mechanism 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 and in clinical infections as described in the section. in vitroINDICATIONS AND USAGE

Gram-Positive Bacteria

spp. spp. (alpha and beta-hemolytic) Enterococcus faecalis
Staphylococcus
Streptococcus pneumoniae
Streptococcus

Gram-Negative Bacteria

      Escherichia coli
Haemophilus influenzae
Helicobacter pylori
Proteus mirabilis

Susceptibility Test Methods:

When available, the clinical microbiology laboratory should provide cumulative susceptibility test results for antimicrobial drugs used in local hospitals and practice areas 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 the most effective antimicrobial. in vitro

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method -(broth or agar) . The MIC values should be interpreted according to the criteria in Table 4. Dilution Techniques:2,4

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds . The zone size should be determined using a standardized test method . Diffusion Techniques:3,43

Susceptibility to amoxicillin of spp Enterobacteriaceae, and , may be inferred by testing ampicillin . Susceptibility to amoxicillin of spp., and beta-hemolytic spp., may be inferred by testing penicillin . The majority of isolates of spp. that are resistant to ampicillin or amoxicillin produce a TEM-type beta-lactamase. A beta-lactamase test can provide a rapid means of determining resistance to ampicillin and amoxicillin . Enterococcus.,H. influenzae4StaphylococcusStreptococcus4Enterococcus4

Susceptibility to amoxicillin of (non-meningitis isolates) may be inferred by testing penicillin or oxacillin . The interpretive criteria for . to amoxicillin are provided in Table 4 . Streptococcus pneumoniae4Spneumoniae4

A report of “Susceptible” indicates the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches a concentration at the infection site necessary to inhibit growth of the pathogen. 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. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration usually achievable at the infection site; other therapy should be selected.

Susceptibility Testing for Helicobacter pylori

Amoxicillin susceptibility testing methods for determining minimum inhibitory concentrations (MICs) and zone sizes have not been standardized, validated, or approved for testing . Specimens for and clarithromycin susceptibility test results should be obtained on isolates from patients who fail triple therapy. If clarithromycin resistance is found, a non-clarithromycin-containing regimen should be used. in vitroH. pyloriH. pylori

Quality Control:

Standardized susceptibility test procedures require use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test control. Standard amoxicillin powder should provide the following range of MIC values provided in Table 5 . For the diffusion technique the criteria provided in Table 5 should be achieved.   2,3,44

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 clavulanic acid mixture was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and clavulanic acid mixture 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 clavulanic acid mixture 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).

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

Randomized, double-blind clinical studies performed in the United States in patients with 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 . Based on the results of these studies, the safety and efficacy of 2 different eradication regimens were established: Amoxicillin 1 gram twice daily/clarithromycin 500 mg twice daily/lansoprazole 30 mg twice daily ( ). Amoxicillin 1 gram three times daily/lansoprazole 30 mg three times daily ( ). All treatments were for 14 days. 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 has been shown to reduce the risk of duodenal ulcer recurrence. H. pyloriH. pylori

Triple Therapy:see Table 6
Dual Therapy:
see Table 7H. pyloriH. pylori