FULL PRESCRIBING INFORMATION: CONTENTS*

Amoxicillin and clavulanate potassium tablets are indicated for the treatment of lower respiratory tract infection due to confirmed or suspected beta-lactamase producing Haemophilus influenzae and Moraxella catarrhalis as follows [see Clinical Pharmacology (12.4), Clinical Studies (14.1)]:

• Amoxicillin and Clavulanate Potassium Tablets: adults and pediatric patients weighing greater than or equal to 40 kg

• The recommended dosage and administration for the amoxicillin and clavulanate potassium tablets, depends on the indication, patient age, weight, and ability to swallow tablets. Therefore, carefully follow the recommended dosage and administration instructions specified below [see Dosage and Administration (2.2, 2.4, 2.6 and 2.8)].
• Amoxicillin and clavulanate potassium tablets should only be used in adults and pediatric patients weighing 40 kg or more who can swallow tablets whole [see Indications and Usage (1), Dosage and Administration (2.2), Use in Specific Populations (8.4)].
• Pediatric patients weighing 40 kg or more who can swallow tablets should receive the adult dose [see Indications and Usage (1), Dosage and Administration (2.2), Use in Specific Populations (8.4)].
• Substitution among amoxicillin and clavulanate potassium formulations should only occur when the amoxicillin-­to-clavulanic acid ratio is matched; AUGMENTIN Chewable Tablets and Oral Suspension are substitutable on a mg-per-mg basis, and certain Amoxicillin and Clavulanate Potassium Tablet strengths are substitutable with specific AUGMENTIN for Oral Suspension or Chewable Tablet strengths. [see Dosage and Administration (2.8)].

Amoxicillin and clavulanate potassium tablets are 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).

Amoxicillin and clavulanate potassium tablets are contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with treatment with amoxicillin/clavulanate potassium.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials. 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, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. Amoxicillin and clavulanate potassium is contraindicated in patients with a history of serious hypersensitivity reactions to amoxicillin, clavulanate, or to other beta-lactam antibacterial drugs [see Contraindications (4.1)]. If an allergic reaction occurs, discontinue amoxicillin and clavulanate potassium and institute appropriate therapy.

Amoxicillin and clavulanate potassium 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 discontinued if lesions progress.

Drug-induced enterocolitis syndrome (DIES) has been reported with use of amoxicillin, a component of amoxicillin and clavulanate potassium tablets [see Adverse Reactions (6.2)], with most cases occurring in pediatric patients. 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 and institute appropriate therapy.

Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use of amoxicillin and clavulanate potassium. Hepatotoxicity is usually reversible; however, deaths have been reported. These cases have generally been associated with serious underlying diseases or concomitant medications. Amoxicillin and clavulanate potassium is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with treatment with amoxicillin and clavulanate potassium [see Contraindications (4.2), Use in Specific Populations (8.7), Adverse Reactions (6.2)].

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

If CDAD is suspected or confirmed, ongoing antibacterial drug 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.

A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Avoid amoxicillin and clavulanate potassium use in patients with mononucleosis [see Adverse Reactions (6.2)].

The possibility of superinfections with mycotic or bacterial pathogens should be considered during therapy. If superinfections occur (commonly involving Pseudomonas spp. or Candida spp.), discontinue amoxicillin and clavulanate potassium and institute appropriate therapy.

Prescribing amoxicillin and 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-resistant bacteria.

Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with amoxicillin and clavulanate potassium may result in increased and prolonged blood levels of amoxicillin. Co-administration of probenecid is not recommended.

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.

The concurrent administration of allopurinol and amoxicillin increases substantially 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. Discontinue allopurinol at the first appearance of skin rash when used concomitantly with amoxicillin and clavulanate potassium.

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. Therefore, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

Risk Summary

Available data from published epidemiologic studies and pharmacovigilance case reports over several decades of use with amoxicillin and clavulanate during pregnancy have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal outcomes. A study in women with preterm prelabor rupture of membranes (PPROM) reported that prophylactic treatment with amoxicillin and clavulanate may be associated with an increased risk of necrotizing enterocolitis in neonates (see Data). Reproduction studies conducted in pregnant rats, given doses greater than or equal to 4 and 10 times the Maximum Recommended Human Dose (MRHD) of amoxicillin trihydrate and clavulanate respectively in amoxicillin and clavulanate potassium based on body surface area, revealed no evidence of fetal harm (see Data).

