2.1 Important Administration Instructions

Amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) may be taken without regard to meals; however, absorption of clavulanate potassium is enhanced when amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) are administered at the start of a meal. To minimize the potential for gastrointestinal intolerance, amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) should be taken at the start of a meal.

2.2 Adult Patients

See dosing regimens of amoxicillin/clavulanate potassium (based on the amoxicillin component) provided in Table 1 below.

2.3 Pediatric Patients

Based on the amoxicillin component, amoxicillin and clavulanate potassium for oral suspension should be dosed as follows:

Neonates and Infants Aged less than 12 Weeks (less than 3 Months): See dosing regimens of amoxicillin/clavulanate potassium provided in Table 2 below.

Patients Aged 12 Weeks (3 Months) and Older and Weighing Less than 40 kg: See dosing regimens provided in Table 3 below.

• The every 12 hour regimen is recommended as it is associated with significantly less diarrhea [see Clinical Studies (14.2)].
• The amoxicillin and clavulanate potassium 200 mg/28.5 mg per 5 mL and amoxicillin and clavulanate potassium 400 mg/57 mg per 5 mL for oral suspension and amoxicillin and clavulanate potassium 200 mg/28.5 mg and amoxicillin and clavulanate tablets (chewable) 400 mg/57 mg contain aspartame and should not be used by phenylketonurics [see Warnings and Precautions (5.8)].

Patients Weighing 40 kg or More: Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations.

• The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium tablets should NOT be used until the child weighs at least 40 kg, due to the different amoxicillin to clavulanic acid ratios in the 250 mg/125 mg tablet of amoxicillin and clavulanate potassium tablets versus the 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium tablets (chewable).

2.4 Patients with Renal Impairment

Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Renal impairment patients with a glomerular filtration rate (GFR) of less than 30 mL/min should NOT receive the 875 mg dose (based on the amoxicillin component) of amoxicillin and clavulanate potassium tablets. See dosing regimens in patients with severe renal impairment provided in Table 4.

2.5 Directions for Mixing Amoxicillin and Clavulanate Potassium for Oral Suspension

Prepare amoxicillin and clavulanate potassium for oral suspension at time of dispensing as follows: Tap bottle until all powder flows freely. Measure a total (see Table 5 below for total amount of water for reconstitution) OF WATER. Add approximately 2/3 of the water to the powder. Replace cap and shake VIGOROUSLY. Add remaining water. Replace cap and shake VIGOROUSLY.

Shake oral suspension well before using. Reconstituted suspension must be stored under refrigeration and discarded after 10 days. Some color change is normal during dosing period.

2.6 Switching between Dosage Forms and between Strengths

Amoxicillin and Clavulanate Potassium Tablet, 250 mg/125 mg are NOT Substitutable with Amoxicillin and Clavulanate Potassium Chewable Tablet, 250 mg/62.5 mg

The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium tablets and the 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium tablets (chewable) should NOT be substituted for each other and the tablet of 250 mg/125 mg amoxicillin and clavulanate potassium tablets should NOT be used in pediatric patients weighing less than 40 kg [see Dosage and Administration (2.3)]. The 250 mg tablet of amoxicillin and clavulanate potassium tablets and the tablet of 250 mg amoxicillin and clavulanate potassium tablets (chewable) do not contain the same amount of clavulanic acid. The 250 mg tablet of amoxicillin and clavulanate potassium tablets contain 125 mg of clavulanic acid whereas the 250 mg tablet of amoxicillin and clavulanate potassium tablets (chewable) contain 62.5 mg of clavulanic acid.

Two Amoxicillin and Clavulanate Potassium Tablets, 250 mg/125 mg are NOT Substitutable with One Amoxicillin and Clavulanate Potassium Tablet, 500 mg/125 mg

Two 250 mg/125 mg amoxicillin and clavulanate potassium tablets should NOT be substituted for one 500 mg/125 mg amoxicillin and clavulanate potassium tablet. Since both the 250 mg and 500 mg tablets of amoxicillin and clavulanate potassium tablets contain the same amount of clavulanic acid (125 mg, as the potassium salt), two 250 mg tablets of amoxicillin and clavulanate potassium tablets are not equivalent to one 500 mg tablet of amoxicillin and clavulanate potassium tablet.

