2.1 Important Administration Instructions

Amoxicillin and clavulanate potassium extended-release tablets should be taken at the start of a meal to enhance the absorption of amoxicillin and to minimize the potential for gastrointestinal intolerance. Amoxicillin and clavulanate potassium extended-release tablets is not recommended to be taken with a high-fat meal because clavulanate absorption is decreased [see Clinical Pharmacology (12.3)].

2.2 Dosage in Adult Patients

The recommended dosage of amoxicillin and clavulanate potassium extended-release tablets is 4,000 mg/250 mg daily according to the following table:

Table 1: Recommended Dosage of Amoxicillin and Clavulanate Potassium Extended-Release Tablets in Adult Patients

Amoxicillin and clavulanate potassium extended-release tablets can be split in half along the score line for patients with difficulty swallowing the tablets whole. Both halves of the tablet must be taken immediately.

2.3 Dosage in Pediatric Patients

Pediatric patients who weigh 40 kg or more and can swallow tablets should receive the adult dose [see Dosage and Administration (2.2) and Use in Specific Populations (8.4)].

2.5 Dosage in Patients with Hepatic Impairment

Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals [see Warnings and Precautions (5.3)].

2.7 Switching between Dosage Forms and between Strengths

Amoxicillin and clavulanate potassium extended-release tablet is NOT substitutable on a mg-to-mg basis with other formulations of amoxicillin and clavulanate potassium. In addition, the extended-release tablets provide an extended time course of plasma amoxicillin concentrations compared to immediate-release tablets. Thus, two amoxicillin and clavulanate potassium 500 mg tablets are not equivalent to one amoxicillin and clavulanate potassium extended-release 1,000 mg tablet.

4.1 Serious Hypersensitivity Reactions

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

4.2 Cholestatic Jaundice/Hepatic Dysfunction

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

4.3 Renal Impairment

Amoxicillin and clavulanate potassium extended-release tablets is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min) and in hemodialysis patients.

5.1 Serious Allergic Reactions, Including Anaphylaxis

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving amoxicillin and clavulanate potassium extended-release tablets. 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 extended-release tablets, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, discontinue amoxicillin and clavulanate potassium extended-release tablets and institute appropriate therapy.

5.2 Severe Cutaneous Adverse Reactions

Amoxicillin and clavulanate potassium extended-release tablets 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 extended-release tablets discontinued if lesions progress.

5.3 Hepatic Dysfunction

Use amoxicillin and clavulanate potassium extended-release tablets with caution in patients with evidence of hepatic dysfunction. Hepatic toxicity associated with the use of amoxicillin and clavulanate potassium extended-release tablets is usually reversible. Deaths have been reported (fewer than one death reported per estimated four million prescriptions worldwide). These have generally been cases associated with serious underlying diseases or concomitant medications [see Contraindications (4.2), and Adverse Reactions (6.2)].

5.4 Clostridioides difficile-Associated Diarrhea (CDAD)

Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin and clavulanate potassium extended- release tablets, 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, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.5 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 extended-release tablets should not be administered to patients with mononucleosis.

5.6 Potential for Microbial Overgrowth

The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur (usually involving Pseudomonas spp. or Candida spp.), the drug should be discontinued and/or appropriate therapy instituted.

5.7 Development of Drug-Resistant Bacteria

Prescribing amoxicillin and clavulanate potassium extended-release tablets 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 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.

In clinical trials, 5,643 patients have been treated with amoxicillin and clavulanate potassium extended-release tablets. The most frequently reported adverse reactions which were suspected or probably drug- related were diarrhea (15%), vaginal mycosis (3%) nausea (2%), and loose stools (2%). Amoxicillin and clavulanate potassium extended-release tablets had a higher rate of diarrhea which required corrective therapy (4% versus 3% for amoxicillin and clavulanate potassium extended-release tablets and all comparators, respectively). Two percent of patients discontinued therapy because of drug-related adverse reactions.

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following have been identified during post-marketing use of amoxicillin and clavulanate potassium products, including amoxicillin and clavulanate potassium extended-release tablets. 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 and clavulanate potassium.

Gastrointestinal: Diarrhea, nausea, vomiting, indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudo membranous colitis. Onset of pseudo membranous colitis symptoms may occur during or after antibacterial treatment [see Warnings and Precautions (5.4)].

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 [see Warnings and Precautions (5.2)].

Liver: A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted in patients treated with ampicillin-class antibacterials, but the significance of these findings is unknown. Hepatic dysfunction, including hepatitis and cholestatic jaundice, [see Contraindications (4.2)], increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been reported with amoxicillin and clavulanate potassium or amoxicillin and clavulanate potassium extended-release tablets. 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 (5.3)].

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 during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. There have been reports of increased prothrombin time in patients receiving amoxicillin and clavulanate potassium and anticoagulant therapy concomitantly.