 

The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Human Data

 

One randomized, controlled trial included 4,826 pregnant women with premature rupture of fetal membranes who were randomly assigned to 250 mg erythromycin (n=1,197), 250 mg amoxicillin and 125 mg clavulanate (n=1,212), amoxicillin and clavulanate plus erythromycin (n=1,192), or placebo (n=1,225) four times daily for 10 days or until delivery. Amoxicillin and clavulanate was associated with a significantly increased rate of proven neonatal necrotizing enterocolitis: 1.9% (n=24) in the amoxicillin and clavulanate only group versus 0.5% (n=6) in the placebo group (p=0.001), and 1.8% (n=44) in the any amoxicillin and clavulanate group versus 0.7% (n=17) in the no amoxicillin and clavulanate group (p=0.0005).

Animal Data

In an embryofetal developmental study in pregnant rats, amoxicillin and clavulanate (2:1 ratio formulation of amoxicillin:clavulanate) were administered at oral doses up to 1,200 mg/kg/day during the period of organogenesis (gestation days (GD) 6 to 15). No evidence of fetal harm was observed. Based on body surface area comparisons, the dose corresponds to approximately 4 times the MRHD for amoxicillin trihydrate and 10 times the MRHD for clavulanate potassium.

In a pre-and postnatal developmental study in pregnant rats, amoxicillin and clavulanate (2:1 ratio formulation of amoxicillin:clavulanate) were administered at oral doses up to 1,200 mg/kg/day beginning from GD 15 through Day 21 of lactation. No effects on maternal reproductive function or on developmental and reproductive parameters of the offspring were observed up to the highest dose, corresponding to approximately 4 times the MRHD for amoxicillin trihydrate and 10 times the MRHD for clavulanate potassium, based on body surface area comparisons.

Risk Summary

Data from a published clinical lactation study report that amoxicillin is present in human milk. There are reports of diarrhea, irritability, and rash in infants exposed to amoxicillin and clavulanate through breast milk; therefore, infants exposed to amoxicillin and clavulanate potassium should be monitored for these symptoms. There are no data on the effects of amoxicillin and clavulanate on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for amoxicillin and clavulanate potassium and any potential adverse effects on the breastfed child from amoxicillin and clavulanate potassium or from the underlying maternal condition.

The five amoxicillin and clavulanate potassium dosage forms (tablets, chewable tablets, oral suspension, XR tablets, and ES-600 for oral suspension) are different products. They are approved for different pediatric indications, age groups, and weights; have different dosing regimens; and have different preparation and administration instructions. Therefore, select the recommended dosage form based on the pediatric indication, age group, and weight [see Dosage and Administration (2)].

Lower Respiratory Tract Infections

The safety and effectiveness of amoxicillin and clavulanate potassium have been established for the treatment of lower respiratory tract infections due to confirmed or suspected beta-lactamase producing isolates of Haemophilus influenzae and Moraxella catarrhalis as follows [see Indications and Usage (1.1), Clinical Pharmacology (12.3), Clinical Studies (14.1)]:

• Amoxicillin and Clavulanate Potassium Tablets: pediatric patients weighing greater than or equal to 40 kg. Effectiveness is supported by adequate and well-controlled studies in adults, with pediatric pharmacokinetic data demonstrating comparable amoxicillin and clavulanate exposures, and under the assumption that disease course and response are sufficiently similar in these pediatric patients to adults.
  Acute Bacterial Sinusitis
  The safety and effectiveness of amoxicillin and clavulanate potassium have been established for the treatment of acute bacterial sinusitis due to confirmed or suspected beta-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis as follows [see Indications and Usage (1.3), Clinical Pharmacology (12.3), Clinical Studies (14.4)]:  
• Amoxicillin and Clavulanate Potassium Tablets:
  pediatric patients weighing greater than or equal to 40 kg. Effectiveness is supported by adequate and well-controlled studies in adults, with pediatric pharmacokinetic data demonstrating comparable amoxicillin and clavulanate exposures, and under the assumption that disease course and response are sufficiently similar in these pediatric patients to adults.
  Acute Bacterial Otitis Media
  The safety and effectiveness of amoxicillin and clavulanate potassium have been established for the treatment of acute bacterial otitis media due to confirmed or suspected beta-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis as follows [see Indications and Usage (1.4), Clinical Pharmacology (12.3), Clinical Studies (14.5)]:  
• Amoxicillin and Clavulanate Potassium Tablets: pediatric patients weighing greater than or equal to 40 kg. Effectiveness is supported by adequate and well-controlled studies in adults, with pediatric pharmacokinetic data demonstrating comparable amoxicillin and clavulanate exposures, and under the assumption that disease course and response are sufficiently similar in these pediatric patients to adults.
  Skin and Skin Structure Infections
  The safety and effectiveness of amoxicillin and clavulanate potassium have been established for the treatment of skin and skin structure infections due to confirmed or suspected beta-lactamase-producing S. aureus, Escherichia coli, and Klebsiella species as follows [see Indications and Usage (1.6), Clinical Pharmacology (12.3)]: 
• Amoxicillin and Clavulanate Potassium Tablets: pediatric patients weighing greater than or equal to 40 kg. Effectiveness is supported by adequate and well-controlled studies in adults, with pediatric pharmacokinetic data demonstrating comparable amoxicillin and clavulanate exposures, and under the assumption that disease course and response are sufficiently similar in these pediatric patients to adults.
  Urinary Tract Infections
  The safety and effectiveness of amoxicillin and clavulanate potassium have been established for the treatment of urinary tract infections due to confirmed or suspected beta-lactamase-producing E. coli, Klebsiella species, and Enterobacter species as follows [see Indications and Usage (1.7), Clinical Pharmacology (12.3), Clinical Studies (14.2)]: 
• Amoxicillin and Clavulanate Potassium Tablets: pediatric patients weighing greater than or equal to 40 kg. Effectiveness is supported by adequate and well-controlled studies in adults, with pediatric pharmacokinetic data demonstrating comparable amoxicillin and clavulanate exposures, and under the assumption that disease course and response are sufficiently similar in these pediatric patients to adults.
  Use Not Established in Certain Pediatric Populations
  The safety and effectiveness of amoxicillin and clavulanate potassium have not been established in the following pediatric populations:  
• Amoxicillin and clavulanate potassium tablets in pediatric patients weighing less than 40 kg, due to different amoxicillin-to-clavulanate ratios from the Chewable Tablets and for Oral Suspension formulations [see Dosage and Administration (2.4)]. 