4.1 Serious Hypersensitivity Reactions

Amoxicillin/clavulanate potassium is contraindicated in patients with a history of serious hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin, clavulanate or to other beta-lactam antibacterial drugs (e.g., penicillins and cephalosporins).

4.2 Cholestatic Jaundice/Hepatic Dysfunction

Amoxicillin/clavulanate potassium is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with amoxicillin/clavulanate potassium.

5.1 Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, including amoxicillin/clavulanate potassium. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. Before initiating therapy with amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable), careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) should be discontinued, and appropriate therapy instituted.

5.2 Severe Cutaneous Adverse Reactions

Amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) may cause severe cutaneous adverse reactions (SCAR), such as Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). If patients develop a skin rash, they should be monitored closely, and amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) discontinued if lesions progress.

5.3 Drug-Induced Enterocolitis Syndrome (DIES)

Drug-induced enterocolitis syndrome (DIES) has been reported with the use of amoxicillin, a component of amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable), [see Adverse Reactions (6.2)], with most cases occurring in pediatric patients ≤18 years of age. DIES is a non-IgE mediated hypersensitivity reaction characterized by protracted vomiting occurring 1 to 4 hours after drug ingestion in the absence of skin or respiratory symptoms. DIES may be associated with pallor, lethargy, hypotension, shock, diarrhea within 24 hours after ingesting amoxicillin, and leukocytosis with neutrophilia. If DIES occurs, discontinue amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) and institute appropriate therapy.

5.4 Hepatic Dysfunction

Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use of amoxicillin/clavulanate potassium. Hepatic toxicity is usually reversible; however, deaths have been reported. Hepatic function should be monitored at regular intervals in patients with hepatic impairment.

5.5 Clostridioides difficile Associated Diarrhea (CDAD)

Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin/clavulanate potassium, 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 antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

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

5.6 Skin Rash in Patients with Mononucleosis

A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Thus, amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) should not be administered to patients with mononucleosis.

5.7 Potential for Microbial Overgrowth

The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfection occurs, amoxicillin/clavulanate potassium should be discontinued and appropriate therapy instituted.

5.8 Phenylketonurics

Amoxicillin and clavulanate potassium tablets (chewable) and amoxicillin and clavulanate potassium for oral suspension contain aspartame which contains phenylalanine. Each 200 mg/28.5 mg chewable tablet of amoxicillin/clavulanate potassium contains 3.4 mg phenylalanine. Each 400 mg/57 mg chewable tablet contains 6.7 mg phenylalanine. Each 5 mL of the 200 mg/28.5 mg per 5 mL oral suspension contains 0.67 mg phenylalanine. Each 5 mL of the 400 mg/57 mg per 5 mL oral suspension contains 1.12 mg phenylalanine. The other formulations of amoxicillin/clavulanate potassium do not contain phenylalanine.

5.9 Development of Drug-Resistant Bacteria

Prescribing amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, or amoxicillin and clavulanate potassium tablets (chewable) 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–resistant bacteria.

6.1 Clinical Trial 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 frequently reported adverse reactions were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%). Less than 3% of patients discontinued therapy because of drug-related adverse reactions. The overall incidence of adverse reactions, and in particular diarrhea, increased with the higher recommended dose. Other less frequently reported adverse reactions (less than 1%) include: Abdominal discomfort, flatulence, and headache.

In pediatric patients (aged 2 months to 12 years), 1 U.S./Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) of amoxicillin/clavulanate potassium for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of amoxicillin/clavulanate potassium for 10 days in the treatment of acute otitis media. A total of 575 patients were enrolled, and only the suspension formulations were used in this trial. Overall, the adverse reactions seen were comparable to that noted above; however, there were differences in the rates of diarrhea, skin rashes/urticaria, and diaper area rashes [see Clinical Studies (14.2)].

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following have been identified during postmarketing use of amoxicillin/clavulanate potassium. 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/clavulanate potassium.

Gastrointestinal: Indigestion, gastritis, stomatitis, glossitis, Drug-induced enterocolitis syndrome (DIES), black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment [see Warnings and Precautions (5.5)].

Immune: Hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock), angioedema, serum sickness–like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), hypersensitivity vasculitis [see Warnings and Precautions (5.1)].

Skin and Appendages: Rashes, pruritus, urticaria, erythema multiforme, SJS, TEN, DRESS, AGEP, exfoliative dermatitis, and linear IgA bullous dermatosis.