Central Nervous System: Agitation, anxiety, behavioral changes, aseptic meningitis, confusion, convulsions, dizziness, headache, 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. Concurrent use with amoxicillin and clavulanate potassium extended-release tablets may result in increased and prolonged blood levels of amoxicillin. Co-administration 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. 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 substantially 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. In controlled clinical trials of amoxicillin and clavulanate potassium extended-release tablets, 25 patients received concomitant allopurinol and amoxicillin and clavulanate potassium extended-release tablets. No rashes were reported in these patients. However, this sample size is too small to allow for any conclusions to be drawn regarding the risk of rashes with concomitant amoxicillin and clavulanate potassium extended-release tablets and allopurinol use.

7.4 Oral Contraceptives

Amoxicillin and clavulanate potassium extended-release tablets 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 and clavulanate potassium extended release tablets, 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 and clavulanate potassium at oral doses up to 1,200 mg/kg/day revealed no evidence of harm to the fetus due to amoxicillin and clavulanate potassium. In terms of body surface area, the doses in rats were 1.6 times the maximum human oral dose of amoxicillin and 13 times the maximum human dose for clavulanate. For mice, these doses were 0.9 and 7.4 times the maximum human oral dose of amoxicillin and clavulanate, respectively. 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 is 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 and clavulanate potassium extended-release tablets 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 and clavulanate potassium may be associated with an increased risk of necrotizing enterocolitis in neonates.

8.3 Nursing Mothers

Amoxicillin has been shown to be excreted in human milk; therefore, caution should be exercised when amoxicillin and clavulanate potassium extended-release tablets is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of amoxicillin and clavulanate potassium extended-release tablets have been established for pediatric patients weighing greater than or equal to 40 kg who are able to swallow tablets. Use of amoxicillin and clavulanate potassium extended-release tablets in these pediatric patients is supported by evidence from adequate and well-controlled trials of adults with acute bacterial sinusitis and community-acquired pneumonia with additional data from a pediatric pharmacokinetic study.

A pharmacokinetic study in pediatric patients (7 to 15 years of age and weighing greater than or equal to 40 kg) was conducted [see Clinical Pharmacology (12.3)].

The adverse event profile in 44 pediatric patients who received at least one dose of amoxicillin and clavulanate potassium extended-release tablets was consistent with the established adverse event profile for the product in adults.

8.5 Geriatric Use

Of the total number of subjects in clinical studies of amoxicillin and clavulanate potassium extended-release tablets, 18% were 65 years or older and 7% were 75 years or older. No overall differences in safety and effectiveness were observed between these subjects and younger subjects, and other clinical experience has not reported 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 dose dependent 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, it may be useful to monitor renal function.

8.6 Renal Impairment

The pharmacokinetics of amoxicillin and clavulanate potassium extended-release tablets have not been studied in patients with renal impairment. Amoxicillin and clavulanate potassium extended-release tablets is contraindicated in patients with a creatinine clearance of less than 30 mL/min and in hemodialysis patients [see Contraindications (4.3)].

8.7 Hepatic Impairment

Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals [see Contraindications (4.2), Warnings and Precautions (5.3)].

12.1 Mechanism of Action

Amoxicillin and clavulanate potassium extended-release tablets is an antibacterial drug [see Microbiology (12.4)].

12.3 Pharmacokinetics

Amoxicillin and clavulanate potassium extended-release tablets is an extended-release formulation which provides sustained plasma concentrations of amoxicillin. Amoxicillin systemic exposure achieved with amoxicillin and clavulanate potassium extended-release tablets is similar to that produced by the oral administration of equivalent doses of amoxicillin alone.

Absorption

Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of amoxicillin and clavulanate potassium extended-release tablets.

In a study of healthy adult volunteers, the pharmacokinetics of amoxicillin and clavulanate potassium extended-release tablets were compared when administered in a fasted state, at the start of a standardized meal (612 kcal, 89.3 g carb, 24.9 g fat, and 14 g protein), or 30 minutes after a high‑fat meal. When the systemic exposure to both amoxicillin and clavulanate is taken into consideration, amoxicillin and clavulanate potassium extended-release tablets is optimally administered at the start of a standardized meal. Absorption of amoxicillin is decreased in the fasted state. Amoxicillin and clavulanate potassium extended-release tablets is not recommended to be taken with a high‑fat meal, because clavulanate absorption is decreased. The pharmacokinetics of the components of amoxicillin and clavulanate potassium extended-release tablets following administration of two amoxicillin and clavulanate potassium extended-release tablets at the start of a standardized meal are presented in Table 2.

Table 2: Mean (SD) Pharmacokinetic Parameter for Amoxicillin and Clavulanate Following Oral Administration of Two Amoxicillin and Clavulanate Potassium Extended-Release Tablets (2,000 mg/125 mg) to Healthy Adult Volunteers (n = 55) Fed a Standardized Meal

* Median (range).