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

The antibacterial activity of amoxicillin/clavulanate is primarily driven by the percentage of the dosing interval during which unbound (free) amoxicillin plasma concentrations exceed the minimum inhibitory concentration (%fT>MIC) of the target bacterial organism. Clavulanate inhibits β-lactamase enzymes and thereby restores activity of amoxicillin against certain β-­lactamase–producing bacteria.

Absorption

Amoxicillin and Clavulanate Potassium Tablets

Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While amoxicillin and 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 and clavulanate potassium was dosed at 30 and 150 minutes after the start of a high‑fat breakfast.

Mean amoxicillin and clavulanate potassium pharmacokinetic parameters in healthy adult subjects following administration of amoxicillin and clavulanate potassium tablets are shown in Table 7.

Table 7: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parametersa,b  with Amoxicillin and Clavulanate Potassium Tablets

a Mean (± standard deviation) values of 14 healthy adult subjects (n= 15 for clavulanate in the low-dose regimens). Peak concentrations occurred ~1.5 hours after the dose.

b Administered at the start of a light meal.

Distribution

The protein binding of amoxicillin and clavulanic acid to human serum is approximately 18% and 25%, respectively. Amoxicillin diffuses readily into most body tissues and fluids, with the exception of the brain and spinal fluid.

Metabolism and Excretion

The half-life of amoxicillin after the oral administration of amoxicillin and clavulanate potassium is approximately 1.3 hours and that of clavulanic acid is approximately 1 hour.

Amoxicillin and Clavulanate Potassium Tablets

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

Drug Interaction Studies

Clinical Studies

Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid [see Drug Interactions (7.1)].

Mechanism of Action

Amoxicillin binds to penicillin-binding proteins within the bacterial cell wall and inhibits bacterial cell wall synthesis. Clavulanic acid is a beta-lactam, structurally related to penicillin, that may inactivate certain beta‑lactamase enzymes.

Resistance

Resistance to penicillins may be mediated by destruction of the beta-lactam ring by a beta­-lactamase, altered affinity of penicillin for target, or decreased penetration of the antibacterial drug to reach the target site. Amoxicillin alone is susceptible to degradation by beta‑lactamases, and therefore its spectrum of activity does not include bacteria that produce these enzymes.

Antimicrobial Activity

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

Lower Respiratory Tract Infections

Gram-negative bacteria:

Haemophilus influenzae

Moraxella catarrhalis

 

Acute Bacterial Sinusitis

Gram-positive bacteria:

Staphylococcus aureus (methicillin-susceptible)

Streptococcus pneumoniae

 

Gram-negative bacteria:

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella pneumoniae

Moraxella catarrhalis

Acute Bacterial Otitis Media

Gram-positive bacteria:

Streptococcus pneumoniae

 

Gram-negative bacteria: 

Haemophilus influenzae

Moraxella catarrhalis

 

Skin and Skin Structure Infections

Gram-positive bacteria: 

Staphylococcus aureus (methicillin-susceptible)

 

Gram-negative bacteria: 

Escherichia coli

Klebsiella spp.

Urinary Tract Infections

 Gram-negative bacteria (including beta-lactamase-producing strains): 

Escherichia coli

Klebsiella spp. 

Enterobacter spp.

