Amoxicillin and Clavulanate Potassium Tablets, USP

 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/clavulanate potassium 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/clavulanate potassium possesses 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 the INDICATIONS AND USAGE section.

Staphylococcus aureus (β-lactamase and non-β-lactamase producing).‡ 

‡ Staphylococci which are resistant to methicillin/oxacillin must be considered resistant to amoxicillin/clavulanic acid.

Enterobacter species (Although most strains of Enterobacter species are resistant in vitro, clinical efficacy has been demonstrated with amoxicillin/clavulanate potassium 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.

Enterococcus faecalis^II 

Staphylococcus epidermidis (β-lactamase and non-β-lactamase producing)

Staphylococcus saprophyticus (β-lactamase and non-β-lactamase producing) 

Streptococcus pneumoniae ^II¶ ,

Streptococcus pyogenes ^II¶

viridans group Streptococcus ^II¶

Eikenella corrodens (β-lactamase and non-β-lactamase producing)

Neisseria gonorrhoeae ^II  (β-lactamase and non-β-lactamase producing) 

Proteus mirabilis ^II (β-lactamase and non-β-lactamase producing)

Bacteroides species, including Bacteroides fragilis (β-lactamase and non-β-lactamase producing)

Fusobacterium species (β-lactamase and non-β-lactamase producing)

Peptostreptococcus species^¶

^II Adequate and well-controlled clinical trials have established the effectiveness of amoxicillin alone in treating certain clinical infections due to these organisms.

^¶ Those are non-β-lactamase-producing organisms and, therefore, are susceptible to amoxicillin alone.

Dilution Techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). Those 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 

**Staphylococci which are susceptible to amoxicillin/clavulanic acid but resistant to methicillin/oxacillin must be considered as resistant.

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

 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:

 †^†Expressed as concentration of amoxicillin in the presence of clavulanic acid at a constant 2 parts amoxicillin to 1 part clavulanic acid.

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 potassium (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

For Other Organisms Except S. pneumoniae ^b and N. gonorrhoeae ^c

^‡‡ 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.

While amoxicillin/clavulanate potassium possesses 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/clavulanate potassium 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 resistance bacteria.

Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with amoxicillin/clavulanate potassium 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/clavulanate potassium and allopurinol administered concurrently.

In common with other broad-spectrum antibiotics, amoxicillin/clavulanate potassium may reduce the efficacy of oral contraceptives.

Oral administration of amoxicillin/clavulanate potassium 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/clavulanate potassium, 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/clavulanate potassium.

Information for Patients:

Patients should be counseled that antibacterial drugs including amoxicillin/clavulanate potassium, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When amoxicillin/clavulanate potassium 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 effectivness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by amoxicillin/clavulanate potassium or other antibacterial drugs in the future.

Long-term studies in animals have not been performed to evaluate carcinogenic potential.

Mutagenesis:

The mutagenic potential of amoxicillin/clavulanate potassium was investigated in vitro with an Ames test, a human lymphocyte cytogenetic assay, a yeast test and a mouse lymphoma forward mutation assay, and in vivo with mouse micronucleus tests and a dominant lethal test. All were negative apart from the in vitro mouse lymphoma assay where weak activity was found at very high, cytotoxic concentrations.

Impairment of Fertility:

Amoxicillin/clavulanate potassium at oral doses of up to 1200 mg/kg/day (5.7 times the maximum human dose, 1480 mg/m²/day, based on body surface area) was found to have no effect on fertility and reproductive performance in rats, dosed with a 2:1 ratio formulation of amoxicillin:clavulanate.

Teratogenic effects. Pregnancy (Category B):

Reproduction studies performed in pregnant rats and mice given amoxicillin/clavulanate potassium at oral dosages up to 1200 mg/kg/day, equivalent to 7200 and 4080 mg/m²/day, respectively (4.9 and 2.8 times the maximum human oral dose based on body surface area), revealed no evidence of harm to the fetus due to amoxicillin/clavulanate potassium. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

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/clavulanate potassium 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/clavulanate potassium 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/clavulanate potassium is 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. (See prescribing information for Amoxicillin and Clavulanate Powder for Oral Suspension and Chewable Tablets).

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 < 65 years old, 32% were ≥ 65 years old and 14% were ≥ 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 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.

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.)

 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, 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.)

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 increases in serum transaminases (AST and/or ALT), serum bilirubin and/or alkaline phosphatase, has been infrequently reported with amoxicillin/clavulanate potassium. It has been reported more commonly in 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.

Interstitial nephritis and hematuria have been reported rarely. Crystalluria has also been reported (see OVERDOSAGE).

 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/clavulanate potassium. There have been rare reports of increased prothrombin time in patients receiving amoxicillin/clavulanate potassium and anticoagulant therapy concomitantly.

Agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported rarely.

 Tooth discoloration (brown, yellow, or gray staining) has been rarely reported. Most reports occured in pediatric patients. Discolorations was reduced or eliminated with brushing or dental cleaning in most cases.

The usual adult dose is one Amoxicillin and Clavulanate Potassium Tablet, USP (amoxicillin, 500 mg, as the trihydrate and clavulanic acid, 125 mg, as clavulanate potassium) every 12 hours or one Amoxicillin and Clavulanate Potassium Tablet 250 mg/125 mg every 8 hours. For more severe infections and infections of the respiratory tract, the dose should be one Amoxicillin and Clavulanate Potassium Tablet, USP (amoxicillin, 875 mg, as the trihydrate and clavulanic acid, 125 mg, as clavulanate potassium) every 12 hours or one Amoxicillin and Clavulanate Potassium Tablet, USP (amoxicillin, 500 mg, as the trihydrate and clavulanic acid, 125 mg, as 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 <30 mL/minute should not receive the 875 mg tablet. Patients with a glomerular filtration rate of 10 to 30 mL/minute 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/minute 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 weighing 40 kg or more should be dosed according to the adult commendations

Due to the different amoxicillin to clavulanic acid ratios in the Amoxicillin and Clavulanate Potassium Tablet 250 mg/125 mg versus the Amoxicillin and Clavulanate Potassium Chewable Tablet 250 mg/62.5, the Amoxicillin and Clavulanate Potassium Tablet 250 mg/125 mg should not be used until the pediatric patient weighs at least 40 kg or more.

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