The half-life of amoxicillin after the oral administration of amoxicillin and clavulanate potassium extended-release tablets is approximately 1.3 hours, and that of clavulanate is approximately 1.0 hour.

Distribution

Neither component in amoxicillin and clavulanate potassium extended-release tablets is highly protein‑bound; clavulanate has been found to be 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. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like amoxicillin, is well distributed in body tissues.

Excretion

Clearance of amoxicillin is predominantly renal, with approximately 60% to 80% of the dose being excreted unchanged in urine, whereas clearance of clavulanate has both a renal (30% to 50%) and a non‑renal component.

Drug Interactions

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

In a study of adults, the pharmacokinetics of amoxicillin and clavulanate were not affected by administration of an antacid (MAALOX®), either simultaneously with or 2 hours after amoxicillin and clavulanate potassium extended-release tablets.

Pediatrics

In a study of pediatric patients with acute bacterial sinusitis, 7 to 15 years of age, and weighing at least 40 kg, the pharmacokinetics of amoxicillin and clavulanate were assessed following administration of amoxicillin and clavulanate potassium extended-release tablets 2000 mg/125 mg (as two 1000 mg/62.5 mg tablets) every 12 hours with food (Table 3).

Table 3: Mean (SD) Pharmacokinetic Parameters for Amoxicillin and Clavulanate Following Oral Administration of Two Amoxicillin and Clavulanate Potassium Extended-Release Tablets (2,000 mg/125 mg) Every 12 Hours with Food to Pediatric Patients (7 to 15 Years of Age and Weighing ≥ 40kg) With Acute Bacterial Sinusitis

* Median (range).

† n=18.

‡ n=17.

12.4 Microbiology

Mechanism of Action

Amoxicillin binds to penicillin-binding proteins within the bacterial cell wall and inhibits bacterial cell wall synthesis.

Clavulanic acid is a β-lactam, structurally related to penicillin, that may inactivate certain β‑lactamase enzymes.

Resistance

Resistance to penicillins may be mediated by destruction of the β-lactam ring by a β-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 β‑lactamases, and therefore its spectrum of activity does not include bacteria that produce these enzymes.

Antimicrobial Activity

Amoxicillin/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)].

Gram-positive Bacteria:

Staphylococcus aureus (methicillin-susceptible)

Streptococcus pneumoniae

Gram-negative Bacteria:

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella pneumoniae

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 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 clinical trials.

Gram-positive bacteria:

Streptococcus pyogenes

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long‑term studies in animals have not been performed to evaluate carcinogenic potential. The mutagenic potential of amoxicillin and 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. Amoxicillin and clavulanate potassium at oral doses of up to 1,200 mg/kg/day (1.9 times the maximum human dose of amoxicillin and 15 times the maximum human dose of clavulanate 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.

14.1 Acute Bacterial Sinusitis

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 amoxicillin and clavulanate potassium 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 amoxicillin and clavulanate potassium 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 amoxicillin and clavulanate potassium 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 time points 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. Microbiologic eradication rates for key pathogens in these studies are shown in Table 4.

Table 4: Clinical Outcome for ABS

* n/N = patients with pathogen eradicated or presumed eradicated/total number of patients.

† Confidence limits calculated using exact probabilities.

‡ S. pneumoniae strains with penicillin MICs of ≥ 2 mcg/mL are considered resistant to penicillin.

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

14.2 Community-Acquired Pneumonia

Four randomized, controlled, double‑blind clinical studies and one non‑comparative study were conducted in adults with community-acquired pneumonia (CAP). In comparative studies, 904 patients received amoxicillin and clavulanate potassium extended-release tablets at a dose of 2,000 mg/125 mg orally every 12 hours for 7 or 10 days. In the non-comparative study to assess both clinical and bacteriological efficacy, 1,122 patients received amoxicillin and clavulanate potassium extended-release tablets 2,000 mg/125 mg orally every 12 hours for 7 days. In the 4 comparative studies, the combined clinical success rate at test of cure ranged from 86% to 95% in clinically evaluable patients who received amoxicillin and clavulanate potassium extended-release tablets.

Data on the efficacy of amoxicillin and clavulanate potassium extended-release tablets in the treatment of community‑ acquired pneumonia due to S.pneumoniae with reduced susceptibility to penicillin were accrued from the 4 controlled clinical studies and the 1 non‑comparative study. The majority of these cases were accrued from the non‑comparative study. Results are shown in Table 5.

Table 5: Clinical Outcome for CAP due to S.pneumoniae

* n/N = patients with pathogen eradicated or presumed eradicated/total number of patients.

† Confidence limits calculated using exact probabilities.

‡ S. pneumoniae strains with penicillin MICs of ≥ 2 mcg/mL are considered resistant to penicillin.

§ Includes one patient each with S. pneumoniae penicillin MICs of 8 and 16 mcg/mL in the Intent‑To‑Treat group only.