Liver: Hepatic dysfunction, including hepatitis and cholestatic jaundice, increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been reported with amoxicillin/clavulanate potassium. It has been reported more commonly in the 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. Deaths have been reported [see Contraindications (4.2), Warnings and Precautions (5.4)].

Renal: Interstitial nephritis, hematuria, and crystalluria have been reported [see Overdosage (10)].

Hemic and Lymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Thrombocytosis was noted in less than 1% of the patients treated with amoxicillin/clavulanate potassium. There have been reports of increased prothrombin time in patients receiving amoxicillin/clavulanate potassium and anticoagulant therapy concomitantly [see Drug Interactions (7.2)].

Central Nervous System: Agitation, anxiety, behavioral changes, aseptic meningitis, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported.

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

7.1 Probenecid

Probenecid decreases the renal tubular secretion of amoxicillin but does not delay renal excretion of clavulanic acid. Concurrent use with amoxicillin/clavulanate potassium may result in increased and prolonged blood concentrations of amoxicillin. Coadministration of probenecid is not recommended.

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 with amoxicillin/clavulanate potassium. 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/clavulanate potassium may affect intestinal flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.

7.5 Effects on Laboratory Tests

High urine concentrations of amoxicillin 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/clavulanate potassium, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

Following administration of 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

Teratogenic Effects: Reproduction studies performed in pregnant rats and mice given amoxicillin/clavulanate potassium (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses up to 1200 mg/kg/day revealed no evidence of harm to the fetus due to amoxicillin/clavulanate potassium. The amoxicillin doses in rats and mice (based on body surface area) were approximately 4 and 2 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, these dose multiples were approximately 9 and 4 times the maximum recommended adult human oral dose (125 mg every 8 hours). 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.

8.2 Labor and Delivery

Oral ampicillin-class antibacterials are poorly absorbed during labor. It is not known whether 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 of the necessity for an obstetrical intervention.

8.3 Nursing Mothers

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

8.4 Pediatric Use

The safety and effectiveness of amoxicillin and clavulanate potassium for oral suspension and amoxicillin and clavulanate potassium tablets (chewable) have been established in pediatric patients. Use of amoxicillin and clavulanate potassium for oral suspension and amoxicillin and clavulanate potassium tablets (chewable) in pediatric patients is supported by evidence from studies of amoxicillin and clavulanate potassium tablets in adults with additional data from a study of amoxicillin and clavulanate potassium for oral suspension in pediatric patients aged 2 months to 12 years with acute otitis media [see Clinical Studies (14.2)].

Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed; clavulanate elimination is unaltered in this age group. Dosing of amoxicillin and clavulanate potassium for oral suspension and amoxicillin and clavulanate potassium tablets (chewable) should be modified in pediatric patients aged less than 12 weeks (less than 3 months) [see Dosage and Administration (2.3)].

8.5 Geriatric Use

Of the 3,119 patients in an analysis of clinical studies of amoxicillin/clavulanate potassium, 32% were greater than or equal to 65 years old, and 14% were  greater than or equal to 75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but 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 adverse 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 Renal Impairment

Amoxicillin is primarily eliminated by the kidney and dosage adjustment is usually required in patients with severe renal impairment (GFR less than 30 mL/min). See Patients with Renal Impairment [see Dosage and Administration (2.4)] for specific recommendations in patients with renal impairment.

12.1 Mechanism of Action

Amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) are antibacterial drugs [see Microbiology (12.4)].

12.3 Pharmacokinetics

Mean amoxicillin and clavulanate potassium pharmacokinetic parameters in normal adults following administration of amoxicillin and clavulanate potassium tablets are shown in Table 6 and following administration of amoxicillin and clavulanate potassium for oral suspension and tablets (chewable) are shown in Table 7.

1. Mean (± standard deviation) values of 14 normal adults (N equals 15 for clavulanate potassium in the low–dose regimens). Peak concentrations occurred approximately 1.5 hours after the dose.
2. Amoxicillin and clavulanate potassium administered at the start of a light meal.

1. Mean (± standard deviation) values of 28 normal adults. Peak concentrations occurred approximately 1 hour after the dose.
2. Amoxicillin and clavulanate potassium administered at the start of a light meal.