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for amoxicillin and clavulanic acid against isolates of similar genus or organism group. However, the efficacy of amoxicillin and clavulanic acid in treating clinical infections caused by these bacteria have not been established in adequate and well-controlled trials.

Gram-positive bacteria: 

Enterococcus faecalis

Staphylococcus epidermidis

Staphylococcus saprophyticus

Streptococcus pyogenes

Viridans group Streptococcus

Gram-negative Bacteria

Eikenella corrodens

Proteus mirabilis

Anaerobic Bacteria

Bacteroides species including Bacteroides fragilis

Fusobacterium species

Peptostreptococcus species

Susceptibility Testing:

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.

Carcinogenesis

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

Mutagenesis 

Amoxicillin and clavulanate (4:1 ratio formulation of amoxicillin:clavulanate) was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and clavulanate was weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at concentrations that were also associated with decreased cell survival. Amoxicillin and clavulanate was negative in the mouse micronucleus test, and in the dominant lethal assay in mice. Clavulanate potassium alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test and was negative in each of these assays.

Impairment of Fertility

Amoxicillin and clavulanate (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 comparisons, these doses correspond to approximately 4 times the MRHD for adults for amoxicillin trihydrate and 10 times the MRHD for clavulanate potassium.

A randomized, controlled trial was conducted in 562 adults with lower respiratory tract infections, comparing amoxicillin and clavulanate potassium tablets 875 mg/125 mg every 12 hours with amoxicillin and clavulanate potassium tablets 500 mg/125 mg every 8 hours. Comparable efficacy was demonstrated between the two regimens.

A randomized, controlled trial was conducted in adults with pyelonephritis (n=361) or complicated urinary tract infection (n=268), defined as urinary tract abnormalities that predispose to relapse after bacteriuria eradication. Patients were randomized 1:1 to receive amoxicillin and clavulanate potassium tablets 875 mg/125 mg every 12 hours (n=308) or amoxicillin and clavulanate potassium tablets 500 mg/125 mg every 8 hours (n=321). Among bacteriologically evaluable patients, bacteriologic success rates were comparable between the two dosing regimens when assessed immediately after therapy and at follow-up visits.

Table 13: Bacteriologic Efficacy Rates in Complicated Urinary Tract Infections in Adults

Adults with a diagnosis of acute bacterial sinusitis (ABS) were evaluated in 3 clinical studies. In one study, 363 patients were randomized to receive either AUGMENTIN XR Extended-Release Tablets 2,000 mg/125 mg orally every 12 hours or levofloxacin 500 mg orally daily for 10 days in a double‑blind, multicenter, prospective trial. These patients were clinically and radiologically evaluated at the test of cure (day 17 to 28) visit. The combined clinical and radiological responses were 84% for AUGMENTIN XR Extended-Release Tablets and 84% for levofloxacin at the test of cure visit in clinically evaluable patients (95% CI for the treatment difference equals ‑9.4, 8.3). The clinical response rates at the test of cure were 87% and 89%, respectively.

The other 2 trials were non‑comparative, multicenter studies designed to assess the bacteriological and clinical efficacy of AUGMENTIN XR Extended-Release Tablets (2,000 mg/125 mg orally every 12 hours for 10 days) in the treatment of 2,288 patients with ABS. Evaluation timepoints were the same as in the prior study. Patients underwent maxillary sinus puncture for culture prior to receiving study medication. Patients with acute bacterial sinusitis due to S. pneumoniae with reduced susceptibility to penicillin were accrued through enrollment in these 2 open‑label non‑comparative clinical trials. Clinical success rates for key pathogens in these studies are shown in Table 15.

Table 15: Clinical Success Rates in Patients with Acute Bacterial Sinusitis

an/N equals patients with pathogen eradicated or presumed eradicated/total number of patients.

bConfidence limits calculated using exact probabilities.

cS. pneumoniae strains with penicillin MICs of greater than or equal to 2 mcg/mL are considered resistant to penicillin.

dIncludes one patient each with S. pneumoniae penicillin MICs of 8 and 16 mcg/mL.

One randomized, controlled US/Canadian clinical trial evaluated two dosing regimens for AUGMENTIN for Oral Suspension in pediatric patients (aged 2 months to 12 years) with acute otitis media. Patients received either 45 mg/6.4 mg/kg/day divided every 12 hours or 40 mg/10 mg/kg/day divided every 8 hours for 10 days. A total of 575 patients were enrolled, with ≥84% evaluable in each group.

Clinical cure rates obtained in the evaluable patients at the end of therapy and follow-up visits are presented in Table 16.

Table 16: Clinical Cure Rates at End of Therapy and Follow-Up Visits

aClinical cure at end of therapy visit was defined as 2 to 4 days after the completion of therapy.

bClinical cure at follow-up visit was defined as 22 to 28 days post‑completion of therapy.