Oral administration of 5 mL of the 250 mg/62.5 mg per 5 mL suspension of amoxicillin and clavulanate potassium for oral suspension provides average peak serum concentrations approximately 1 hour after dosing of 6.9 mcg/mL for amoxicillin and 1.6 mcg/mL for clavulanic acid. The areas under the serum concentration curves obtained during the first 4 hours after dosing were 12.6 mcg*h/mL for amoxicillin and 2.9 mcg*h/mL for clavulanic acid when 5 mL of the 250 mg/62.5 mg per 5 mL suspension of amoxicillin and clavulanate potassium for oral suspension or equivalent dose of 10 mL of the 125 mg/31.25 mg per 5 mL suspension of amoxicillin and clavulanate potassium were administered to normal adults. One 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium tablets (chewable) or two 125 mg/31.25 mg chewable tablets of amoxicillin and clavulanate potassium tablets (chewable) are equivalent to 5 mL of the 250 mg/62.5 mg per 5 mL suspension of amoxicillin and clavulanate potassium for oral suspension and provide similar serum concentrations of amoxicillin and clavulanic acid.

Amoxicillin serum concentrations achieved with amoxicillin/clavulanate potassium are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. Time above the minimum inhibitory concentration of 1 mcg/mL for amoxicillin has been shown to be similar after corresponding every 12 hour and every 8–hour dosing regimens of amoxicillin/clavulanate potassium in adults and children.

Absorption: Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While amoxicillin/clavulanate potassium can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In one study, the relative bioavailability of clavulanate was reduced when amoxicillin/clavulanate potassium was dosed at 30 and 150 minutes after the start of a high–fat breakfast.

Distribution: Neither component in amoxicillin/clavulanate potassium is highly protein–bound; clavulanic acid is approximately 25% bound to human serum and amoxicillin approximately 18% bound.

Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid.

Two hours after oral administration of a single 35 mg/kg dose of suspension of amoxicillin/clavulanate potassium to fasting children, average concentrations of 3 mcg/mL of amoxicillin and 0.5 mcg/mL of clavulanic acid were detected in middle ear effusions.

Metabolism and Excretion: The half–life of amoxicillin after the oral administration of amoxicillin/clavulanate potassium is 1.3 hours and that of clavulanic acid is 1 hour.

Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single 250 mg/125 mg or 500 mg/125 mg tablet of amoxicillin/clavulanate potassium.

12.4 Microbiology

Amoxicillin is a semisynthetic antibacterial with in vitro bactericidal activity against Gram–positive and Gram–negative bacteria. Amoxicillin is, however, susceptible to degradation by beta–lactamases, and therefore, the spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a beta–lactam, structurally related to the penicillins, which possesses the ability to inactivate some beta–lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid–mediated beta–lactamases frequently responsible for transferred drug resistance.

The formulation of amoxicillin and clavulanic acid in amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) protect amoxicillin from degradation by some beta–lactamase enzymes and extends the antibacterial spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin.

Amoxicillin and clavulanic acid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1)].

Gram–Positive Bacteria

Staphylococcus aureus

Gram–Negative Bacteria

Enterobacter species

Escherichia coli

Haemophilus influenzae

Klebsiella species

Moraxella catarrhalis

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for amoxicillin and clavulanic acid. However, the efficacy of amoxicillin and clavulanic acid in treating clinical infections due to these bacteria has not been established in adequate and well–controlled clinical trials.

Gram–Positive Bacteria

Enterococcus faecalis

Staphylococcus epidermidis

Staphylococcus saprophyticus

Streptococcus pneumoniae

Streptococcus pyogenes

Viridans group Streptococcus

Gram–Negative Bacteria

Eikenella corrodens

Proteus mirabilis

Anaerobic Bacteria

Bacteroides species including Bacteroides fragilis

Fusobacterium species

Peptostreptococcus species

Susceptibility Test Methods

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Amoxicillin/clavulanate potassium (4:1 ratio formulation of amoxicillin:clavulanate) was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin/clavulanate potassium 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/clavulanate potassium 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.

Amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses of up to 1,200 mg/kg/day was found to have no effect on fertility and reproductive performance in rats. Based on body surface area, this dose of amoxicillin is approximately 4 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, the dose multiple is approximately 9 times higher than the maximum recommended adult human oral dose (125 mg every 8 hours), also based on body surface area.

14.1 Lower Respiratory Tract and Complicated Urinary Tract Infections

Data from 2 pivotal trials in 1,191 patients treated for either lower respiratory tract infections or complicated urinary tract infections compared a regimen of 875 mg/125 mg tablets of amoxicillin and clavulanate potassium tablets every 12 hours to 500 mg/125 mg tablets of amoxicillin and clavulanate potassium tablets dosed every 8 hours (584 and 607 patients, respectively). Comparable efficacy was demonstrated between the every 12 hours and every 8 hours dosing regimens. There was no significant difference in the percentage of adverse events in each group. The most frequently reported adverse event was diarrhea; incidence rates were similar for the 875 mg every 12 hours and 500 mg every 8 hours dosing regimens (15% and 14%, respectively); however, there was a statistically significant difference (p less than 0.05) in rates of severe diarrhea or withdrawals with diarrhea between the regimens: 1% for 875 mg every 12 hours regimen versus 2% for the 500 mg every 8 hours regimen.

In one of these pivotal trials, patients with either pyelonephritis (n equals 361) or a complicated urinary tract infection (i.e., patients with abnormalities of the urinary tract that predispose to relapse of bacteriuria following eradication, n equals 268) were randomized (1:1) to receive either 875 mg/125 mg tablets of amoxicillin and clavulanate potassium tablets every 12 hours (n equals 308) or 500 mg/125 mg tablets of amoxicillin and clavulanate potassium tablets every 8 hours (n equals 321).

The number of bacteriologically evaluable patients was comparable between the two dosing regimens. Amoxicillin and clavulanate potassium tablets produced comparable bacteriological success rates in patients assessed 2 to 4 days immediately following end of therapy. The bacteriologic efficacy rates were comparable at one of the follow–up visits (5 to 9 days post–therapy) and at a late post–therapy visit (in the majority of cases, this was 2 to 4 weeks post–therapy), as seen in Table 8.

As noted, before, though there was no significant difference in the percentage of adverse events in each group, there was a statistically significant difference in rates of severe diarrhea or withdrawals with diarrhea between the regimens.

14.2 Acute Bacterial Otitis Media and Diarrhea in Pediatric Patients

One U.S./Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) of amoxicillin and clavulanate potassium for oral suspension for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of amoxicillin and clavulanate potassium for oral suspension for 10 days in the treatment of acute otitis media. Only the suspension formulations were used in this trial. A total of 575 pediatric patients (aged 2 months to 12 years) were enrolled, with an even distribution among the 2 treatment groups and a comparable number of patients were evaluable (i.e., greater than or equal to 84%) per treatment group. Otitis media–specific criteria were required for eligibility and a strong correlation was found at the end of therapy and follow–up between these criteria and physician assessment of clinical response. The clinical efficacy rates at the end of therapy visit (defined as 2 to 4 days after the completion of therapy) and at the follow–up visit (defined as 22 to 28 days post–completion of therapy) were comparable for the 2 treatment groups, with the following cure rates obtained for the evaluable patients: At end of therapy, 87% (n equals 265) and 82% (n equals 260) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively. At follow–up, 67% (n equals 249) and 69% (n equals 243) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively.

Diarrhea was defined as either: (a) 3 or more watery or 4 or more loose/watery stools in 1 day; OR (b) 2 watery stools per day or 3 loose/watery stools per day for 2 consecutive days. The incidence of diarrhea was significantly lower in patients who received the every 12 hours regimen compared to patients who received the every 8 hours regimen (14% and 34%, respectively). In addition, the number of patients with either severe diarrhea or who were withdrawn with diarrhea was significantly lower in the every 12 hours treatment group (3% and 8% for the every 12 hours/10 day and every 8 hours/10 day, respectively). In the every 12 hours treatment group, 3 patients (1%) were withdrawn with an allergic reaction, while 1 patient in the every 8 hours group was withdrawn for this reason. The number of patients with a candidal infection of the diaper area was 4% and 6% for the every 12 hours and every 8 hours groups, respectively.

It is not known if the finding of a statistically significant reduction in diarrhea with the oral suspensions dosed every 12 hours, versus suspensions dosed every 8 hours of amoxicillin and clavulanate potassium tablets, can be extrapolated to the chewable tablets of amoxicillin and clavulanate potassium tablets. The presence of mannitol in the chewable tablets of amoxicillin and clavulanate potassium tablets may contribute to a different diarrhea profile. The every 12 hour oral suspensions (200 mg/28.5 mg per 5 mL and 400 mg/57 mg per 5 mL) of amoxicillin and clavulanate potassium tablets are sweetened with aspartame.